Perindopril 10 / indapamide 2.5 / amlodipine 5 krka
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Perindopril 5/indapamide 1.25/amlodipine 5 KRKA
Perindopril 10/indapamide 2.5/amlodipine 5 KRKA
Perindopril 10/indapamide 2.5/amlodipine 10 KRKA
(Perindopril 5/indapamide 1.25/amlodipine 5 KRKA)
(Perindopril 10/indapamide 2.5/amlodipine 5 KRKA)
(Perindopril 10/indapamide 2.5/amlodipine 10 KRKA)
Composition:
Active substances: perindopril arginine, indapamide, amlodipine;
One tablet contains 5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril), 1.25 mg of indapamide, and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besilate)
or
One tablet contains 10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril), 2.5 mg of indapamide, and 5 mg of amlodipine (equivalent to 6.935 mg of amlodipine besilate),
or
One tablet contains 10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril), 2.5 mg of indapamide, and 10 mg of amlodipine (equivalent to 13.87 mg of amlodipine besilate);
Excipients: calcium chloride hexahydrate; microcrystalline cellulose; microcrystalline cellulose (type 112); pregelatinized starch; sodium starch glycolate (type A); sodium bicarbonate; colloidal hydrated silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
Tablets 5 mg/1.25 mg/5 mg: white or almost white, round, biconvex tablets with engraving «K1» on one side of the tablet;
Tablets 10 mg/2.5 mg/5 mg: white or almost white, capsule-shaped, biconvex tablets with engraving «K3» on one side of the tablet;
Tablets 10 mg/2.5 mg/10 mg: white or almost white, oval, biconvex tablets with engraving «K2» on one side of the tablet.
Pharmacotherapeutic group. Combined angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors in combination with other agents. Perindopril, amlodipine and indapamide.
ATC code C09BX01.
Pharmacological Properties
Pharmacodynamics
Perindopril/indapamide/amlodipine is a combination of three antihypertensive components with complementary mechanisms of blood pressure control in patients with arterial hypertension. Perindopril arginine salt is an angiotensin-converting enzyme (ACE) inhibitor, indapamide is a chlorosulfonamide diuretic, and amlodipine is a dihydropyridine calcium channel blocker. The pharmacological effect of the medicinal product is due to the properties of each component (perindopril/indapamide/amlodipine). In addition, the combination of perindopril/indapamide provides additional synergism of the antihypertensive effect of both components.
Mechanism of Action
Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II, a vasoconstrictive substance; in addition, the enzyme stimulates aldosterone secretion by the adrenal cortex and promotes the breakdown of the vasodilatory substance bradykinin into an inactive heptapeptide.
This leads to:
- decreased aldosterone secretion;
- increased plasma renin activity due to loss of negative feedback by aldosterone;
- with long-term treatment — reduction in total peripheral resistance, predominantly affecting vascular beds in muscles and kidneys, without concomitant salt and water retention or reflex tachycardia.
Perindopril also exerts antihypertensive effects in patients with low or normal plasma renin levels.
Perindopril acts via its active metabolite — perindoprilat. Other metabolites are inactive.
In studies conducted in patients with heart failure, the following effects were observed:
- reduction in filling pressure of the left and right ventricles;
- reduction in total peripheral vascular resistance;
- increase in cardiac output and normalization of cardiac index;
- improvement in regional blood flow in skeletal muscles.
Significant improvement in exercise tolerance tests has been observed.
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide reduces sodium reabsorption in the cortical segment of the nephron. It increases urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, thereby promoting diuresis and antihypertensive effects.
Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker or calcium antagonist) that blocks transmembrane calcium ion influx into smooth muscle cells of the myocardium and blood vessels.
Pharmacodynamic Effect
Perindopril/indapamide demonstrates a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure in the supine or standing position in patients with arterial hypertension, regardless of age.
In clinical trials, concomitant administration of perindopril and indapamide resulted in synergistic antihypertensive effects compared to each component administered alone.
Perindopril is effective in mild, moderate, and severe arterial hypertension. It reduces systolic and diastolic arterial pressure both in the supine and standing positions. The maximum hypotensive effect is achieved 4–6 hours after a single dose and lasts for at least 24 hours. Perindopril provides a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.
In patients with a reversible response, blood pressure stabilization occurs on average within 1 month of treatment and is maintained without tachyphylaxis.
Discontinuation of treatment is not associated with a withdrawal syndrome.
Perindopril has vasodilatory properties, improves large artery elasticity, corrects structural changes in arteries, and reduces left ventricular hypertrophy. Additional therapy with a thiazide diuretic results in further synergistic effects.
The combination of an ACE inhibitor with a thiazide reduces the risk of diuretic-induced hypokalemia compared to monotherapy with either component alone.
Indapamide as monotherapy exerts a 24-hour antihypertensive effect, which occurs at doses where the diuretic effect is weak.
Its antihypertensive action is proportional to improved arterial status and reduction in total and arteriolar peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
For thiazide and thiazide-like diuretics, the antihypertensive effect reaches a plateau with increasing dose, while adverse effects continue to increase. If treatment is ineffective, the dose should not be increased.
Moreover, short-, medium-, and long-term treatment of patients with arterial hypertension with indapamide has been shown to:
- have no effect on lipid metabolism (triglycerides, low- and high-density lipoproteins);
- have no effect on carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.
Amlodipine. The mechanism of amlodipine’s antihypertensive action is due to direct relaxation of vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully elucidated, but amlodipine reduces total ischemic burden through the following actions:
- Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate remains unchanged, reduced cardiac workload decreases myocardial energy consumption and oxygen demand.
