Lopridam
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPRIDAM (LOPRIDAM)
Composition:
Active substances: perindopril, indapamide, amlodipine;
One tablet contains 4 mg of perindopril erbumine, equivalent to 3.338 mg of perindopril, 1.25 mg of indapamide, and 5 mg of amlodipine in the form of amlodipine besylate 6.934 mg;
One tablet contains 8 mg of perindopril erbumine, equivalent to 6.676 mg of perindopril, 2.5 mg of indapamide, and 5 mg of amlodipine in the form of amlodipine besylate 6.934 mg;
One tablet contains 8 mg of perindopril erbumine, equivalent to 6.676 mg of perindopril, 2.5 mg of indapamide, and 10 mg of amlodipine in the form of amlodipine besylate 13.868 mg;
Excipients: microcrystalline cellulose PH 112, anhydrous calcium hydrogen phosphate, iron oxide red (E 172), sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
for dosage (4 mg/1.25 mg/5 mg): round marbled tablets of dark pink color, 7 mm in diameter, with imprint «4 1.25 5» on one side;
for dosage (8 mg/2.5 mg/5 mg): round marbled tablets of pink color, 9.4 mm in diameter, with imprint «8 2.5 5» on one side;
for dosage (8 mg/2.5 mg/10 mg): round marbled tablets of dark pink color, 9.4 mm in diameter, with imprint «8 2.5 10» on one side.
Pharmacotherapeutic group.
Angiotensin-converting enzyme (ACE) inhibitors, combinations of ACE inhibitors, calcium channel blockers and diuretics. Perindopril, amlodipine and indapamide.
ATC code C09B X01.
Pharmacological Properties.
Pharmacodynamics.
Lopridam is a combination of three antihypertensive components whose mechanisms of action complement each other to control blood pressure in patients with arterial hypertension. Perindopril is an ACE inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium ion antagonist.
The combination of these components exerts an additive antihypertensive effect, resulting in a greater reduction in blood pressure than when each component is used individually.
Mechanism of Action
Perindopril
Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictive substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilatory substance) degradation into inactive heptapeptides.
As a result of ACE inhibition:
- aldosterone secretion is reduced;
- plasma renin activity increases, while aldosterone does not exert a negative effect;
- total peripheral vascular resistance decreases due to predominant effects on muscle and renal vessels, without water and salt retention or reflex tachycardia, even during long-term treatment.
Perindopril reduces blood pressure even in patients with normal or low plasma renin levels. Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive.
Perindopril reduces cardiac workload through:
- vasodilatory effects on veins (possibly due to changes in prostaglandin metabolism) – reducing preload on the heart;
- reduction of total peripheral vascular resistance – reducing afterload on the heart.
Studies conducted in patients with heart failure have demonstrated that perindopril use leads to:
- reduced filling pressure in the left and right ventricles;
- reduced total peripheral vascular resistance;
- increased cardiac output and improved cardiac index;
- increased regional blood flow in muscles; furthermore, physical exercise test parameters significantly improve.
Indapamide
Indapamide is a sulfonamide diuretic with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. It increases urinary excretion of sodium and chloride and, to a lesser extent, potassium and magnesium, thereby enhancing diuresis and exerting antihypertensive effects.
Amlodipine
Amlodipine is a dihydropyridine calcium ion antagonist (slow channel blocker or calcium ion antagonist) that inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of amlodipine's antihypertensive effect is due to direct relaxation of vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully understood, but it is known that the drug reduces overall ischemic load through the following actions:
Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate does not change, reduced cardiac workload decreases myocardial energy consumption and oxygen demand.
The mechanism of action of amlodipine also likely includes dilation of major coronary arteries and coronary arterioles in both unaffected and ischemic areas of the myocardium. This dilation increases oxygen delivery to the myocardium in patients with Prinzmetal's angina.
Pharmacodynamic Effects
Perindopril
Perindopril effectively reduces blood pressure in arterial hypertension of any severity: mild, moderate, and severe. Reduction in systolic and diastolic blood pressure is observed both in supine and standing positions.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for more than 24 hours.
Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.
In patients who respond to treatment, blood pressure normalization occurs within one month and is maintained without tachyphylaxis.
Discontinuation of therapy is not associated with a rebound effect.
Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy.
Additional synergism develops when a thiazide diuretic is added if necessary.
The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy.
Indapamide
The antihypertensive effect of indapamide as monotherapy lasts for 24 hours. This effect occurs at doses where diuretic properties are minimal.
The antihypertensive effect of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of adverse reactions increases. If treatment is insufficiently effective, dose escalation is not recommended.
Additionally, studies of varying duration (short, medium, and long-term) involving patients with arterial hypertension have demonstrated that indapamide:
- does not affect lipid metabolism (triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C));
- does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.
Perindopril/Indapamide
In patients with hypertension, regardless of age, perindopril arginine/indapamide at a dose of 5 mg/1.25 mg exerts a dose-dependent antihypertensive effect on diastolic and systolic blood pressure in both supine and standing positions. This hypotensive effect lasts for 24 hours. Blood pressure reduction is achieved in less than one month without tachyphylaxis; discontinuation of treatment is not associated with a rebound effect. During clinical trials, concomitant administration of perindopril and indapamide resulted in a synergistic hypotensive effect compared to each drug administered separately.
Amlodipine
In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant blood pressure reduction over 24 hours, both in supine and standing positions. Due to its slow onset of action, acute arterial hypotension is not a characteristic feature of amlodipine use.
Pharmacokinetics.
The use of perindopril/indapamide and amlodipine in a fixed combination does not alter their pharmacokinetic properties compared to their use as monotherapy.
Absorption and Bioavailability
Perindopril
After oral administration, perindopril is rapidly absorbed, and maximum plasma concentration (Cmax) is reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.
Since food intake reduces conversion to perindoprilat, perindopril should be administered orally as a single daily dose in the morning before meals.
Indapamide
Indapamide is rapidly and completely absorbed in the gastrointestinal tract.
Cmax is reached approximately 1 hour after oral administration.
Amlodipine
After oral administration of therapeutic doses of amlodipine, it is well absorbed, and Cmax in blood is reached within 6–12 hours. Absolute bioavailability is approximately 64–80%. Food intake does not affect amlodipine bioavailability.
