Co-prenesa®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-PRENESSAÒ (CO-PRENESSAÒ)
Composition:
Active substances: perindopril, indapamide;
One tablet contains 2 mg of perindopril tert-butylamine and 0.625 mg of indapamide, or 4 mg of perindopril tert-butylamine and 1.25 mg of indapamide, or 8 mg of perindopril tert-butylamine and 2.5 mg of indapamide;
Excipients: calcium chloride, hexahydrate; lactose, monohydrate; crospovidone; microcrystalline cellulose; sodium hydrogen carbonate; colloidal anhydrous silicon dioxide; magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties:
tablets 2 mg/0.625 mg: round, slightly biconvex tablets, white to almost white in color, with beveled edges and a short engraved line on one side;
tablets 4 mg/1.25 mg: round, slightly biconvex tablets, white to almost white in color, with beveled edges and a notch on one side;
tablets 8 mg/2.5 mg: round, slightly biconvex tablets, white to almost white in color, with a notch on one side.
Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme inhibitors. Perindopril and diuretics. ATC code C09B A04.
Pharmacological Properties.
Pharmacodynamics.
Co-Perindopril® is a combination of perindopril tert-butylamine salt, an angiotensin-converting enzyme (ACE) inhibitor, and indapamide, a sulfonamide diuretic. The pharmacological action of the drug is determined by the properties of each component (perindopril and indapamide) and their additive synergism.
Mechanism of Action
Related to Co-Perindopril®
Co-Perindopril® is characterized by an additional enhancement of the antihypertensive effect of both components.
Related to Perindopril
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 degradation of the vasodilatory substance bradykinin into an inactive heptapeptide.
Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, increases plasma renin activity (due to suppression of negative feedback on renin release), and reduces aldosterone secretion. Perindopril also exerts antihypertensive effects in patients with low and normal plasma renin levels.
With continuous treatment, this results in a reduction of peripheral vascular resistance due to effects on muscular and renal vessels without salt and water retention or reflex tachycardia.
Perindopril acts via its active metabolite—perindoprilat. Other metabolites are inactive.
Perindopril reduces cardiac load through a vasodilatory effect on veins, possibly due to changes in prostaglandin metabolism (reducing preload), and by decreasing total peripheral resistance (reducing afterload).
In studies conducted in patients with heart failure, a reduction in filling pressure of the left and right ventricles was observed; a decrease in total peripheral vascular resistance; an increase in cardiac output and normalization of cardiac index; and an increase in regional blood flow in muscles.
Significant improvement in exercise tolerance tests was observed.
Related to Indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide reduces sodium reabsorption in the cortical segment. It increases urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, thus leading to increased diuresis and antihypertensive effects.
Antihypertensive Effect Characteristics
Related to Co-Perindopril®
In patients with arterial hypertension, regardless of age, the drug demonstrates a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure in both supine and standing positions.
This antihypertensive effect lasts for 24 hours.
Normalization of arterial pressure occurs within one month and is maintained without development of tachyphylaxis.
Upon discontinuation of the drug, no rebound effect occurs.
In clinical trials, concomitant administration of perindopril and indapamide resulted in synergistic antihypertensive effects compared to each individual component.
The impact of the low-dose combination Co-Perindopril®, 2 mg/0.625 mg, on cardiovascular morbidity and mortality has not been studied.
Related to Perindopril
Perindopril is active in mild, moderate, and severe arterial hypertension. It reduces systolic and diastolic arterial pressure both in supine and standing positions. Maximum hypotensive effect is achieved 4–6 hours after single administration and lasts for at least 24 hours. Perindopril demonstrates a high level of residual ACE inhibition (approximately 80%) 24 hours after administration.
In patients with a reversible response, stabilization of arterial pressure 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 elasticity of large arteries, corrects structural changes in arteries, and reduces left ventricular hypertrophy. Additional therapy with a thiazide diuretic leads to additional synergism.
The combination of an ACE inhibitor and a thiazide reduces the risk of diuretic-induced hypokalemia compared to monotherapy with either component.
Clinical Data on Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)
Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].
ONTARGET was a study involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study involving patients with type 2 diabetes and diabetic nephropathy.
The studies did not demonstrate significant beneficial effects on renal and/or cardiovascular morbidity and mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) was a study evaluating the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease and cardiovascular disease. The study was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, or renal function impairment) were more frequent in the aliskiren group compared to the placebo group.
Use in Children
There are no data on the use of Co-Perindopril® in children.
Related to Indapamide
Indapamide as monotherapy demonstrates an antihypertensive effect lasting 24 hours. This occurs at doses where the diuretic effect is mild.
Its antihypertensive action is proportional to improved arterial status and reduction in total and arteriolar peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
With increasing doses of thiazide and thiazide-like diuretics, the antihypertensive effect reaches a plateau while adverse effects continue to increase. If treatment is ineffective, the dose should not be increased.
Moreover, it has been demonstrated that short-, medium-, and long-term treatment of patients with arterial hypertension with indapamide does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins), nor does it affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes.