- Amlodipine promotes dilation of major coronary arteries and coronary arterioles in both normal and ischemic myocardial regions. This dilation increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina).
In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant reduction in arterial pressure over 24 hours, both in the supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute hypotension.
Amlodipine is not associated with any negative metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes mellitus, and gout.
Pediatric Use
There are no data on the use of the perindopril/indapamide/amlodipine combination in children.
The European Medicines Agency has waived the obligation to submit results of studies with the reference medicinal product containing perindopril arginine / indapamide / amlodipine besylate in all subgroups of the pediatric population with arterial hypertension (for pediatric use, see section "Children").
Pharmacokinetics
Perindopril/indapamide/amlodipine
Concomitant administration of perindopril/indapamide and amlodipine does not alter their pharmacokinetic properties compared to administration of each component separately.
Perindopril
Absorption and Bioavailability. After oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Since food intake reduces the conversion of perindopril to perindoprilat and decreases its bioavailability, perindopril arginine is recommended to be taken orally as a single daily dose in the morning before a meal.
Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding is low (less than 20% of perindoprilat binds to ACE), but depends on concentration.
Metabolism. Perindopril is a prodrug. 27% of the total absorbed perindopril is converted into the active metabolite perindoprilat. Five additional inactive metabolites are also formed. Peak plasma concentration of perindoprilat is reached within 3–4 hours.
Elimination. Perindoprilat is excreted in urine, and the elimination half-life of the unbound fraction is approximately 17 hours, allowing steady-state levels to be achieved within 4 days.
Linearity/Non-linearity. A linear relationship between perindopril dose and plasma concentration has been demonstrated.
Special Patient Populations
Elderly Patients. In elderly individuals, particularly those with cardiac or renal insufficiency, perindoprilat elimination is reduced.
Renal Impairment. Dose adjustment is recommended according to the degree of renal impairment (creatinine clearance).
Dialysis. Perindoprilat is removed from the circulation by dialysis, with a clearance rate of 70 mL/min.
Cirrhosis. In hepatic cirrhosis, perindopril kinetics are altered: hepatic clearance of the parent compound is halved, but the amount of perindoprilat formed remains unchanged. Therefore, dose adjustment is not required in this condition (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").
Indapamide
Absorption. Indapamide is rapidly and almost completely absorbed in the gastrointestinal tract. Peak serum concentration of indapamide is reached approximately 1 hour after administration.
Distribution. Plasma protein binding of indapamide is 79%.
Biological Transformation and Elimination. The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Regular administration does not lead to indapamide accumulation.
Approximately 70% of indapamide is excreted primarily via the kidneys, and 22% is excreted in feces as inactive metabolites.
Special Patient Populations. Pharmacokinetic parameters of the drug are not altered in patients with renal impairment.
Amlodipine
Absorption and Bioavailability. After oral administration in therapeutic doses, amlodipine is well absorbed and reaches peak blood concentration 6–12 hours after intake. Absolute bioavailability ranges from 64% to 80%.
Distribution. The volume of distribution is approximately 21 L/kg. Food intake does not affect amlodipine bioavailability. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Metabolism. Amlodipine is metabolized in the liver into inactive metabolites. 60% of the administered dose is excreted in urine, and 10% is excreted unchanged.
Elimination. The elimination half-life from plasma is approximately 35–50 hours, allowing once-daily dosing.
Special Patient Populations
Elderly Patients. The time to reach peak plasma concentration of amlodipine is similar in elderly and younger patients. In elderly individuals, there is a tendency toward reduced amlodipine clearance, leading to increased AUC (area under the concentration-time curve) and prolonged half-life. Dose adjustment is not required in elderly patients, but dose escalation should be performed cautiously.
Patients with Hepatic Impairment. Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, resulting in prolonged half-life and increased AUC by approximately 40–60%.
Clinical characteristics.
Indications.
Indicated for the treatment of arterial hypertension in patients who require therapy with perindopril, indapamide and amlodipine at doses available in the fixed combination.
Contraindications
- Hemodialysis.
- Uncompensated decompensated heart failure.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Moderate renal impairment (creatinine clearance < 60 mL/min) (related to the medicinal products Perindopril 10/Indapamide 2.5/Amlodipine 5 KRKA and Perindopril 10/Indapamide 2.5/Amlodipine 10 KRKA).
- Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, any other angiotensin-converting enzyme (ACE) inhibitor, or to any excipient.
- History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy (see section "Special precautions for use").
- Hereditary or idiopathic angioedema (see section "Special precautions for use").
- Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding").
- Hepatic encephalopathy.
- Severe hepatic impairment.
- Hypokalemia.
- Severe arterial hypotension.
- Shock, including cardiogenic shock.
- Left ventricular outflow tract obstruction (e.g., severe aortic stenosis).
- Hemodynamically unstable heart failure following acute myocardial infarction.
- Concomitant use of medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
- Concomitant use of sacubitril/valsartan therapy. The medicinal product must not be used within 36 hours of the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
- Extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
- Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions for use").
Interaction with other medicinal products and other forms of interaction
Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy affecting the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").
Medicinal products increasing the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy may be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").
Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (see section "Special precautions for use").
Medicinal products causing hyperkalemia
Although serum potassium levels usually remain within normal limits, certain medicinal products or therapeutic classes may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and cotrimoxazole [trimethoprim/sulfamethoxazole] (since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride). Concomitant use of these medicinal products increases the risk of hyperkalemia and is therefore not recommended. If concomitant use is indicated, they should be used with caution and serum potassium levels should be closely monitored.
Concomitant use contraindicated (see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, cardiovascular events, and mortality is increased.
Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consider using a different type of dialysis membrane or another class of antihypertensive agents. Concomitant use is not recommended
Perindopril/indapamide. Reversible increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium preparations is not recommended. However, if combination therapy is essential, serum lithium concentrations should be closely monitored (see section "Special precautions for use").
Perindopril. Aliskiren: In all other patients, as in patients with diabetes or impaired renal function, the risk of hyperkalemia, worsening renal function, cardiovascular events, and mortality is increased (see section "Special precautions for use").
Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) should only be considered in selected cases with careful monitoring of renal function, potassium levels, and blood pressure (see section "Special precautions for use").
Estramustine: increased risk of adverse reactions such as angioedema.
Potassium-sparing agents (e.g., triamterene, amiloride, etc.), potassium salts: risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use is essential, they should be used with caution and serum potassium levels should be frequently monitored. For spironolactone use in heart failure, see below «Concomitant use requires special attention» below.
Amlodipine. Dantrolene (infusion): In animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalemia, it is recommended to avoid concomitant administration of calcium channel blockers such as amlodipine in patients with established or suspected malignant hyperthermia.
Grapefruit or grapefruit juice: In some patients, increased bioavailability of amlodipine may occur, leading to enhanced hypotensive effect.
Concomitant use requires special attention
Perindopril/indapamide. Baclofen potentiates the antihypertensive effect. Blood pressure should be monitored and the dose of antihypertensive agent adjusted if necessary.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including high-dose acetylsalicylic acid. When ACE inhibitors are used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including possible development of acute renal failure, and elevated serum potassium levels, particularly in patients with pre-existing impaired renal function. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured. Additionally, monitoring of renal function after initiation of concomitant therapy and during ongoing treatment should be considered.
Perindopril. Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the blood glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.
In patients receiving diuretics, particularly those with fluid and electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, and salt intake prior to starting perindopril therapy, which should begin at low doses with gradual titration. In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, diuretic use should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure on background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.
Indapamide. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may cause torsades de pointes, including but not limited to:
- Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
- Class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol);
- Certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide);
- Other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine).
Serum potassium levels should be maintained, corrected if necessary, and QT interval monitored.
Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives increase the risk of hypokalemia (additive effect). Serum potassium levels should be monitored and corrected as needed, especially when used concomitantly with cardiac glycosides. Non-stimulant laxatives are recommended.
Cardiac glycosides. Hypokalemia and/or hypomagnesemia predispose to digitalis toxicity. Monitoring of plasma potassium and magnesium levels and ECG is recommended, with treatment adjustment as needed.
Allopurinol. Concomitant use with indapamide increases the risk of hypersensitivity reactions to allopurinol.
Amlodipine. Concomitant use of CYP3A4 inducers may alter plasma concentrations of amlodipine. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant use, especially with potent CYP3A4 inducers (e.g., rifampicin, St. John's wort (Hypericum perforatum)).
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may cause significant increases in amlodipine concentrations, increasing the risk of arterial hypotension. These changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be required.
Increased risk of hypotension exists in patients taking clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.
Concomitant use to be considered
Perindopril/indapamide/amlodipine. Tricyclic antidepressants, neuroleptics increase antihypertensive effects and risk of orthostatic hypotension (additive effect).
Concomitant use of other antihypertensive agents may cause additional blood pressure reduction.
Corticosteroids, tetracosactide: reduced antihypertensive effect (due to water and salt retention by corticosteroids).
Perindopril. Antihypertensives and vasodilators: concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.
Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids, or procainamide: concomitant use with ACE inhibitors increases the risk of leukopenia.
ACE inhibitors may enhance the hypotensive effect of certain anesthetic agents.
Diuretics (thiazide and loop diuretics): prior treatment with high-dose diuretics may cause dehydration, increasing the risk of hypotension at the start of perindopril therapy.
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Rarely, concomitant use of ACE inhibitors, particularly perindopril, with injectable gold compounds (sodium aurothiomalate) has been associated with reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).
Indapamide. Metformin may cause lactic acidosis due to possible development of functional renal impairment associated with diuretic use, especially loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men or 12 mg/L (110 µmol/L) in women.
Dehydration due to diuretic use increases the risk of acute renal failure, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administration.
Calcium salts: risk of hypercalcemia due to reduced urinary calcium excretion.
Cyclosporine: risk of increased creatinine levels without affecting circulating cyclosporine levels, even in the absence of water and sodium deficiency.
Amlodipine: Clinical studies have demonstrated that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Tacrolimus: risk of increased plasma tacrolimus concentration with concomitant use of amlodipine. To avoid tacrolimus toxicity when used concomitantly with amlodipine, plasma levels should be monitored and dosage adjusted if necessary.
mTOR inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use with mTOR inhibitors may potentiate their effects.
Cyclosporine: interaction studies between cyclosporine and amlodipine have been conducted only in kidney transplant patients, where increased fluctuations in cyclosporine trough concentrations (on average 0 to 40%) were observed. In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and dosage reduced if necessary.
Concomitant use of amlodipine 10 mg with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to monotherapy. Patients taking amlodipine should have their simvastatin dose limited to 20 mg daily.
Special precautions for use.
All the special precautions for use described below for the individual active substances of the medicinal product also apply to the fixed combination of perindopril/indapamide/amlodipine.
Lithium
Concomitant use of lithium and the combination of perindopril/indapamide is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Data indicate that concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by using ACE inhibitors together with angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use of two RAAS blockers is considered absolutely necessary, it may only be carried out under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes
Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Cases of neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, during immunosuppressive therapy, with allopurinol, procainamide, or in combination with these factors, especially if renal function is impaired. Some of these patients have developed severe infections, sometimes resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended. In addition, patients should be informed about the need to report any signs of infection (e.g., sore throat, fever) to their physician (see section "Adverse reactions").