Distribution
Perindopril
The volume of distribution of free perindopril is approximately 0.2 L/kg. Protein binding of perindopril to plasma proteins is 20%, particularly to ACE, but depends on concentration.
Indapamide
Protein binding to plasma proteins is 79%.
Amlodipine
The volume of distribution is approximately 21 L/kg. In vitro studies indicate that approximately 97.5% of circulating amlodipine is protein-bound.
Biotransformation and Elimination
Perindopril
Perindopril is a prodrug. 27% of the total absorbed perindopril is converted into the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Cmax of perindoprilat in plasma is reached within 3–4 hours.
Perindoprilat is excreted in urine, and the elimination half-life of the unbound fraction is approximately 17 hours, achieving steady-state levels within 4 days.
Indapamide
The elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated dosing does not cause accumulation. Indapamide is primarily excreted in urine (70% of dose) and feces (22%) as inactive metabolites.
Amlodipine
Amlodipine is extensively metabolized in the liver, forming inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.
The elimination half-life of a single daily dose in plasma ranges from 35 to 50 hours.
Linearity/Non-linearity
Perindopril
A linear relationship between perindopril dose and its plasma concentration has been demonstrated.
Special Patient Groups
Elderly Patients
Perindopril
In elderly individuals and patients with cardiac or renal insufficiency, perindoprilat elimination is reduced.
Amlodipine
Time to reach maximum plasma concentration of amlodipine is the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased area under the concentration-time curve (AUC) and prolonged elimination half-life. Increased AUC and prolonged elimination half-life in patients with congestive heart failure corresponded to predictions for this age group.
Patients with Renal Impairment
Perindopril
In patients with renal impairment, dose adjustment is recommended depending on the degree of impairment (creatinine clearance). Perindoprilat clearance is 70 mL/min.
Indapamide
In patients with renal insufficiency, pharmacokinetic parameters do not change.
Patients with Hepatic Impairment
Perindopril
In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent compound reduced by half, but the amount of formed perindoprilat remains unchanged; therefore, dose adjustment is not required in this condition (see sections "Indications" and "Special Instructions").
Amlodipine
There are insufficient data on amlodipine use in patients with hepatic impairment. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and increased AUC by approximately 40–60%.
Clinical characteristics.
Indications.
Treatment of arterial hypertension controlled with perindopril, indapamide, and amlodipine at doses available in fixed combination.
Contraindications.
- Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, another ACE inhibitor, or to any of the components of the medicinal product.
- History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions").
- Concomitant use with sacubitril/valsartan therapy. The medicinal product must not be used earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
- Hereditary or idiopathic angioedema.
- Pregnancy or women planning pregnancy (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
- Concomitant use of the medicinal product Lopridam and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
- Extracorporeal treatment methods 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 solitary functioning kidney (see section "Special precautions").
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Moderate renal insufficiency (creatinine clearance < 60 mL/min) when taking Lopridam containing the combination of active substances in doses of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg.
- Hepatic encephalopathy.
- Severe hepatic dysfunction.
- Hypokalemia.
- Concomitant use of antiarrhythmic drugs that may cause torsades de pointes ventricular tachycardia (see section "Interaction with other medicinal products and other forms of interaction").
- Use in patients undergoing hemodialysis.
- Use in patients with untreated decompensated heart failure.
- Severe arterial hypotension.
- Shock (including cardiogenic shock).
- Impaired outflow from the left ventricle (e.g., severe aortic stenosis).
- Heart failure with unstable hemodynamics following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS), associated with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, increases the frequency of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Pharmacological properties", "Contraindications", and "Special precautions").
Medicinal products that may cause hyperkalemia
Some medicinal products or therapeutic classes of medicinal products may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Concomitant administration of these medicinal products increases the risk of developing hyperkalemia.
Concomitant use is contraindicated
| Drug component |
Interacting component |
Description of interaction |
| Perindopril |
Aliskiren |
In patients with diabetes mellitus or patients with renal impairment, the risk of hyperkalemia, worsening of renal function, and cardiovascular events and mortality increases. |
| Sacubitril/valsartan |
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special warnings and precautions for use"). |
|
| Extracorporeal treatment methods |
Extracorporeal treatment methods involving blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or switching to another class of antihypertensive agents. |
Concomitant use is not recommended
| Active ingredient |
Interacting component |
Description of interaction |
| Perindopril |
Aliskiren |
In patients without diabetes mellitus or in patients with renal impairment, the risk of hyperkalaemia, worsening of renal function, cardiovascular events and mortality increases (see section "Special precautions"). |
| Concomitant use of ACE inhibitors and angiotensin receptor blockers |
Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS. Dual blockade (e.g. combining an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with careful monitoring of renal function, potassium levels and blood pressure (see section "Special precautions"). |
|
| Estrogenic steroids |
Increased risk of adverse reactions such as angioedema. |
|
| Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes |
Although serum potassium levels usually remain within normal limits, hyperkalaemia may occur in some patients receiving perindopril, particularly in those with impaired renal function (additive effect). Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Therefore, these agents are not recommended for concomitant use with perindopril. However, if concomitant use of these medicinal products is necessary, they should be used with caution and frequent monitoring of plasma potassium levels is required. For use of spironolactone in heart failure, see "Concomitant use requiring special attention". |
|
| Perindopril/indapamide |
Lithium |
Reversible increases in serum lithium concentration and increased lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium-containing medications is not recommended. However, if such combination is necessary, serum lithium concentrations should be closely monitored (see section "Special precautions"). |
| Amlodipine |
Dantrolene (infusion) |
In animal studies, ventricular fibrillation and cardiovascular collapse leading to death were observed after administration of verapamil followed by intravenous dantrolene infusion, due to development of hyperkalaemia. Due to the risk of hyperkalaemia in patients prone to malignant hyperthermia or during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided. |
Concomitant use requiring special attention
| Active ingredient |
Interacting component |
Description of interaction |
| Perindopril |
Antidiabetic agents (insulin, oral hypoglycemics) |
Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemics) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment. |
| Non-potassium-sparing diuretics |