Pharmacokinetics.
Related to Co-Perindopril®
Concomitant administration of perindopril and indapamide does not alter their pharmacokinetic properties compared to administration of individual components.
Related to Perindopril
Absorption and Bioavailability
After oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, with maximum 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, thereby decreasing its bioavailability, perindopril tert-butylamine is recommended to be taken orally as a single daily dose in the morning before food.
Metabolism
Perindopril is a prodrug. 27% of the absorbed perindopril is converted into the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.
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.
Elimination
Perindoprilat is excreted in urine, and the half-life of the unbound fraction is approximately 17 hours, leading to steady-state levels within 4 days.
Linearity/Non-linearity
A linear relationship between perindopril dose and plasma concentration has been demonstrated.
Special Populations
Elderly Patients
In elderly individuals and patients with heart or kidney failure, elimination of perindoprilat is reduced.
Renal Impairment
In renal impairment, dosage adjustment is recommended depending on the degree of impairment (creatinine clearance).
Dialysis
Perindoprilat is removed from the circulation by dialysis, with a clearance rate of 70 mL/min.
Cirrhosis
In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent molecule reduced by half, but the amount of formed perindoprilat remains unchanged; therefore, the dose does not need to be adjusted in this condition.
Related to Indapamide
Absorption
Indapamide is rapidly and almost completely absorbed in the gastrointestinal tract.
Distribution
Maximum plasma concentration of indapamide is reached approximately 1 hour after administration. Plasma protein binding of indapamide is 79%.
Biotransformation and Elimination
The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Regular administration of the drug does not lead to accumulation of indapamide. 70% of indapamide is excreted primarily by the kidneys and 22% is excreted in feces as inactive metabolites.
Renal Impairment
Pharmacokinetic parameters of the drug remain unchanged in patients with renal impairment.
Clinical characteristics.
Indications.
Essential hypertension.
Contraindications.
Related to perindopril
- Hypersensitivity to the active substance or to any other component of the medicinal product, or to other ACE inhibitors.
- History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions for use").
- Hereditary or idiopathic angioedema.
- Concomitant administration with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
- Pregnancy or women planning pregnancy.
- Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). The medicinal product Co-Perensa® must not be used earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" 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 single functioning kidney (see section "Special precautions for use").
Related to indapamide
- Hypersensitivity to indapamide or to other sulfonamides.
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Hepatic encephalopathy or severe hepatic dysfunction.
- Hypokalemia.
Related to Co-Perensa®
Co-Perensa®, 2 mg/0.625 mg, 4 mg/1.25 mg and 8 mg/2.5 mg
- Hypersensitivity to any component of the medicinal product.
Due to insufficient therapeutic experience, Co-Perensa® should not be used in:
- Patients undergoing hemodialysis.
- Patients with untreated decompensated heart failure.
Co-Perensa®, 2 mg/0.625 mg, 4 mg/1.25 mg
- Severe renal impairment (creatinine clearance < 30 mL/min).
Co-Perensa®, 8 mg/2.5 mg
- Severe and moderate renal impairment (creatinine clearance < 60 mL/min).
Interaction with other medicinal products and other forms of interaction.
Common to perindopril and indapamide
Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentration and signs of lithium toxicity have been observed during concomitant use of lithium with ACE inhibitors. Concomitant use of perindopril with lithium is not recommended; however, if combination therapy is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").
Concomitant use requiring special monitoring
Baclodfen: enhanced antihypertensive effect. Monitoring of blood pressure and renal function is required; dose adjustment may be necessary.
Non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥3 g/day)
Administration of NSAIDs, particularly acetylsalicylic acid in anti-inflammatory doses, cyclooxygenase-2 inhibitors, and non-selective NSAIDs, may reduce the antihypertensive effect of ACE inhibitors. Additionally, NSAIDs and ACE inhibitors may jointly increase serum potassium levels, potentially leading to worsening renal function, including acute renal failure, especially in patients with pre-existing renal impairment. This combination should be used with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter.
Concomitant use requiring monitoring
Tricyclic antidepressants (imipramine-like), neuroleptics: enhanced hypotensive effect and increased risk of orthostatic hypotension (additive effect).
Related to perindopril
Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, 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 use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").
Medicinal products that may cause hyperkalemia
Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Co-Perensa®. Certain drugs or therapeutic classes may induce hyperkalemia, such as aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory agents, heparins, immunosuppressive agents such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Combination with these agents increases the risk of hyperkalemia. Therefore, concomitant use of Co-Perensa® with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.
Contraindicated combinations (see section "Contraindications")
Aliskiren
Concomitant use of perindopril and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment due to increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality (see section "Contraindications").
Extracorporeal treatments involving blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or 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 another class of antihypertensive agents.
Sacubitril/valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as the combination of ACE inhibitors and sacubitril/valsartan increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").
Concomitant use not recommended
Aliskiren
Concomitant use of perindopril and aliskiren is not recommended in all other patient groups, except those with diabetes mellitus or renal impairment, due to increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality (see section "Special precautions for use").