Renovascular hypertension
In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). The use of diuretics increases this risk. Impaired renal function may manifest only as slight changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.
Hypersensitivity/angioedema
Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported during treatment with ACE inhibitors, including perindopril. This phenomenon may occur at any time during treatment.
In such cases, perindopril must be discontinued immediately, and appropriate monitoring of the patient should be maintained until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, and antihistamine therapy may be helpful in relieving symptoms.
Angioedema involving swelling of the larynx may be fatal. If swelling spreads to the tongue, glottis, or larynx, creating a risk of airway obstruction, emergency treatment is required immediately. This may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or securing airway patency.
It has been reported that ACE inhibitors more frequently cause angioedema in individuals of non-Caucasian race compared to patients of other races.
Patients with a history of angioedema, even if not related to ACE inhibitor use, have an increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, no prior facial angioedema was observed, and C1-esterase levels were within normal limits. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain occurring in patients taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications").
Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.
Anaphylactoid reactions during desensitization therapy
Isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with insect venom-containing preparations (bees, wasps). ACE inhibitors should be used with caution in patients undergoing desensitization and avoided during immunotherapy with animal-derived venomous substances.
However, such reactions can be avoided in patients requiring both ACE inhibitors and desensitization therapy by temporarily discontinuing ACE inhibitors at least 24 hours before desensitization.
Anaphylactoid reactions during LDL apheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.
Patients on hemodialysis
Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux polyacrylonitrile membranes (e.g., AN 69®). Such patients should use a different type of dialysis membrane or be prescribed another class of antihypertensive agents.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via suppression of the RAAS. Therefore, this medicinal product is not recommended for such patients.
Pregnancy
ACE inhibitors should not be prescribed during pregnancy. If continued treatment with ACE inhibitors is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with proven safety during pregnancy. If pregnancy is diagnosed, treatment with an ACE inhibitor should be discontinued immediately and, if necessary, replaced with another alternative medicinal product approved for use in pregnant women (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Hepatic encephalopathy
In patients with impaired liver function, the use of thiazide and thiazide-like diuretics, especially in the presence of electrolyte imbalance, may lead to hepatic encephalopathy, which may progress to coma. In such cases, diuretic therapy should be discontinued immediately.
Photosensitization
Cases of photosensitization reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section "Adverse reactions"). If such reactions occur, diuretic therapy is recommended to be discontinued. If diuretic therapy must be resumed, exposed areas should be protected from sunlight or artificial ultraviolet sources.
Renal function
The medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Therapy with the medicinal product containing the perindopril/indapamide combination at doses of 10 mg/2.5 mg (i.e., perindopril/indapamide/amlodipine 10 mg/2.5 mg/5 mg and 10 mg/2.5 mg/10 mg) is contraindicated in patients with moderate renal impairment (creatinine clearance < 60 mL/min).
If laboratory blood tests in some patients with arterial hypertension but no signs of kidney damage show signs of functional renal impairment, the use of the medicinal product should be discontinued; treatment may be resumed at a lower dose or with one of its components alone.
In such patients, potassium and creatinine levels should be monitored frequently: 2 weeks after initiation of treatment and then every 2 months during therapeutic stabilization. Cases of renal impairment have mainly been observed in patients with severe heart failure or impaired renal function, particularly renal artery stenosis.
This combination is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
The risk of arterial hypotension and/or renal impairment (in cases of heart failure, fluid and electrolyte deficiency, etc.) is associated with significant stimulation of the RAAS. This phenomenon has mainly been observed with perindopril use in patients with marked fluid and electrolyte deficiency (e.g., strict salt-free diet or prolonged diuretic therapy), low baseline blood pressure, renal artery stenosis, congestive heart failure, or patients with cirrhosis of the liver accompanied by edema and ascites. Blockade of this system by an ACE inhibitor, particularly during the first dose and the first 2 weeks of treatment, may cause a sharp decrease in blood pressure and/or an increase in plasma creatinine levels, indicating the development of functional renal impairment. This condition may occasionally have an acute onset and very rarely may occur at any stage of therapy. In such cases, treatment should be initiated with a lower dose, gradually increasing it. In patients with ischemic heart disease or cerebrovascular disease, a significant decrease in blood pressure may lead to myocardial infarction or stroke.
Thiazide and thiazide-like diuretics show the greatest efficacy when there is no renal impairment or when impairment is mild (serum creatinine approximately below 25 mg/L, i.e., 220 μmol/L, in adults). In elderly patients, plasma creatinine levels should correspond to age, body weight, and sex.
Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment leads to decreased glomerular filtration. This may result in increased blood urea and creatinine levels. Such transient functional renal impairment has no adverse consequences in patients with normal renal function but may exacerbate pre-existing renal impairment.
Amlodipine may be used in patients with renal impairment at usual doses. Changes in amlodipine plasma concentration do not correlate with the degree of renal impairment.
Studies on the use of the fixed combination perindopril/indapamide/amlodipine in patients with renal dysfunction have not been conducted. For patients with impaired renal function, the dosage of the fixed combination perindopril/indapamide/amlodipine should correspond to individually adjusted doses of the monocomponents.
Hypotension, fluid and electrolyte deficiency
There is a risk of sudden decrease in blood pressure in patients with sodium deficiency (e.g., patients with renal artery stenosis). Therefore, systematic monitoring for clinical signs of fluid and electrolyte deficiency, which may occur during intercurrent vomiting or diarrhea, is required. In such patients, serum electrolyte levels should be monitored regularly.