In patients receiving diuretics, especially those with impaired water-electrolyte balance, excessive reduction in arterial pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be minimized by discontinuing the diuretic, increasing circulating blood volume (CBV), and increasing salt intake prior to starting perindopril, which should be initiated at low doses with gradual dose escalation. In arterial hypertension, when a previously prescribed diuretic may have caused fluid/electrolyte depletion, it should be discontinued before starting ACE inhibitor therapy (in such cases, diuretic therapy may be reintroduced later), or the ACE inhibitor should be started at a low dose with gradual dose increase. In chronic heart failure, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the dose of non-potassium-sparing diuretics. In all cases, renal function (serum creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy. |
|
| Potassium-sparing diuretics (eplerenone, spironolactone) |
Concomitant use of eplerenone or spironolactone at doses of 12.5–50 mg daily with low doses of ACE inhibitors: in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, failure to follow prescribing recommendations increases the risk of hyperkalemia (possibly fatal). Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter. |
|
| Racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) |
In patients receiving concomitant mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), the risk of angioedema is increased (see section "Special precautions"). |
|
| Trimethoprim, co-trimoxazole (trimethoprim/sulfamethoxazole) |
Caution is advised when perindopril is used concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride (see section "Special precautions"). |
|
| Ciclosporin |
Concomitant use of ACE inhibitors with ciclosporin increases the risk of hyperkalemia. Monitoring of serum potassium levels is recommended. |
|
| Heparin |
Concomitant use of ACE inhibitors with heparin increases the risk of hyperkalemia. Monitoring of serum potassium levels is recommended. |
|
| Indapamide |
Drugs that may induce torsades de pointes (paroxysmal torsade-type ventricular tachycardia) |
Due to the risk of hypokalemia, indapamide should be used cautiously in combination with drugs that may provoke paroxysmal torsade-type ventricular tachycardia (torsades de pointes): class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide, bretylium); certain neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); and other drugs such as bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, moxifloxacin, sparfloxacin, intravenous vincaamine, methadone, astemizole, terfenadine. Measures should be taken to prevent plasma potassium depletion; potassium levels should be corrected if necessary and QT interval monitored. |
| Drugs that reduce potassium levels |
Amphotericin B (intravenous), glucocorticoids and mineralocorticoids (systemic), tetracosactide, and laxatives increase the risk of decreased serum potassium (additive effect). Serum potassium levels should be monitored and corrected as needed, especially when used concomitantly with cardiac glycosides. Laxatives that do not stimulate peristalsis are recommended. |
|
| Cardiac glycosides |
Hypokalemia and/or hypomagnesemia potentiates the toxic effects of cardiac glycosides; therefore, monitoring of plasma potassium/magnesium levels and ECG is required, and therapy should be reviewed if necessary. |
|
| Allopurinol |
Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol. |
|
| Perindopril/indapamide |
Baclofen |
Enhances antihypertensive effect. Blood pressure and renal function should be monitored, and dose adjustment may be necessary. |
| NSAIDs, including acetylsalicylic acid at doses ≥ 3 g daily |
When ACE inhibitors are co-administered 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 increases the risk of impaired renal function, including acute renal failure, and hyperkalemia, particularly in patients with pre-existing renal impairment. Therefore, these drugs should be used cautiously, especially in elderly patients. Patients should maintain adequate fluid intake. Renal function should be monitored after initiation of combination therapy and at regular intervals thereafter. |
|
| Amlodipine |
CYP3A4 inhibitors |
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may significantly enhance the effect of amlodipine, potentially leading to an increased risk of arterial hypotension. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. Close patient monitoring and possible dose adjustment are recommended. |
| Tacrolimus |
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment are required when used concomitantly with amlodipine. |
|
| mTOR inhibitors (mammalian target of rapamycin) |
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Amlodipine may increase the effects of mTOR inhibitors when used concomitantly. |
Concomitant use with caution
| Active pharmaceutical ingredient |
Component involved in interaction |
Description of interaction |
| Perindopril |
Antihypertensive agents and vasodilators |
Concomitant use of other antihypertensive drugs may enhance the hypotensive effect of perindopril. Concurrent administration with nitroglycerin and other nitrates or other vasodilating agents may further reduce blood pressure. |
| Allopurinol, cytostatic agents, immunosuppressants, systemic corticosteroids or procainamide |
Concomitant use with ACE inhibitors increases the risk of leukopenia (see section "Special warnings and precautions for use"). |
|
| Anesthetic agents |
ACE inhibitors may potentiate the hypotensive effect of certain anesthetic agents (see section "Special warnings and precautions for use"). |
|
| Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin) |
In patients receiving a combination of a gliptin and an ACE inhibitor, the risk of angioedema is increased because gliptins reduce dipeptidyl peptidase-IV (DPP-IV) activity. |
|
| Sympathomimetics |
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. |
|
| Gold preparations |
Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may rarely cause reactions similar to those observed with nitrates (symptoms: facial flushing, nausea, vomiting, and arterial hypotension). |
|
| Indapamide |
Potassium-sparing diuretics (amiloride, spironolactone, triamterene) |
When combination therapy is indicated in certain patients, hypokalaemia (especially in patients with diabetes mellitus or renal insufficiency) or hyperkalaemia may occur. Serum potassium levels and ECG should be monitored and therapy adjusted if necessary. |
| Metformin |
Metformin may cause lactic acidosis due to functional renal impairment associated with diuretic therapy, especially loop diuretics. Metformin should not be prescribed if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women. |
|
| Iodinated contrast agents |
In case of dehydration due to diuretic use, the risk of acute renal failure increases, especially when high doses of iodinated contrast agents are administered. Fluid balance should be restored prior to administration of contrast agents. |
|
| Calcium (salts) |
There is a risk of hypercalcaemia due to reduced urinary excretion of calcium. |
|
| Cyclosporine, tacrolimus |
There is a risk of increased creatinine concentration without affecting circulating cyclosporine levels, even in the absence of water and sodium depletion. |
|
| Corticosteroids, tetracosactide (systemic) |
Antihypertensive effect may be reduced (due to water and salt retention by corticosteroids). |
|
| Perindopril/ |
Imipramine-like antidepressants (tricyclic), neuroleptics |
May enhance antihypertensive effect and increase the risk of orthostatic hypotension (additive effect). |
| Amlodipine |
CYP3A4 inducers |
Concomitant use with CYP3A4 inducers may alter plasma concentrations of amlodipine. Therefore, careful monitoring of the patient and dose adjustment are required during and after concomitant use of amlodipine with CYP3A4 inducers (especially potent ones such as rifampicin and St. John's wort). Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effect. |
| Other antihypertensive agents |
The hypotensive effect of amlodipine is additive to that of other antihypertensive drugs. |
|
| Cyclosporine |
Studies on interactions between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average by 0–40%) have been observed. Monitoring of cyclosporine concentrations should be considered in kidney transplant patients receiving amlodipine, and cyclosporine dosage reduced if necessary. |
|
| Simvastatin |
Concomitant administration of multiple doses of amlodipine (10 mg) and simvastatin (80 mg) increases exposure to simvastatin by 77% compared to simvastatin alone. The dose of simvastatin in patients taking amlodipine should not exceed 20 mg daily. |
|
| Atorvastatin, digoxin, warfarin |
In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin. |
Special precautions for use.