Concomitant therapy with ACE inhibitors and angiotensin receptor blockers
Published data report 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 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) may be considered only in individual cases with careful monitoring of renal function, potassium levels, and blood pressure.
Estramustine
Risk of increased incidence of adverse reactions such as angioedema.
Potassium-sparing diuretics (e.g., triamterene, amiloride…), potassium (salts)
Hyperkalemia (potentially fatal), especially when combined with renal impairment (additive hyperkalemic effect). Combination of perindopril with the above-mentioned agents is not recommended (see section "Special precautions for use"). However, if concomitant administration is necessary, it should be done with caution and careful monitoring of plasma potassium levels. For use of spironolactone in heart failure, see section "Concomitant use requiring special monitoring".
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Increased risk of hyperkalemia in patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly (see section "Special precautions for use").
Concomitant use requiring special monitoring
Antidiabetic agents (insulin, oral hypoglycemic agents)
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects, increasing the risk of hypoglycemia. This effect is more likely during the first weeks of combination therapy and in patients with renal impairment.
Diuretics not containing potassium
In patients taking diuretics, especially those with disturbed water-electrolyte balance, 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, or increasing salt intake before starting perindopril therapy. Treatment should begin with low doses and gradually increase.
In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (in such cases, 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, initiation of ACE inhibitor therapy should begin with the lowest dose, possibly after reducing the diuretic dose.
In any case, renal function (creatinine level) must be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone or spironolactone)
Concomitant use of eplerenone or spironolactone at doses of 12.5–50 mg daily with low-dose ACE inhibitors is indicated:
- In the treatment of 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 this combination, ensure absence of hyperkalemia and renal impairment.
Careful monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.
Racecadotril
ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk increases with concomitant use of racecadotril (a medicinal product used to treat acute diarrhea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
In patients receiving mTOR inhibitors concomitantly, the risk of angioedema is increased (see section "Special precautions for use").
Concomitant use requiring monitoring
Antihypertensive agents and vasodilators
Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may lead to additional reduction in blood pressure.
Allopurinol, cytostatics or immunosuppressants, systemic corticosteroids (systemic use), or procainamide: concomitant administration of these agents with ACE inhibitors may increase the risk of leukopenia (see section "Special precautions for use"). Anesthetics: ACE inhibitors may enhance the hypotensive effects of certain anesthetics (see section "Special precautions for use").
Gold preparations: rare reactions similar to those seen with nitrates (facial flushing, nausea, vomiting, and hypotension) may occur with concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate).
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)
Concomitant use with an ACE inhibitor increases the risk of angioedema due to reduced dipeptidyl peptidase-IV (DPP-IV) activity caused by gliptins.
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Cyclosporine
Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin
Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.
Related to indapamide
Concomitant use requiring special monitoring
Medicinal products causing torsades de pointes: due to the risk of hypokalemia, indapamide should be used with caution when co-administered with medicinal products that may cause torsades de pointes, such as, but not limited to: class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium); certain phenothiazine antipsychotics (e.g., chlorpromazine, zuclopenthixol, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (pimozide); and other substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine). Hypokalemia should be prevented and corrected if necessary; QT interval should be monitored.
Medicinal products that reduce potassium levels, amphotericin B (intravenous), systemic glucocorticoids and mineralocorticoids (systemic use), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Serum potassium levels should be checked and corrected if necessary; particular caution is required when using cardiac glycosides. Stimulant laxatives should not be used.
Cardiac glycosides: hypokalemia and/or hyponatremia enhance the toxic effect of cardiac glycosides. Monitoring of plasma potassium, magnesium, and ECG is recommended, and therapy should be reviewed if necessary.
Allopurinol: concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.
Concomitant use requiring monitoring
Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
Despite the rationale for using this combination in certain patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.
Metformin: in functional renal impairment associated with diuretic use, particularly loop diuretics, the risk of lactic acidosis with metformin use increases. Metformin should not be used 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 cases of dehydration associated with diuretic use, administration of iodinated contrast agents, especially at high doses, increases the risk of acute renal failure. Adequate hydration must be restored before administration of iodinated contrast agents.
Calcium salts: risk of hypercalcemia due to reduced renal excretion of calcium.
Cyclosporine, tacrolimus: risk of increased plasma creatinine concentration without changes in cyclosporine blood levels, even in the absence of fluid/salt volume depletion.
Corticosteroids, tetracosactide (systemic administration)
Reduced antihypertensive effect (salt and water retention due to corticosteroids).
Special precautions for use.
Use requiring special caution
Common to perindopril and indapamide
For the low-dose combination of Co-Prenes, tablets 2 mg/0.625 mg, no significant reduction in adverse reactions has been demonstrated compared to the lowest approved doses of the individual monocomponents, except for hypokalemia (see section "Special precautions for use"). Idiosyncratic reactions to new antihypertensive agents cannot be excluded. To minimize this risk, patient monitoring is required.