In case of pronounced hypotension, intravenous administration of isotonic sodium chloride solution may be necessary.
Transient hypotension is not a contraindication for continued use of the medicinal product. After restoration of circulating blood volume (CBV) and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the components of the medicinal product.
Initially, decreased sodium concentration may be asymptomatic, so regular laboratory monitoring of this parameter is very important. More frequent monitoring is necessary for elderly patients and patients with liver cirrhosis (see sections "Adverse reactions" and "Overdose"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia may lead to dehydration and orthostatic arterial hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are low.
Potassium levels
Treatment with the combination of indapamide, perindopril, and amlodipine does not exclude the possibility of hypokalemia, particularly in patients with diabetes mellitus or renal impairment. As with any antihypertensive agent combined with a diuretic, serum potassium levels should be monitored regularly.
In some patients receiving ACE inhibitors, including perindopril, increased plasma potassium concentration has been observed. ACE inhibitors may cause hyperkalaemia because they suppress aldosterone release. In patients with normal renal function, this effect is usually insignificant. Risk factors for hyperkalaemia include: renal impairment, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes; use of other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole [trimethoprim/sulfamethoxazole]), and especially aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may also lead to significant increases in serum potassium, especially in patients with impaired renal function. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and should have serum potassium levels and renal function monitored. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, they should be used with caution, with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").
Decreased potassium levels and hypokalaemia are the main risks associated with thiazide and thiazide-like diuretics. Hypokalaemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly associated with severe hypokalaemia. Prevention of decreased potassium levels (< 3.4 mmol/L) is necessary in high-risk patients (elderly patients, poorly nourished patients regardless of polypharmacy, patients with liver cirrhosis accompanied by edema and ascites, patients with ischemic heart disease, and patients with heart failure). In case of hypokalaemia, cardiotoxicity of cardiac glycosides and the risk of arrhythmias increase. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalaemia, as well as bradycardia, may promote the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia torsades de pointes, which may be fatal. In all these cases, more frequent monitoring of serum potassium levels is necessary. The first determination of this parameter should be performed within the first week of treatment. If serum potassium levels are decreased, correction is required. Hypokalaemia associated with low serum magnesium concentration may be resistant to treatment unless serum magnesium levels are corrected.
Magnesium levels
Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesaemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Calcium levels
Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight transient increase in plasma calcium levels. Markedly elevated calcium levels may be due to previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued until parathyroid function is evaluated (see section "Adverse reactions").
Renovascular hypertension
The primary treatment for renovascular hypertension is revascularization. However, for patients with renovascular hypertension awaiting surgery or when surgery is not possible, ACE inhibitors may be beneficial.
If perindopril/indapamide/amlodipine is prescribed to patients with diagnosed or suspected renal artery stenosis, therapy should be initiated in a hospital setting with low doses, monitoring renal function and potassium levels. Functional renal impairment, reversible after discontinuation of treatment, has been observed in some patients.
Cough
Dry cough has been reported during treatment with ACE inhibitors. This cough is persistent and resolves after discontinuation of the drug. When this symptom occurs, iatrogenic etiology of cough should be considered. If ACE inhibitor therapy is still preferred, continuation of treatment may be considered.
Atherosclerosis
The risk of hypotension exists in all patients, but perindopril should be prescribed with particular caution to patients with ischemic heart disease or cerebral circulation insufficiency. In such cases, treatment should be initiated with a low dose.
Hypertensive crisis
The safety and efficacy of amlodipine use in patients with hypertensive crisis have not been studied.
Heart failure / severe heart failure
Amlodipine should be prescribed with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III, IV), the incidence of pulmonary oedema with amlodipine use was higher compared to placebo. Calcium channel blockers, including amlodipine, should be prescribed with caution in patients with congestive heart failure, as they increase the risk of cardiovascular complications and fatal outcomes.
Treatment in patients with severe heart failure (class IV) should be initiated under medical supervision with a reduced initial dose. β-blocker therapy for patients with arterial hypertension and coronary insufficiency should not be discontinued: the ACE inhibitor is added to the β-blocker.
Aortic or mitral valve stenosis / hypertrophic cardiomyopathy
ACE inhibitors should be prescribed with caution to patients with left ventricular outflow tract obstruction.
Patients with diabetes mellitus
In patients with insulin-dependent diabetes mellitus (due to the tendency for spontaneous increase in potassium levels), treatment should be initiated under medical supervision with a reduced initial dose.
In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored, especially during the first month of ACE inhibitor therapy.
In patients with diabetes mellitus, blood glucose levels should be monitored carefully, particularly when potassium levels are low.
Racial characteristics
Perindopril, like other ACE inhibitors, reduces blood pressure less effectively in hypertensive patients of non-Caucasian race compared to patients of other races, possibly due to lower plasma renin levels in these patients.
Surgery / anaesthesia
ACE inhibitors may cause hypotension during anaesthesia, especially when anaesthetics that lower blood pressure are used. Therefore, it is recommended to discontinue long-acting ACE inhibitors, such as perindopril, one day before surgery if possible.
Hepatic impairment
Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapid hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. If a patient develops jaundice or a significant increase in liver enzymes while taking ACE inhibitors, ACE inhibitor use should be discontinued and appropriate medical evaluation performed (see section "Adverse reactions").
In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are higher; dosage recommendations are lacking. Amlodipine therapy should be initiated with the lowest doses, with caution at the beginning of therapy and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.
Studies on the use of the fixed combination perindopril/indapamide/amlodipine in patients with hepatic dysfunction have not been conducted. Given the known effects of individual components of this combination, the medicinal product is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment.