All the warnings listed below regarding individual components also apply to the medicinal product Lopridam as a whole.
Special warnings
Dual blockade of the RAAS
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of developing arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren is not recommended (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
If dual blockade therapy is absolutely necessary, it should be conducted only under specialist supervision, with careful monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
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").
Neutropenia/agranulocytosis/thrombocytopenia/anaemia
Cases of neutropenia/agranulocytosis, thrombocytopenia, and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagen vascular disease, immunosuppressive therapy, allopurinol, procainamide, or a combination of these factors, especially if renal function is impaired. In some of these patients, serious infectious diseases have been observed, in several cases resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell counts is recommended. They should also be advised to report any signs of infection (sore throat, fever) (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").
Renovascular hypertension
The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with an increased risk of arterial hypotension and renal failure (see section "Contraindications"). The use of diuretics may be a contributing factor. Impaired renal function may be associated with only minor 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 (see section "Side effects"). This may occur at any time during treatment. In such cases, perindopril should be discontinued immediately, and appropriate monitoring should be initiated until symptoms completely resolve. If swelling is limited to the face and lips, the condition usually improves without treatment, and antihistamines may be helpful in alleviating symptoms.
Angioedema involving swelling of the larynx may be fatal. If swelling spreads to the tongue, glottis, or larynx, with a risk of airway obstruction, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 mL) and/or securing airway patency.
It has been reported that ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races.
Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").
The risk of developing angioedema may be increased when ACE inhibitors are used concomitantly with other drugs that may cause angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated within 36 hours after the last dose of sacubitril/valsartan.
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or 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 racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.
Rare cases of intestinal angioedema have been observed in patients treated with ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, prior angioedema of the face was not observed, and C-1 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. When performing differential diagnosis of abdominal pain in patients receiving ACE inhibitors, intestinal angioedema should be considered.
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 bee or wasp venom-containing products. ACE inhibitors should be used cautiously in patients with allergies after desensitization and avoided during immunotherapy with animal-derived venom-containing medicinal products. However, such reactions can be avoided in patients requiring both ACE inhibitors and desensitization therapy by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization.
Anaphylactoid reactions during LDL apheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.
Patients undergoing 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 usually do not respond to antihypertensive therapy acting via RAAS inhibition. Therefore, this medicinal product is not recommended for such patients.
Pregnancy
ACE inhibitors are contraindicated during pregnancy. If ACE inhibitor therapy needs to be continued and the patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during ACE inhibitor therapy, treatment should be discontinued immediately, and the medicinal product should be replaced with another if necessary.
Hepatic encephalopathy
In patients with impaired liver function, the use of thiazide and thiazide-like diuretics, especially in the presence of electrolyte imbalance, may precipitate hepatic encephalopathy, which may progress to hepatic coma. If this occurs, diuretic therapy should be discontinued immediately.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Medicinal products containing sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of myopia or eye pain and usually occur within a period ranging from several hours to several weeks after initiation of treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure is not controlled, immediate therapeutic or surgical intervention may be required. Risk factors for developing angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Photosensitivity
Cases of photosensitivity have been reported during treatment with thiazides and thiazide diuretics (see section "Side effects"). If such reactions occur, diuretic therapy is recommended to be discontinued. During re-administration of diuretics, exposure to direct sunlight and artificial UV radiation should be avoided.
Sportsmen
Sportsmen should be aware that the medicinal product contains an active substance (indapamide) that may cause a positive result in doping controls.
Precautions for use
Renal function
- Perindopril/indapamide therapy is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
In moderate renal impairment (creatinine clearance < 60 mL/min), the use of Lopridam containing 8 mg/2.5 mg perindopril/indapamide (i.e., in doses of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg) is contraindicated.
If laboratory signs of renal impairment develop in patients with arterial hypertension without pre-existing signs of renal dysfunction, the drug should be discontinued; resumption of therapy with a lower dose or one of the components may be considered.
Such patients require frequent monitoring of potassium and creatinine: 2 weeks after initiation of therapy and subsequently every 2 months during therapeutic stabilization. Cases of renal impairment have been observed predominantly in patients with severe heart failure or renal dysfunction, including 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.
- Thiazide and thiazide-like diuretics demonstrate maximum efficacy when renal function is normal or only slightly impaired (serum creatinine level below approximately 25 mg/L, i.e., 220 µmol/L in adults).
In elderly patients, plasma creatinine levels should correspond to age, body weight, and sex according to the Cockcroft formula:
clcr = (140 − age) × body weight / 0.814 × plasma creatinine level,
where: age is expressed in years,
body weight is expressed in kilograms,
plasma creatinine level is expressed in µmol/L.
This formula is suitable for elderly men and can be adapted for women by multiplying the result by 0.85.
Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment leads to decreased glomerular filtration. As a result, increased blood urea and creatinine levels may be observed. This transient functional renal impairment has no consequences in patients with normal renal function but may exacerbate pre-existing renal impairment.
- Indapamide can be used in patients with renal impairment at standard doses. Plasma concentration fluctuations of indapamide do not depend on the degree of renal impairment.
Indapamide is not removed by hemodialysis.