Lithium
Concomitant use of lithium and perindopril/indapamide combinations is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Related to perindopril
Dual blockade of the RAAS
Concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren has been associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure). Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) or aliskiren is not recommended.
However, in individual cases, it may be used under careful monitoring of renal function, potassium levels, and blood pressure.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have occurred in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and without other risk factors during ACE inhibitor therapy. Perindopril should be used with particular caution in patients with collagen vascular diseases or those receiving immunosuppressants, allopurinol, or procainamide, as well as in combination with some of these risk factors, especially in the presence of impaired renal function. Some patients developed severe infections, which in certain cases were unresponsive to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell count should be performed, and patients should be instructed to report any signs of infection, such as sore throat or fever (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").
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"). Diuretic therapy may be a contributing factor. Decreased renal function may be associated only with minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.
Hypersensitivity/angioedema
Angioedema of the face, lips, mucous membranes, tongue, pharynx, and/or larynx has occurred in some patients treated with ACE inhibitors, including perindopril (see section "Undesirable effects"). It may occur at any time during treatment. In such cases, perindopril must be discontinued immediately, and thorough evaluation should be performed until symptoms completely resolve. In cases of facial and lip swelling, the condition may improve without treatment, but antihistamines may relieve symptoms.
Laryngeal angioedema may be fatal. In cases of tongue, glottis, or laryngeal swelling, airway obstruction is possible. In such cases, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3–0.5 mL) and/or airway support.
ACE inhibitors cause angioedema more frequently in patients of African descent than in individuals of other races.
Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema when taking ACE inhibitors.
Rare cases of intestinal angioedema have been reported in patients taking ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); in some cases, intestinal angioedema occurred without prior facial angioedema, and C1-esterase inhibitor levels were normal. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography or ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to rule out intestinal angioedema.
Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (including airway or tongue swelling, 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 taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If 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 other NEP inhibitors (e.g., racecadotril) with ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, a careful benefit-risk assessment should be performed before initiating NEP inhibitors, such as racecadotril, in patients taking perindopril.
Anaphylactoid reactions during desensitization
In patients taking ACE inhibitors during desensitization procedures (e.g., to wasp or bee venom), isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported. ACE inhibitors should be used with caution in patients with allergies undergoing desensitization and avoided in those undergoing immunotherapy with venom. However, these reactions can be prevented by temporarily discontinuing ACE inhibitors for at least 24 hours before treatment in patients requiring both ACE inhibitors and desensitization.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be prevented by temporarily discontinuing ACE inhibitors before each apheresis session.
Patients undergoing hemodialysis
Anaphylactoid reactions have been observed in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69®) while receiving ACE inhibitor therapy. For such patients, consideration should be given to using alternative dialysis membranes or a different class of antihypertensive agents.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.
Potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes
Combination of potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes with perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Pregnancy
ACE inhibitor therapy should not be initiated during pregnancy. If continued antihypertensive therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately, and if necessary, alternative therapy with a medicinal product approved for use in pregnant women should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Related to indapamide
Hepatic encephalopathy
In patients with impaired liver function, thiazide and thiazide-like diuretics may precipitate hepatic encephalopathy, especially with electrolyte imbalances, which may progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.
Photosensitization
Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If diuretics must be reintroduced, protection of vulnerable areas from sunlight or artificial ultraviolet sources is recommended.
Use requiring caution
Common to perindopril and indapamide
Renal function impairment
Co-Prenes® is contraindicated in patients with moderate to severe renal impairment (creatinine clearance <30 mL/min).
If laboratory signs of renal impairment develop in patients with arterial hypertension without pre-existing signs of renal dysfunction during treatment, the drug should be discontinued, with possible resumption at a lower dose or with one of its components. Such patients require monitoring of potassium and creatinine levels two weeks after initiation of therapy and every two months during therapeutic stabilization. Cases of renal impairment occurred predominantly in patients with severe heart failure or pre-existing renal dysfunction, including those with renal artery stenosis.
The drug is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
Arterial hypotension and water and electrolyte deficiency
There is a risk of sudden drop in blood pressure in patients with existing sodium deficiency (especially in patients with renal artery stenosis). Therefore, symptoms of water and electrolyte deficiency, which may occur with vomiting or diarrhea, should be systematically checked. Such patients require regular monitoring of plasma electrolyte levels.
In cases of significant arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Temporary arterial hypotension does not contraindicate further use of the drug. After restoration of circulating blood volume and normalization of blood pressure, therapy may be resumed at a lower dose or with one of the components.
Potassium levels
The combination of perindopril and indapamide does not exclude the possibility of hypokalemia, especially in patients with diabetes mellitus or renal impairment. As with any diuretic-containing drug, regular monitoring of potassium levels is required.
Related to perindopril
Cough
A dry, non-productive, persistent cough may occur with ACE inhibitors, which resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. If ACE inhibitor therapy remains preferable, continuation of treatment may be considered.
Children
Safety and efficacy data for perindopril use in children and adolescents, either alone or in combination, are not established.