Uric acid
In patients with elevated uric acid levels, an increase in the number of gout attacks may occur.
Elderly patients
Renal function and potassium levels should be checked before initiating treatment. To reduce the risk of sudden hypotension, especially in the presence of fluid or electrolyte deficiency, the initial dose should be adjusted according to the blood pressure response to treatment. Dose escalation in elderly patients should be performed cautiously (see sections "Method of administration and dosage" and "Pharmacokinetics").
Choroidal effusion, acute myopia (nearsightedness), and secondary angle-closure glaucoma
Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical, surgical, or other interventions may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Sportsmen
Sportsmen should be aware that this medicinal product contains an active substance that may result in a positive doping test.
Sodium levels
The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., nearly sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
The medicinal product is contraindicated during pregnancy (see section "Contraindications").
Perindopril. The use of ACE inhibitors is contraindicated during pregnancy. Epidemiological data on the risk of teratogenic effects from ACE inhibitor use during the first trimester of pregnancy are insufficient, so a slight increase in risk cannot be excluded. The medicinal product is contraindicated in pregnant women or women planning pregnancy. If continued treatment with ACE inhibitors is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with proven safety during pregnancy. If pregnancy is confirmed during ACE inhibitor therapy, its use must be discontinued immediately and replaced with another alternative medicinal product approved for use in pregnant women.
It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia).
If a woman has taken ACE inhibitors from the second trimester of pregnancy, ultrasound evaluation of fetal renal and skull bone function is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Indapamide. Data on indapamide use during pregnancy are limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may lead to decreased circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and fetal growth retardation. Additionally, hypoglycemia and thrombocytopenia have been observed rarely in newborns. Animal studies did not reveal direct or indirect toxic effects on reproductive function.
Amlodipine. The safety of amlodipine use in pregnant women has not been established. Animal studies revealed toxic effects on reproductive function at high doses.
Period of breastfeeding
The medicinal product is not recommended during breastfeeding.
Perindopril. Perindopril use during breastfeeding is not recommended due to lack of data. In particular, alternative treatment with a confirmed safety profile during breastfeeding should be prescribed when breastfeeding a newborn or premature infant.
Indapamide. Available information on indapamide/metabolite penetration into breast milk is insufficient. Hypersensitivity to sulfonamide derivatives and hypokalaemia may develop. Risk to newborns/infants cannot be excluded.
Indapamide belongs to thiazide-like diuretics, whose use has been associated with reduced and suppressed lactation.
Amlodipine. Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated as an interquartile range of 3–7% with a maximum of 15%. The effect of amlodipine on infants is unknown.
Fertility
Perindopril and indapamide. Reproductive toxicity studies did not reveal effects on fertility in male and female animals. Effects on human fertility are not expected.
Amlodipine. Reversible biochemical changes in spermatozoa heads have been reported in some patients treated with calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. It is known that animal studies revealed a negative effect of the drug on male fertility.
Ability to affect reaction speed when driving vehicles or operating machinery
Studies on the effect of the medicinal product on the ability to drive vehicles or operate other automated systems have not been conducted.
The active substances perindopril and indapamide do not affect the ability to drive vehicles or operate machinery. However, individual reactions related to decreased blood pressure may occur in some patients.
Amlodipine may have a slight or moderate effect on the ability to drive vehicles and operate machinery. Impaired reaction may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea. As a result, the ability to drive vehicles and operate other automated systems may be impaired. Caution is recommended, especially at the beginning of treatment.
Method of Administration and Dosage
Administer orally.
Take 1 tablet of the medicinal product once daily, preferably in the morning before food.
The fixed-dose combination is not intended for initial therapy.
If necessary, the dose of the fixed combination may be adjusted or individual dose titration of each component may be recommended.
Special Patient Groups
Patients with Renal Impairment (see sections "Contraindications" and "Special Warnings and Precautions for Use")
The medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min). The use of perindopril/indapamide/amlodipine in doses of 10 mg/2.5 mg/5 mg and 10 mg/2.5 mg/10 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min). Treatment should be initiated with appropriate dosing of individual components.
Routine medical monitoring should include frequent checks of creatinine and potassium levels.
Concomitant use of perindopril with aliskiren is contraindicated in patients with renal impairment (eGFR [estimated glomerular filtration rate] < 60 mL/min/1.73 m²) (see section "Contraindications").
Patients with Hepatic Impairment (see sections "Contraindications", "Special Warnings and Precautions for Use" and "Pharmacokinetics")
The medicinal product is contraindicated in patients with severe hepatic impairment. The medicinal product should be used with caution in patients with mild to moderate hepatic impairment due to the lack of dosage recommendations for amlodipine.
Elderly Patients (see section "Special Warnings and Precautions for Use")
Note that the elimination of perindoprilat is reduced in elderly patients (see section "Pharmacokinetics"). The medicinal product may be prescribed to elderly patients taking into account renal function (see section "Contraindications").
Children
There are no data on the safety and efficacy of the medicinal product in children; therefore, it is not recommended for use in this age group.
Overdose
There are no data on overdose of perindopril/indapamide/amlodipine in humans.
Perindopril/Indapamide
Symptoms. The most common reaction in case of perindopril/indapamide overdose is arterial hypotension, sometimes accompanied by nausea, vomiting, seizures, dizziness, somnolence, confusion, oliguria, which may progress to anuria (due to hypovolemia). Electrolyte and fluid balance disturbances may occur (decreased serum sodium and potassium levels).
Treatment. Emergency measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal. Subsequently, correction of fluid and electrolyte balance should be performed in a hospital setting until corresponding parameters normalize.