Hypotension, water and sodium depletion
- Patients receiving perindopril/indapamide are at risk of sudden arterial hypotension in the presence of pre-existing sodium depletion (particularly in patients with renal artery stenosis). Therefore, patients should be systematically evaluated for signs of water and electrolyte depletion, which may occur due to vomiting or diarrhea. In such patients, plasma electrolyte levels should be monitored regularly.
In case of pronounced arterial hypotension, intravenous administration of isotonic sodium chloride solution may be required.
Transient hypotension is not a contraindication for further drug use. After restoration of circulating blood volume and normalization of blood pressure, therapy may be resumed at a lower dose or with one of the drug components.
- Marked stimulation of the RAAS has been observed in cases of pronounced water and electrolyte depletion (strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or patients with liver cirrhosis with edema and ascites.
Blocking this system with an ACE inhibitor, especially during the first dose and the first two weeks of treatment, may cause sudden reduction in blood pressure and/or increased plasma creatinine levels, confirming the presence of functional renal impairment. This may occasionally have an acute onset and occur at any time. In such cases, treatment should be initiated with a lower dose, gradually increasing it.
- Sodium levels should be checked before starting indapamide therapy and then at regular intervals. Initial reduction in sodium concentration may be asymptomatic, so regular laboratory monitoring of this parameter is required. More frequent monitoring is necessary for elderly patients and patients with liver cirrhosis (see sections "Side effects" and "Overdose"). Any diuretic may cause hyponatremia, which may sometimes have serious consequences. Hyponatremia 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 phenomenon are low).
Potassium levels
- Treatment with the combination of indapamide, perindopril, and amlodipine does not exclude the possibility of hypokalaemia, particularly in patients with diabetes mellitus or renal impairment. As with any antihypertensive agent combined with a diuretic, plasma potassium levels should be monitored regularly.
- ACE inhibitors may cause hyperkalaemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually minor. However, patients with impaired renal function and/or those taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers, are at risk of developing hyperkalaemia. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and monitor serum potassium levels and renal function (see section "Interaction with other medicinal products and other forms of interaction").
- Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalaemia include renal impairment, impaired 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 causing increased plasma potassium concentration (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, other ACE inhibitors, angiotensin receptor blockers, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors, and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may lead to significant increases in plasma potassium levels. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of the above-mentioned drugs 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 plasma potassium levels and hypokalaemia are the main risks associated with the use of thiazide and thiazide-like diuretics.
Prevention of hypokalaemia (< 3.4 mmol/L) is necessary in high-risk patients (elderly patients and/or those with poor nutrition, patients taking multiple medications, patients with liver cirrhosis with edema and ascites, patients with ischemic heart disease (IHD), and patients with heart failure).
In case of hypokalaemia, the 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 lead to the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, which may be fatal.
In all these cases, more frequent monitoring of plasma potassium levels is required. The first determination of this parameter should be performed within the first week of treatment.
If low potassium levels occur, correction is required. Hypokalaemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are corrected.
Magnesium in plasma
It has been demonstrated that thiazides and related diuretics, including indapamide, increase magnesium excretion in urine, which may lead to hypomagnesaemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").
Risk of rhabdomyolysis
Indapamide is known to cause hypokalaemia and hyponatraemia, which may lead to muscle disorders/rhabdomyolysis, especially in the presence of additional risk factors (trauma, muscle injury, concomitant use of drugs that may cause hypokalaemia or hyponatraemia).
Calcium levels
Thiazide and thiazide-like diuretics may reduce calcium excretion in urine and lead to slight and transient increases in plasma calcium levels. Markedly elevated calcium levels may be a consequence of previously undiagnosed hyperparathyroidism. Treatment should be discontinued until parathyroid function is evaluated.
Uric acid levels
In patients with elevated uric acid levels, there may be a tendency to increased frequency of gout attacks during indapamide therapy.
Renovascular hypertension
The treatment for renovascular hypertension is revascularization. However, for patients with renovascular hypertension awaiting surgery or in whom surgery is not possible, ACE inhibitors may be beneficial.
If Lopridam is prescribed to patients diagnosed with or suspected of renal artery stenosis, therapy should be initiated in a hospital setting with low doses, monitoring potassium levels. In some patients, functional renal impairment developed, which was reversible after discontinuation of treatment.
Atherosclerosis
The risk of arterial hypotension exists in all patients, but perindopril should be prescribed with particular caution to patients with IHD or cerebral circulation insufficiency. In such cases, treatment should be initiated with a low dose.
Patients with impaired liver function
- Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant increases in liver enzymes while receiving an ACE inhibitor should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Side effects").
- In patients with impaired liver function, prolonged elimination half-life and high AUC values of amlodipine are observed; dosing recommendations are lacking. Amlodipine therapy should be initiated at the lowest doses, with caution during the initial phase of therapy and dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.
Heart failure/severe heart failure
- Treatment of patients with heart failure requires special attention. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the number of reports of pulmonary edema was higher in the amlodipine group compared to the placebo group (see section "Pharmacological properties"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular complications and mortality.
- In patients with severe heart failure (stage IV), treatment should be initiated under medical supervision with a reduced initial dose. β-blocker therapy in patients with arterial hypertension and coronary insufficiency should not be discontinued: the ACE inhibitor is added to the β-blocker.
Stenosis of aortic or mitral valves/hypertrophic cardiomyopathy
ACE inhibitors should be prescribed with caution to patients with left ventricular outflow obstruction.
Hypertensive crisis
The safety and efficacy of amlodipine use in patients with severe arterial hypertension have not been established.
Patients with diabetes mellitus
In patients with insulin-dependent diabetes mellitus (due to the tendency to spontaneous increase in potassium levels), treatment should be initiated under medical supervision with a reduced initial dose.
Glucose levels should be carefully monitored in patients with diabetes mellitus who previously received oral antidiabetic agents or insulin, particularly during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction") or during indapamide therapy, especially when potassium levels are low.
Ethnic differences
As with other ACE inhibitors, perindopril is less effective in reducing blood pressure in patients of Black race compared to patients of other races, possibly due to a higher prevalence of low-renin states among dark-skinned patients with arterial hypertension.
Surgery/anesthesia
ACE inhibitors may cause arterial hypotension during anesthesia, especially when anesthetics that reduce blood pressure are used.