Risk of arterial hypotension and/or renal impairment (in heart failure, water and electrolyte imbalance)
Significant stimulation of the RAAS, especially with marked water and electrolyte imbalance (strict low-sodium diet or prolonged diuretic therapy), has been observed in patients with initially low blood pressure, renal artery stenosis, heart failure with congestion, or cirrhosis with edema and ascites.
Thus, blockade of this system by an ACE inhibitor may cause, particularly after the first dose and during the first two weeks of treatment, unexpected drop in blood pressure and/or increase in plasma creatinine levels, indicating functional renal impairment. Occasionally, this may present as an acute episode, although rarely, with varying duration.
In such cases, treatment should be initiated with a lower dose, gradually increasing it.
Elderly patients
Renal function and plasma potassium levels should be checked before initiating treatment. Initial dose should be adjusted according to blood pressure response, especially in cases of water and electrolyte imbalance, to avoid unexpected arterial hypotension.
Atherosclerosis
The risk of arterial hypotension exists in all patients, but particular attention should be paid to patients with ischemic heart disease or cerebral circulation insufficiency. Such patients should start treatment with a low dose.
Renovascular hypertension
Treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be acceptable for patients with renovascular hypertension awaiting surgical correction or when such surgery is not possible.
Use of Co-Prenes®, 8 mg/2.5 mg, is not recommended in patients with known or suspected renal artery stenosis, as treatment should be initiated in hospital with a dose lower than Co-Prenes, 8 mg/2.5 mg.
In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, ACE inhibitor use increases the risk of hypotension and renal impairment (see section "Contraindications"). Diuretic therapy may be a contributing factor. Loss of renal function may manifest only as minor changes in plasma creatinine levels, even in patients with stenosis of one renal artery.
If Co-Prenes® is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in hospital with a low dose, and renal function and potassium levels should be monitored, as functional renal impairment, reversible upon discontinuation of treatment, has occurred in some patients.
Heart failure/severe heart failure
In patients with severe heart failure (NYHA class IV), treatment should be initiated under medical supervision with a reduced initial dose; therefore, Co-Prenes®, 8 mg/2.5 mg, is not suitable as an initial dose. Beta-blockers should not be discontinued in hypersensitive patients with coronary insufficiency: an ACE inhibitor should be added to beta-blocker therapy.
Diabetic patients
In patients with insulin-dependent diabetes mellitus (with spontaneous tendency to increased potassium levels), treatment with Co-Prenes®, 8 mg/2.5 mg, is not advisable; therefore, treatment should be initiated under medical supervision with a reduced initial dose.
Patients with diabetes mellitus receiving oral antidiabetic agents or insulin require careful monitoring of blood glucose levels during the first months of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Racial origin
Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in hypertensive patients of African descent compared to individuals of other races, possibly due to low plasma renin levels in these patients.
Surgery/general anesthesia
ACE inhibitors may cause arterial hypotension during anesthesia, especially when the anesthetic agent has hypotensive potential.
Therefore, it is recommended that therapy with long-acting ACE inhibitors, such as perindopril, be discontinued, if possible, one day before surgery.
Stenosis of aortic or mitral valve/hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with aortic valve stenosis.
Hepatic impairment
ACE inhibitor therapy has occasionally been associated with a syndrome beginning as cholestatic jaundice progressing to fulminant hepatic necrosis and (sometimes) resulting in death. The mechanism of this syndrome is not established. If jaundice or significant increase in liver enzyme activity occurs, ACE inhibitor use should be discontinued, and medical monitoring and treatment should be initiated (see section "Undesirable effects").
Hyperkalemia
ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. In patients with normal liver function, the hyperglycemic effect is not increased.
Risk factors for hyperkalemia include renal impairment or reduced renal function, age (>70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium concentration (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, especially aldosterone antagonists or angiotensin receptor blockers, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus). Use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients taking ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and undergo careful monitoring of serum potassium levels and renal function (see section "Interaction with other medicinal products and other forms of interaction").
Related to indapamide
Water and electrolyte balance
Plasma sodium levels
Plasma sodium concentration should be determined before starting treatment and at regular intervals during treatment. Since decreased plasma sodium concentration may initially be asymptomatic, regular monitoring is required. In elderly patients and patients with liver cirrhosis, plasma sodium concentration should be measured more frequently (see sections "Overdose" and "Undesirable effects").
Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may cause dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the frequency and extent of this effect are minor.
Plasma potassium levels
The main risk of thiazide and thiazide-like diuretic therapy is decreased potassium concentration and hypokalemia. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly in combination with severe hypoglycemia. In patients with poor nutrition and/or taking multiple medications, elderly patients, patients with liver cirrhosis and ascites, ischemic heart disease, and heart failure, hypokalemia (< 3.4 mmol/L) should be prevented.
In such patients, hypokalemia increases the cardiotoxicity of digitalis drugs and the risk of arrhythmias.
Patients with prolonged QT interval are also at risk, whether due to hereditary or iatrogenic causes. Hypokalemia (and bradycardia) is thus a factor predisposing to dangerous arrhythmias, including polymorphic ventricular tachycardia of the torsades de pointes type, sometimes with fatal outcome.