In case of significant hypotension, the patient should be placed in a supine position with low head elevation. If necessary, administer isotonic sodium chloride solution intravenously or use any other method to restore blood volume.
Perindoprilat, the active metabolite of perindopril, can be removed from the body by hemodialysis (see subsection "Pharmacokinetics").
Amlodipine
Data on intentional amlodipine overdose in humans are limited.
Symptoms. Based on available data, ingestion of very high doses is expected to cause excessive peripheral vasodilation and reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may not manifest immediately (after 24–48 hours following administration) and may require mechanical ventilation. Early resuscitation measures (particularly fluid overload) aimed at supporting perfusion and cardiac output may be triggering factors.
Treatment. Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, and monitoring of circulating blood volume and urine output.
Administration of a vasoconstrictor may be beneficial to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract the effects of calcium channel blockade.
In some cases, gastric lavage may be appropriate. Studies in healthy volunteers have shown that administration of activated charcoal 2 hours after intake of 10 mg amlodipine reduces the rate of amlodipine absorption. Because amlodipine is highly protein-bound, hemodialysis is considered ineffective.
Adverse Reactions
Summary of safety profile
The most commonly observed adverse reactions during treatment with perindopril, indapamide, and amlodipine administered separately are: hypokalemia, dizziness, headache, paresthesia, somnolence, dysgeusia, visual disturbances, diplopia, tinnitus, vertigo, palpitations, flushing, arterial hypotension (and associated symptoms), dyspnea, gastrointestinal disorders (abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, change in defecation pattern), pruritus, skin rashes, maculopapular rash, muscle cramps, ankle swelling, asthenia, edema, and fatigue.
List of adverse reactions
The adverse effects that may occur during treatment with the medicinal product are classified by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).
| Body system |
Adverse reactions |
Frequency |
||
| Perindopril |
Indapamide |
Amlodipine |
||
| Infections and infestations |
Rhinitis |
Very rare |
- |
Uncommon |
| Blood and lymphatic system |
Eosinophilia |
Unknown1 |
- |
- |
| Agranulocytosis2 |
Very rare |
Very rare |
- |
|
| Aplastic anemia |
- |
Very rare |
- |
|
| Pancytopenia |
Very rare |
- |
||
| Leukopenia2 |
Very rare |
Very rare |
Very rare |
|
| Neutropenia2 |
Very rare |
- |
- |
|
| Hemolytic anemia |
Very rare |
Very rare |
- |
|
| Thrombocytopenia2 |
Very rare |
Very rare |
Very rare |
|
| Immune system |
Hypersensitivity reactions |
- |
Uncommon |
Very rare |
| Endocrine system |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
- |
- |
| Metabolism and nutrition |
Hypoglycemia3 |
Uncommon1 |
- |
- |
| Hyperkalemia, reversible after discontinuation2 |
Uncommon1 |
- |
- |
|
| Hypnatremia2 |
Uncommon1 |
Uncommon |
- |
|
| Hyperglycemia |
- |
- |
Very rare |
|
| Hypercalcemia |
- |
Very rare |
- |
|
| Hypokalemia2 |
- |
Common |
- |
|
| Hypochloremia |
- |
Uncommon |
- |
|
| Hypomagnesemia |
- |
Uncommon |
- |
|
| Psychiatric |
Insomnia |
- |
- |
Uncommon |
| Mood disorders |
Uncommon |
- |
Uncommon |
|
| Depression |
Uncommon |
- |
Uncommon |
|
| Sleep disorders |
Uncommon |
- |
- |
|
| Confusion |
Very rare |
- |
Uncommon |
|
| Nervous system |
Dizziness |
Common |
- |
Common |
| Headache |
Common |
Uncommon |
Common |
|
| Paraesthesia |
Common |
Uncommon |
Uncommon |
|
| Somnolence |
Uncommon1 |
- |
Common |
|
| Hypesthesia |
- |
- |
Uncommon |
|
| Disturbance of taste |
Common |
- |
Uncommon |
|
| Tremor |
- |
- |
Uncommon |
|
| Syncope |
Uncommon1 |
Unknown |
Uncommon |
|
| Hypertension |
- |
- |
Very rare |
|
| Peripheral neuropathy |
- |
- |
Very rare |
|
| Extrapyramidal disorders (extrapyramidal syndrome) |
- |
- |
Unknown |
|
| Stroke, possibly secondary to excessive hypotension in patients at high risk2 |
Very rare |
- |
- |
|
| Development of hepatic encephalopathy on the background of peripheral neuropathy caused by hepatic insufficiency4 |
- |
Unknown |
- |
|
| Eye |
Visual disturbance |
Common |
Unknown |
Common |
| Acute angle-closure glaucoma |
- |
Unknown |
- |
|
| Choroidal effusion |
- |
Unknown |
- |
|
| Diplopia |
- |
- |
Common |
|
| Myopia2 |
- |
Unknown |
- |
|
| Blurred vision |
- |
Unknown |
- |
|
| Ear and labyrinth disorders |
Tinnitus |
Common |
- |
Uncommon |
| Vertigo |
Common |
Uncommon |
- |
|
| Cardiac |
Pounding heartbeat |
Uncommon1 |
- |
Common |
| Tachycardia |
Uncommon1 |
- |
- |
|
| Angina pectoris2 |