Therefore, when treating with long-acting ACE inhibitors such as perindopril, the drug should be discontinued, if possible, one day before surgery.
Cough
A dry cough has been reported during ACE inhibitor therapy. This cough is persistent and resolves after discontinuation of the drug. When this symptom occurs, iatrogenic aetiology of cough should be considered. If ACE inhibitor therapy is desired, continuation of therapy may be considered.
Elderly patients
Renal function and potassium levels should be checked before initiating treatment. To reduce the risk of sudden arterial hypotension, especially in the presence of water or electrolyte depletion, the initial dose should be adjusted according to the blood pressure response to treatment.
Dose escalation of amlodipine in elderly patients should be done cautiously (see sections "Pharmacological properties" and "Method of administration and dosage").
Children
The efficacy and tolerability of the medicinal product Lopridam in children and adolescents have not been established.
Precautions regarding excipients
This medicinal product contains less than 1 mmol (23 mg)/tablet of sodium, i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding.
Use of the medicinal product Lopridam is contraindicated in pregnant women and women planning pregnancy.
Use of the medicinal product Lopridam is contraindicated during breastfeeding. Therefore, a decision should be made to either discontinue breastfeeding or discontinue Lopridam, taking into account the benefit of treatment for the mother.
Pregnancy
Warnings related to perindopril
The use of ACE inhibitors is contraindicated during pregnancy (see sections "Contraindications" and "Special precautions for use").
Epidemiological data on the teratogenic risk associated with angiotensin II receptor blockers in the first trimester of pregnancy do not allow definitive conclusions, but a slight increase in risk cannot be excluded. If ACE inhibitor therapy needs to be continued and the patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used.
If pregnancy is confirmed during ACE inhibitor therapy, treatment should be discontinued immediately and replaced with another medicinal product permitted during pregnancy if necessary.
In the second and third trimesters of pregnancy, ACE inhibitors have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalaemia) (see section "Pharmacological properties").
If ACE inhibitors are taken during the second or third trimester of pregnancy, monitoring of fetal renal function and skull ossification process by ultrasound is required. Newborns whose mothers took ACE inhibitors should be monitored for possible arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Warnings related to indapamide
Data on the use of indapamide in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may lead to reduced circulating blood volume in the pregnant woman and uteroplacental perfusion, which may cause fetoplacental ischemia and delayed fetal development.
Animal studies do not indicate direct or indirect harmful effects and reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of indapamide during pregnancy.
Warnings related to amlodipine
The safety of amlodipine use during pregnancy has not been established.
Animal studies have shown reproductive toxicity after administration of high doses of the drug.
Period of breastfeeding
Use of the medicinal product Lopridam is contraindicated during breastfeeding (see section "Contraindications").
Warnings related to perindopril
Due to limited data, perindopril use during breastfeeding is contraindicated; in such cases, alternative therapy with a better safety profile during lactation should be used, especially when breastfeeding newborns and premature infants.
Warnings related to indapamide
Data on the penetration of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalaemia may develop. The risk of drug effects on the newborn/infant cannot be excluded.
Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation.
Indapamide is contraindicated during breastfeeding.
Warnings related to amlodipine
Amlodipine is excreted in breast milk. The interquartile range of the amount of drug transferred to the infant's body is 3–7% of the dose received by the mother, with a maximum possible amount of 15%. The effect of amlodipine on the infant's body is unknown.
Fertility
Warnings related to perindopril and indapamide
Reproductive toxicity studies showed no effect on fertility in male and female rats. No effect on human fertility is expected.
Warnings related to amlodipine
Cases of reversible biochemical changes in the sperm head have been reported in some patients taking calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. Adverse effects on male fertility were observed in rat studies.
Ability to influence reaction speed when driving or operating machinery.
The medicinal product Lopridam has a moderate effect on the ability to react when driving or operating machinery.
If patients taking Lopridam experience dizziness, headache, fatigue, or nausea, their reaction ability may be impaired. Caution is advised, especially at the beginning of treatment.
Method of Administration and Dosage.
Dosage
The patient should take the dosage corresponding to the previously prescribed treatment.
The usual dose of the medicinal product Lopridam is one tablet once daily.
Elderly patients (see section "Special Warnings")
Note that the elimination of perindoprilat is reduced in elderly patients (see section "Pharmacological Properties").
Prescribing the drug to elderly patients should take into account blood pressure and renal function.
Patients with renal impairment (see section "Special Warnings")
Special considerations for perindopril/indapamide
The use of this medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
The use of Lopridam at doses of 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min).
Dose adjustment is not required in patients with creatinine clearance ≥60 mL/min. Regular medical monitoring should include careful monitoring of creatinine and potassium levels.
Special considerations for amlodipine
Plasma concentrations of amlodipine do not correlate with the degree of renal impairment; therefore, standard dosing is recommended. Amlodipine is not removed by dialysis (see section "Pharmacological Properties").
Patients with hepatic impairment
The use of this medicinal product is contraindicated in patients with severe hepatic impairment. Lopridam should be prescribed with caution to patients with mild to moderate hepatic impairment due to the lack of dosing recommendations for amlodipine.
Method of Administration
The drug should preferably be taken in the morning before food.
Children
The safety and efficacy of the medicinal product Lopridam in children and adolescents have not been established; therefore, it should not be prescribed to patients in this age group.
Overdose.
Cases of overdose with Lopridam have not been reported.
Symptoms
Related to perindopril/indapamide
The most common adverse reaction in case of overdose is arterial hypotension, which may be accompanied by nausea, vomiting, convulsions, dizziness, somnolence, confusion, oliguria, which may progress to anuria (due to hypovolemia). Electrolyte and fluid imbalances may occur (decreased plasma potassium and sodium levels).
Related to amlodipine
Experience with intentional overdose in humans is limited.
Available data indicate that significant overdose may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of prolonged, severe generalized arterial hypotension up to shock with fatal outcome have been reported.
Non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may not manifest immediately (within 24–48 hours after ingestion) and may require ventilatory support. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (particularly fluid overload) aimed at maintaining perfusion and cardiac output.
Treatment
Related to perindopril/indapamide
Emergency measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of fluid and electrolyte balance under hospital conditions until these parameters return to normal.