In all cases, such patients require more frequent monitoring of plasma potassium levels. The first measurement of plasma potassium concentration should be performed within the first week after starting treatment.
If low potassium levels are detected, dose adjustment should be performed. Hypokalemia associated with low serum magnesium concentration may be resistant to treatment unless serum magnesium levels are corrected.
Magnesium levels
Thiazide and thiazide-like diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").
Calcium levels
Thiazide and related diuretics may reduce urinary calcium excretion and cause slight transient increase in plasma calcium concentration. Persistent hypercalcemia may indicate hyperparathyroidism. Therefore, diuretic therapy should be discontinued until parathyroid function is evaluated.
Blood glucose
In patients with diabetes mellitus, blood glucose levels should be carefully monitored, especially in cases of hypokalemia.
Uric acid
In patients with hyperuricemia, a tendency to gout attacks may be observed.
Renal function and diuretics
Thiazide and related diuretics are more effective with normal or mildly impaired renal function (plasma creatinine level in adults < 25 mg/L or 220 µmol/L).
In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and sex using the Cockcroft formula:
creatinine clearance = (140 – age) × body weight / 0.814 × plasma creatinine level;
where: age in years; body weight in kilograms; plasma creatinine level in µmol/L.
This formula is suitable for elderly men and should be adapted for women by multiplying the result by 0.85.
Hypovolemia occurring at the beginning of treatment due to water and sodium loss from diuretic use may cause decreased glomerular filtration. This may lead to increased blood urea and creatinine levels. In patients with normal renal function, this transient functional renal impairment resolves without consequences, but in patients with pre-existing renal impairment, it may worsen.
Athletes
Athletes should be aware that the drug contains an active substance (indapamide) that may cause a positive doping test.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Sulfonamide or sulfonamide-derived drugs 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 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. Primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, rapid medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Excipients
The drug contains lactose and should not be administered to patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
The drug contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
The drug is contraindicated in pregnant women or women planning pregnancy.
Special precautions related to perindopril
ACE inhibitor use is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). ACE inhibitor use is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").
There is no convincing epidemiological evidence of teratogenic risk with ACE inhibitor use during the first trimester of pregnancy, but a small increase in this risk cannot be excluded. If continued antihypertensive therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women.
It is known that ACE inhibitor use during the second and third trimesters of pregnancy has toxic effects on the embryo (impaired renal function, oligohydramnios, delayed skull bone formation) and on the newborn (renal failure, arterial hypotension, hyperkalemia).
If ACE inhibitor use occurred during the second and third trimesters, ultrasound evaluation of renal function and skull structure of the newborn is recommended.
Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension.
Special precautions related to indapamide
Data on indapamide use during pregnancy (less than 300 pregnancy cases) are limited. Prolonged use of a thiazide diuretic during the third trimester may reduce circulating blood volume and uteroplacental perfusion in the pregnant woman, potentially causing fetoplacental ischemia and fetal growth retardation. Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity.
As a precautionary measure, indapamide use during pregnancy should be avoided.
Period of breastfeeding
Co-Prenes is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of therapy for the mother.
Special precautions related to perindopril
Perindopril use during breastfeeding is not recommended due to lack of data in this patient group. Alternative therapy with a proven safety profile should be preferred, especially during breastfeeding of a newborn or premature infant.
Special precautions related to indapamide
Insufficient data are available on the passage of indapamide/metabolites into human milk. Increased sensitivity to sulfonamide-derived drugs and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide diuretics, which during breastfeeding suppress milk secretion.
Indapamide is not recommended during breastfeeding.
Fertility
Reproductive toxicity studies did not show effects on fertility in male and female rats. The effect on human fertility is unknown.
Ability to affect reaction speed when driving or operating machinery.
The two active substances, when used separately or in combination as Co-Prenes®, do not affect the ability to drive or operate machinery, but individual reactions related to decreased blood pressure may occur in some patients, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive or operate machinery may be impaired.
Method of Administration and Dosage
For oral use.
Co-Preneza®, 2 mg/0.625 mg
The usual dose is 1 tablet of Co-Preneza®, 2 mg/0.625 mg, once daily, preferably taken in the morning before meals. If blood pressure is not adequately controlled after one month of treatment, the dose may be doubled.
Co-Preneza®, 4 mg/1.25 mg
Co-Preneza®, 4 mg/1.25 mg tablets are indicated for patients in whom blood pressure is not adequately controlled with perindopril monotherapy.
The usual dose is 1 tablet of Co-Preneza®, 4 mg/1.25 mg, once daily, preferably taken in the morning before meals.
Whenever possible, individual dose titration with the individual components is recommended. Co-Preneza®, 4 mg/1.25 mg tablets should be prescribed when blood pressure is not adequately controlled with Co-Preneza®, 2 mg/0.625 mg tablets (when feasible).