Very rare |
- |
- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Very rare |
Very rare |
Uncommon |
|
| Myocardial infarction, possibly after excessive hypotension in patients at high risk2 |
Very rare |
- |
Very rare |
|
| Ventricular tachycardia torsade de pointes (potentially fatal)3 |
- |
Unknown |
- |
|
| Vascular |
Arterial hypotension (and symptoms associated with hypotension)2 |
Common |
Very rare |
|
| Vasculitis |
Uncommon1 |
- |
Very rare |
|
| Flushing |
Uncommon |
- |
Common |
|
| Raynaud's phenomenon |
Unknown |
- |
Very rare |
|
| Respiratory, thoracic and mediastinal |
Cough2 |
Common |
- |
Uncommon |
| Dyspnea |
Common |
- |
Common |
|
| Bronchospasm |
Uncommon |
- |
- |
|
| Eosinophilic pneumonia |
Very rare |
- |
- |
|
| Gastrointestinal |
Abdominal pain |
Common |
- |
Common |
| Constipation |
Common |
Uncommon |
Common |
|
| Diarrhea |
Common |
- |
Common |
|
| Dyspepsia |
Common |
- |
Common |
|
| Nausea |
Common |
Uncommon |
Common |
|
| Vomiting |
Common |
Uncommon |
Uncommon |
|
| Dry mouth |
Uncommon |
Uncommon |
Uncommon |
|
| Change in defecation rhythm |
- |
- |
Common |
|
| Gingival hyperplasia |
- |
- |
Very rare |
|
| Pancreatitis |
Very rare |
Very rare |
Very rare |
|
| Gastritis |
Very rare |
|||
| Hepatobiliary system |
Hepatitis2 |
Very rare |
Unknown |
Very rare |
| Jaundice |
- |
- |
Very rare |
|
| Liver function disorders |
- |
Very rare |
- |
|
| Skin and subcutaneous tissue |
Itching |
Common |
- |
Uncommon |
| Rash |
Common |
- |
Uncommon |
|
| Maculopapular rash |
- |
Common |
- |
|
| Urticaria2 |
Uncommon |
Very rare |
Uncommon |
|
| Angioneurotic edema2 |
Uncommon |
Very rare |
Very rare |
|
| Alopecia |
- |
- |
Uncommon |
|
| Purpura |
- |
Uncommon |
Uncommon |
|
| Skin color changes |
- |
- |
Uncommon |
|
| Hyperhidrosis |
Uncommon |
- |
Uncommon |
|
| Exanthema |
- |
- |
Uncommon |
|
| Photosensitivity reaction |
Uncommon1 |
Unknown2 |
Very rare |
|
| Pemphigoid |
Uncommon1 |
- |
- |
|
| Worsening of psoriasis symptoms |
Uncommon1 |
- |
- |
|
| Multiform erythema |
Very rare |
- |
Very rare |
|
| Toxic epidermal necrolysis |
- |
Very rare |
Unknown |
|
| Quincke's edema |
- |
- |
Very rare |
|
| Musculoskeletal and connective tissue |
Muscle cramps |
Common |
Unknown |
Common |
| Ankle swelling |
- |
- |
Common |
|
| Arthralgia |
Uncommon1 |
- |
Uncommon |
|
| Muscle weakness |
- |
Unknown |
- |
|
| Myalgia |
Uncommon1 |
- |
Uncommon |
|
| Rhabdomyolysis |
- |
Unknown |
- |
|
| Back pain |
- |
- |
Uncommon |
|
| Exacerbation of pre-existing systemic lupus erythematosus |
- |
Unknown |
- |
|
| Renal and urinary |
Urinary disorders |
- |
- |
Uncommon |
| Nocturia |
- |
- |
Uncommon |
|
| Frequency of urination |
- |
- |
Uncommon |
|
| Acute renal failure |
Uncommon |
Very rare |
- |
|
| Renal failure |
Uncommon |
- |
- |
|
| Anuria/oliguria |
Uncommon |
- |
- |
|
| Reproductive system and breast |
Erectile dysfunction |
Uncommon |
Uncommon |
Uncommon |
| Gynecomastia |
- |
- |
Uncommon |
|
| General disorders |
Asthenia |
Common |
- |
Common |
| Fatigue |
- |
Uncommon |
Common |
|
| Edema |
- |
- |
Very common |
|
| Chest pain |
Uncommon1 |
- |
Uncommon |
|
| Pain |
- |
- |
Uncommon |
|
| Malaise |
Uncommon1 |
- |
Uncommon |
|
| Peripheral edema |
Uncommon1 |
- |
- |
|
| Pyrexia |
Uncommon1 |
- |
- |
|
| Investigations |
Weight gain |
- |
- |
Uncommon |
| Weight loss |
- |
- |
Uncommon |
|
| Increased plasma urea levels |
Uncommon1 |
- |
- |
|
| Elevated plasma creatinine levels |
Uncommon1 |
- |
- |
|
| Elevated plasma bilirubin levels |
Uncommon |
- |
- |
|
| Elevated liver enzyme levels |
Uncommon |
Unknown |
Very rare |
|
| Decreased hemoglobin levels and red blood cell count2 |
Very rare |
- |
- |
|
| QT interval prolongation on ECG3 |
- |
Unknown |
- |
|
| Elevated plasma glucose levels |
- |
Unknown |
- |
|
| Elevated plasma uric acid levels |
- |
Unknown |
- |
|
| Injury, poisoning and procedural complications |
Fall |
Uncommon1 |
- |
- |
1 The frequency of adverse reactions identified from spontaneous reports is estimated based on clinical trial data.
2 See section "Special precautions for use".
3 See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
4 See sections "Contraindications" and "Special precautions for use".
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store in the original packaging to protect from moisture and light.
This medicinal product does not require special storage temperature conditions.
Keep out of the reach and sight of children.
Packaging. 10 tablets per blister; 3 or 9 blisters per cardboard box.
Prescription status. Prescription-only medicine.
Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.
Address of the manufacturer and location of its operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.