In case of significant arterial hypotension, the patient should be placed in a supine position with low head elevation. If necessary, isotonic saline should be administered intravenously or any other method used to restore blood volume.
Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see section "Pharmacological Properties").
Related to amlodipine
In case of clinically significant arterial hypotension due to amlodipine overdose, active cardiovascular support is required, including monitoring of cardiac and pulmonary function, placing the patient in a supine position with slightly elevated lower limbs, and monitoring of circulating blood volume and diuresis.
Administration of vasoconstrictors may be helpful to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate is recommended to counteract calcium channel blockade.
In individual cases, gastric lavage may be necessary. Studies in healthy volunteers have shown that administration of activated charcoal 2 hours after ingestion of 10 mg amlodipine reduces the rate of amlodipine absorption.
Since amlodipine is highly protein-bound, elimination by hemodialysis is unlikely.
Adverse Reactions
Related to the use of perindopril/indapamide
Short description of the safety profile
The use of perindopril suppresses the RAAS and reduces potassium loss caused by indapamide.
Hypokalemia (potassium level < 3.4 mmol/L) was observed in 4% of patients treated with the combination of perindopril/arginine/indapamide 5 mg/1.25 mg.
Hypokalemia (potassium level < 3.4 mmol/L) was observed in 6% of patients treated with the combination of perindopril/arginine/indapamide 10 mg/2.5 mg.
Indapamide 1.5 mg: plasma potassium levels < 3.4 mmol/L were observed in 10% of patients and < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.23 mmol/L.
Indapamide 2.5 mg: plasma potassium levels < 3.4 mmol/L were observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.41 mmol/L.
The most frequently observed adverse reactions were:
- For perindopril: dizziness, headache, paraesthesia, dysgeusia, visual disturbance, vertigo, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, dyspepsia, diarrhoea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia;
- For indapamide: the most frequently observed adverse reactions are hypokalemia, hypersensitivity reactions, mainly skin-related, in patients predisposed to allergic and asthmatic reactions, and maculopapular rash.
Table of adverse reactions
The adverse reactions listed below have been observed during treatment with perindopril, indapamide, or amlodipine, and are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).
| MedDRA Classification |
Adverse Reactions |
Frequency |
|
| Perindopril |
Indapamide |
||
| Infections and infestations |
Rhinitis |
Very rare |
- |
| Blood and lymphatic system disorders |
Eosinophilia |
Uncommon |
- |
| Agranulocytosis (see section "Special warnings and precautions for use") |
Very rare |
Very rare |
|
| Aplastic anemia |
- |
Very rare |
|
| Pancytopenia |
Very rare |
||
| Leukopenia |
Very rare |
Very rare |
|
| Neutropenia (see section "Special warnings and precautions for use") |
Very rare |
||
| Hemolytic anemia |
Very rare |
Very rare |
|
| Thrombocytopenia (see section "Special warnings and precautions for use") |
Very rare |
Very rare |
|
| Immune system disorders |
Hypersensitivity reactions, mainly skin-related, in patients predisposed to allergic and asthmatic reactions: |
- |
Common |
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
- |
| Metabolism and nutrition disorders |
Hypoglycemia (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction") |
Uncommon* |
- |
| Hyperkalemia, reversible after discontinuation of treatment (see section "Special warnings and precautions for use") |
Uncommon* |
- |
|
| Hyponatremia (see section "Special warnings and precautions for use") |
Uncommon* |
Uncommon |
|
| Hypochloremia |
- |
Uncommon |
|
| Hypomagnesemia |
- |
Uncommon |
|
| Hypercalcemia |
- |
Very rare |
|
| Hypokalemia (see section "Special warnings and precautions for use") |
- |
Common |
|
| Psychiatric disorders |
Mood changes |
Uncommon |
- |
| Sleep disorders |
Uncommon |
- |
|
| Depression |
Uncommon |
- |
|
| Confusion |
Very rare |
- |
|
| Nervous system disorders |
Dizziness |
Common |
- |
| Headache |
Common |
Uncommon |
|
| Paresthesia |
Common |
Uncommon |
|
| Dysgeusia |
Common |
- |
|
| Somnolence |
Uncommon* |
- |
|
| Syncope |
Uncommon* |
Frequency not known |
|
| Stroke, possibly secondary to excessive hypotension in high-risk patients (see section "Special warnings and precautions for use") |
Very rare |
- |
|
| Development of hepatic encephalopathy in case of liver insufficiency (see sections "Contraindications", "Special warnings and precautions for use") |
- |
Frequency not known |
|
| Eye disorders |
Visual disturbance |
Common |
Frequency not known |
| Myopia (see section "Special warnings and precautions for use") |
- |
Frequency not known |
|
| Blurred vision |
- |
Frequency not known |
|
| Choroidal effusion |
- |
Frequency not known |
|
| Angle-closure glaucoma |
- |
Frequency not known |
|
| Ear and labyrinth disorders |
Vertigo |
Common |
Uncommon |
| Tinnitus |
Common |
- |
|
| Cardiac disorders |
Palpitations |
Uncommon* |
- |
| Tachycardia |
Uncommon* |
- |
|
| Angina pectoris (see section "Special warnings and precautions for use") |
Very rare |
- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Very rare |
Very rare |
|
| Myocardial infarction, possibly after excessive hypotension in high-risk patients (see section "Special warnings and precautions for use") |
Very rare |
- |
|
| Paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction") |
- |
Frequency not known |
|
| Vascular disorders |
Arterial hypotension (and symptoms associated with hypotension) (see section "Special warnings and precautions for use") |
Common |
Very rare |
| Vasculitis |
Uncommon* |
- |
|
| Hot flushes |
Uncommon |
||
| Raynaud's phenomenon |
Frequency not known |
- |
|
| Respiratory, thoracic and mediastinal disorders |
Cough (see section "Special warnings and precautions for use") |
Common |
- |