In the presence of clinical indications, a direct switch from perindopril monotherapy to Co-Preneza®, 4 mg/1.25 mg tablets may be considered.
Co-Preneza®, 8 mg/2.5 mg
Co-Preneza®, 8 mg/2.5 mg tablets are indicated for the treatment of arterial hypertension as a replacement in patients already receiving perindopril and indapamide separately in the same doses.
The usual dose is 1 tablet of Co-Preneza®, 8 mg/2.5 mg, once daily, preferably taken in the morning before meals.
The maximum daily dose is 1 tablet of Co-Preneza®, 8 mg/2.5 mg.
Special Populations
Elderly Patients (see section "Special Instructions")
Co-Preneza®, 2 mg/0.625 mg
Treatment should be initiated at the usual dose of 1 tablet of Co-Preneza®, 2 mg/0.625 mg, once daily.
Co-Preneza®, 4 mg/1.25 mg
Treatment should be initiated according to the response of blood pressure and renal function.
Co-Preneza®, 8 mg/2.5 mg
In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and gender. If renal function is normal, elderly patients may be treated according to blood pressure response.
Renal Impairment
Co-Preneza®, 2 mg/0.625 mg, 4 mg/1.25 mg
The use of this medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated with appropriate doses of the individual components of the medicinal product. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.
Co-Preneza® 8 mg/2.5 mg
The use of this medicinal product is contraindicated in patients with severe hepatic impairment (creatinine clearance < 30 mL/min). Patients with moderate hepatic impairment do not require dose adjustment.
Hepatic Impairment
The use of this medicinal product is contraindicated in patients with severe hepatic impairment.
Dose adjustment is not required in patients with moderate hepatic impairment.
Children
This medicinal product is not recommended for use in children due to insufficient data on safety and efficacy in this patient group.
Overdose
Symptoms that may occur include: arterial hypotension, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria up to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, and cough may also occur.
Treatment. Emergency measures include rapid elimination of the drug from the body—gastric lavage and/or administration of activated charcoal—followed by correction of fluid and electrolyte imbalances under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with low head elevation. Recommended treatment includes intravenous administration of 0.9% sodium chloride solution or any other method of volemic expansion. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special Instructions").
Adverse Reactions
Summary of Safety Profile
Perindopril therapy suppresses the RAAS and tends to reduce potassium losses induced by indapamide.
Hypokalemia (potassium level <3.4 mmol/L) was observed in 2% of patients treated with Co-Perindopril tablets 2 mg/0.625 mg.
Hypokalemia (potassium level <3.4 mmol/L) was observed in 4% of patients treated with Co-Perindopril tablets 4 mg/1.25 mg.
Hypokalemia (potassium level <3.4 mmol/L) was observed in 6% of patients treated with Co-Perindopril tablets 8 mg/2.5 mg.
The most commonly observed adverse reactions are:
- With perindopril: dizziness, headache, paresthesia, dysgeusia, visual disturbance, vertigo, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia;
- With indapamide: hypokalemia, hypersensitivity reactions, predominantly dermatological, in patients predisposed to allergic and asthmatic reactions, and maculopapular eruptions.
List of Adverse Reactions
The adverse effects that may occur during treatment are classified according to the following frequency:
Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).
| Body system |
Adverse reactions |
Frequency |
||
| Perindopril |
Indapamide |
|||
| Infections and infestations |
Rhinitis |
Very rare |
- |
|
| Blood and lymphatic system disorders |
Eosinophilia |
Unknown1) |
- |
|
| Agranulocytosis2) |
Very rare |
Very rare |
||
| Aplastic anemia |
- |
Very rare |
||
| Pancytopenia |
Very rare |
- |
||
| Leukopenia |
Very rare |
Very rare |
||
| Neutropenia2) |
Very rare |
- |
||
| Hemolytic anemia |
Very rare |
Very rare |
||
| Thrombocytopenia2) |
Very rare |
Very rare |
||
| Immune system disorders |
Hypersensitivity reactions (mainly dermatological, in patients predisposed to allergic and asthmatic reactions and maculopapular rashes) |
- |
Common |
|
| Endocrine disorders |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
Uncommon |
- |
|
| Metabolism and nutrition disorders |
Hypoglycemia3) |
Uncommon1) |
- |
|
| Hyperkalemia, reversible upon discontinuation2) |
Uncommon1) |
- |
||
| Hyponatremia2) |
Uncommon1) |
Uncommon |
||
| Hypercalcemia |
- |
Very rare |
||
| Hypokalemia2) |
- |
Common |
||
| Hypochloremia |
- |
Uncommon |
||
| Hypomagnesemia |