| Dyspnea |
Common |
- |
|
| Bronchospasm |
Uncommon |
- |
|
| Eosinophilic pneumonia |
Very rare |
- |
|
| Gastrointestinal disorders |
Abdominal pain |
Common |
|
| Constipation |
Common |
Uncommon |
|
| Diarrhea |
Common |
||
| Dyspepsia |
Common |
||
| Nausea |
Common |
Uncommon |
|
| Vomiting |
Common |
Uncommon |
|
| Dry mouth |
Uncommon |
Uncommon |
|
| Pancreatitis |
Very rare |
Very rare |
|
| Hepatobiliary disorders |
Hepatitis (see section "Special warnings and precautions for use") |
Very rare |
Frequency not known |
| Liver function abnormalities |
- |
Very rare |
|
| Skin and subcutaneous tissue disorders |
Pruritus |
Common |
- |
| Rash |
Common |
- |
|
| Maculopapular rash |
Common |
||
| Urticaria (see section "Special warnings and precautions for use") |
Uncommon |
Very rare |
|
| Angioedema (see section "Special warnings and precautions for use") |
Uncommon |
Very rare |
|
| Purpura |
- |
Uncommon |
|
| Hyperhidrosis |
Uncommon |
||
| Photosensitivity reaction |
Uncommon* |
Frequency not known |
|
| Pemphigoid |
Uncommon* |
- |
|
| Worsening of psoriasis symptoms |
Uncommon* |
- |
|
| Multiform erythema |
Very rare |
- |
|
| Toxic epidermal necrolysis |
- |
Very rare |
|
| Stevens-Johnson syndrome |
- |
Very rare |
|
| Musculoskeletal and connective tissue disorders |
Muscle cramps |
Common |
- |
| Exacerbation of pre-existing systemic lupus erythematosus |
- |
Frequency not known |
|
| Arthralgia |
Uncommon* |
- |
|
| Muscle weakness |
- |
Frequency not known |
|
| Rhabdomyolysis |
- |
Frequency not known |
|
| Myalgia |
Uncommon* |
Frequency not known |
|
| Renal and urinary disorders |
Patients with impaired renal function |
Uncommon |
- |
| Anuria/Oliguria |
Uncommon |
- |
|
| Acute renal failure |
Uncommon |
Very rare |
|
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
| General disorders and administration site conditions |
Asthenia |
Common |
- |
| Chest pain |
Uncommon* |
- |
|
| Malaise |
Uncommon* |
- |
|
| Peripheral edema |
Uncommon* |
- |
|
| Hyperthermia |
Uncommon* |
- |
|
| Fatigue |
- |
Uncommon |
|
| Investigations |
Increased plasma urea levels |
Uncommon* |
- |
| Increased plasma creatinine levels |
Uncommon* |
- |
|
| Increased plasma bilirubin levels |
Uncommon |
- |
|
| Elevated liver enzymes |
Uncommon |
Frequency not known |
|
| Decreased hemoglobin levels and red blood cell count (see section "Special warnings and precautions for use") |
Very rare |
- |
|
| Hyperglycemia |
- |
Frequency not known |
|
| Elevated blood uric acid levels |
- |
Frequency not known |
|
| QT interval prolongation on ECG (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction") |
- |
Frequency not known |
|
| Injury, poisoning and procedural complications |
Fall |
Uncommon* |
- |
*The frequency of adverse reactions is based on spontaneous reports during clinical trials.
Warnings related to amlodipine
Short description of the safety profile
The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and fatigue.
Table of adverse reactions
The following adverse reactions have been observed during treatment with amlodipine and are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).
Within each column, adverse reactions are listed in order of decreasing severity.
| MedDRA Classification |
Adverse Reactions |
Frequency |
| Blood and lymphatic system disorders |
Leukopenia, thrombocytopenia |
Very rare |
| Immune system disorders |
Allergic reactions |
Very rare |
| Metabolism and nutrition disorders |
Hypoglycemia |
Very rare |
| Psychiatric disorders |
Depression, mood changes (including anxiety), insomnia |
Uncommon |
| Confusion |
Rare |
|
| Nervous system disorders |
Somnolence, dizziness, headache (especially at the beginning of treatment) |
Common |
| Tremor, dysgeusia, syncope, hypoesthesia, paresthesia |
Uncommon |
|
| Hypertonia, peripheral neuropathy |
Very rare |
|
| Extrapyramidal disorders |
Frequency unknown |
|
| Eye disorders |
Visual disturbances (including diplopia) |
Common |
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
| Cardiac disorders |
Palpitations |
Common |
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Uncommon |
|
| Myocardial infarction |
Very rare |
|
| Vascular disorders |
Flushing |
Common |
| Arterial hypotension |
Uncommon |
|
| Vasculitis |
Very rare |
|
| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
Common |
| Cough, rhinitis |
Uncommon |
|
| Gastrointestinal disorders |
Abdominal pain, nausea, dyspepsia, intestinal dysfunction (including constipation and diarrhea) |
Common |
| Vomiting, dry mouth |
Uncommon |
|
| Pancreatitis, gastritis, gingival hyperplasia |
Very rare |
|
| Hepatobiliary disorders |
Hepatitis, jaundice, increased levels of liver enzymes* |
Very rare |
| Skin and subcutaneous tissue disorders |
Alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, rash, exanthema, urticaria |
Uncommon |
| Angioneurotic edema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity |
Very rare |
|
| Toxic epidermal necrolysis |
Frequency unknown |
|
| Musculoskeletal and connective tissue disorders |
Ankle swelling, muscle cramps |
Common |
| Arthralgia, myalgia, back pain |
Uncommon |
|
| Renal and urinary disorders |
Urinary disorders, nocturia, increased frequency of urination |
Uncommon |
| Reproductive system and breast disorders |
Impotence, gynecomastia |
Uncommon |
| General disorders and administration site conditions |
Edema |
Very common |
| Fatigue, asthenia |
Common |
|
| Chest pain, pain, malaise |
Uncommon |
|
| Investigations |
Increased body weight, decreased body weight |
Uncommon |
*mainly against a background of cholestasis.
Reporting of suspected adverse reactions
Reporting of adverse reactions after marketing authorization is important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store in the original blister pack to protect from light and moisture.
Keep out of reach of children.
Packaging. 15 tablets per blister. 2 or 4 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Zentiva, k.s.
Manufacturer's address and location of business activity.
U Kabelovny 130, Dolni Měcholupy, Prague-Dolni Měcholupy, 102 00, Czech Republic.