- |
Uncommon |
||
| Psychiatric disorders |
Mood disorders |
Uncommon |
- |
|
| Sleep disorders |
Uncommon |
- |
||
| Depression |
Uncommon |
- |
||
| Confusion |
Very rare |
- |
||
| Nervous system disorders |
Dizziness |
Common |
- |
|
| Headache |
Common |
Uncommon |
||
| Paresthesia |
Common |
Uncommon |
||
| Disturbance of taste |
Common |
- |
||
| Somnolence |
Uncommon1) |
- |
||
| Syncope |
Uncommon1) |
Unknown |
||
| Stroke, possibly secondary to excessive hypotension in patients at high risk2) |
Very rare |
- |
||
| Development of hepatic encephalopathy in case of liver insufficiency2) |
- |
Unknown |
||
| Eye disorders |
Visual disturbance |
Common |
Unknown |
|
| Myopia2) |
- |
Unknown |
||
| Blurred vision |
- |
Unknown |
||
| Acute angle-closure glaucoma |
- |
Unknown |
||
| Choroidal effusion |
- |
Unknown |
||
| Ear and labyrinth disorders |
Vertigo |
Common |
Uncommon |
|
| Tinnitus |
Common |
- |
||
| Cardiac disorders |
Pounding heartbeat |
Uncommon1) |
- |
|
| Tachycardia |
Uncommon1) |
- |
||
| Angina pectoris2) |
Very rare |
- |
||
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Very rare |
Very rare |
||
| Myocardial infarction, possibly after excessive hypotension in patients at high risk2) |
Very rare |
- |
||
| Paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) 3) |
Unknown |
|||
| Vascular disorders |
Arterial hypotension (and symptoms related to hypotension)2) |
Common |
Very rare |
|
| Vasculitis |
Uncommon1) |
- |
||
| Flushing |
Uncommon |
- |
||
| Raynaud's phenomenon |
Unknown |
- |
||
| Respiratory, thoracic and mediastinal disorders |
Cough2) |
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 |
Hepatitis2) |
Very rare |
Unknown |
|
| Liver function disorders |
- |
Very rare |
||
| Skin and subcutaneous tissue disorders |
Pruritus |
Common |
- |
|
| Rash |
Common |
- |
||
| Maculopapular rash |
- |
Common |
||
| Urticaria2) |
Uncommon |
Very rare |
||
| Angioedema2) |
Uncommon |
Very rare |
||
| Purpura |
- |
Uncommon |
||
| Hyperhidrosis |
Uncommon1) |
- |
||
| Photosensitivity reaction |
Uncommon1) |
Unknown |
||
| Pemphigoid |
Uncommon |
- |
||
| Worsening of psoriasis symptoms |
Uncommon1) |
- |
||
| Multiform erythema |
Very rare |
- |
||
| Toxic epidermal necrolysis |
- |
Very rare |
||
| Stevens-Johnson syndrome |
- |
Very rare |
||
| Musculoskeletal and connective tissue disorders |
Leg cramps |
Common |
- |
|
| Exacerbation of pre-existing systemic lupus erythematosus |
- |
Unknown |
||
| Arthralgia |
Uncommon1) |
- |
||
| Myalgia |
Uncommon1) |
- |
||
| Muscle weakness |
- |
Unknown |
||
| Rhabdomyolysis |
- |
Unknown |
||
| Renal and urinary disorders |
Renal impairment |
Uncommon |
- |
|
| Acute renal failure |
Uncommon |
Very rare |
||
| Anuria/oliguria |
Uncommon |
- |
||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
|
| General disorders and administration site conditions |
Asthenia |
Common |
- |
|
| Chest pain |
Uncommon1) |
- |
||
| Malaise |
Uncommon1) |
- |
||
| Peripheral edema |
Uncommon1) |
- |
||
| Pyrexia |
Uncommon1) |
- |
||
| Fatigue |
- |
Uncommon |
||
| Investigations |
Increase in plasma urea levels |
Uncommon1) |
- |
|
| Increase in plasma creatinine levels |
Uncommon1) |
- |
||
| Increase in plasma bilirubin levels |
Uncommon |
- |
||
| Increase in liver enzymes |
Uncommon |
Unknown |
||
| Decrease in hemoglobin levels and red blood cell count2) |
Very rare |
- |
||
| Increase in plasma glucose levels |
- |
Unknown |
||
| Increase in plasma uric acid levels |
- |
Unknown |
||
| QT interval prolongation on ECG3) |
- |
Unknown |
||
| Injury, poisoning and procedural complications |
Falls |
Uncommon1) |
- |
|
- The frequency of adverse reactions is based on spontaneous reports during clinical trials.
- See section "Special precautions for use".
- See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
Description of selected adverse reactions
During phase II and III studies comparing 1.5 mg and 2.5 mg of indapamide, plasma potassium analysis revealed a dose-dependent effect of indapamide:
Indapamide 1.5 mg: plasma potassium level < 3.4 mmol/L was 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 average decrease in plasma potassium level was 0.23 mmol/L.
Indapamide 2.5 mg: plasma potassium level < 3.4 mmol/L was 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 average decrease in plasma potassium level was 0.41 mmol/L.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua/.
Shelf life. 3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture.
Keep out of reach and sight of children.
Packaging.
10 tablets in a blister; 3, 6, or 9 blisters in a cardboard box.
15 tablets in a blister; 2, 4, or 6 blisters in a cardboard box.
Prescription category. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.