Perindopril-darnitsa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERINDOPRIL-DARNYTSIA (Perindopril-Darnytsia)
Composition:
Active substance: perindopril;
One tablet contains 4 mg or 8 mg of perindopril tert-butylamine, equivalent to 3.338 mg or 6.676 mg of perindopril;
Excipients: lactose monohydrate; microcrystalline cellulose; colloidal silicon dioxide (hydrophobic); magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: white or almost white tablets, flat cylindrical in shape, bevelled with a break line and a score.
Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, single-component. Perindopril. ATC code C09AA04.
Pharmacological Properties
Pharmacodynamics
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE). The converting enzyme, or kininase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictive angiotensin II, and also causes the breakdown of the vasodilator bradykinin into inactive heptapeptide. Inhibition of ACE leads to a decrease in angiotensin II concentration in plasma, resulting in increased plasma renin activity (via feedback mechanism) and reduced aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also leads to increased activity of circulating and local kallikrein-kinin system (and thus also leads to activation of the prostaglandin system). This mechanism of action underlies the blood pressure-lowering effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).
Perindopril tert-butylamine acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.
Arterial Hypertension
Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension—mild, moderate, and severe. Reduction in systolic and diastolic blood pressure is observed in patients both in the supine and standing positions.
Perindopril reduces peripheral vascular resistance, leading to a decrease in arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate.
Renal blood flow usually increases, while glomerular filtration rate (GFR) remains largely unchanged.
The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (minimum effect / maximum effect over 24 hours) of perindopril ranges from 87% to 100%.
Arterial blood pressure decreases rapidly. In patients who respond to the drug, normalization of blood pressure occurs within one month and is maintained without tachyphylaxis.
Upon discontinuation of perindopril, there is no rebound effect.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.
Combination therapy with a thiazide diuretic produces an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.
Heart Failure
Perindopril tert-butylamine reduces cardiac workload by decreasing preload and afterload.
Studies involving patients with heart failure have demonstrated:
- reduction in filling pressures of the right and left ventricles;
- decreased systemic peripheral resistance;
- increased cardiac index and improved cardiac output;
- increased regional myocardial blood flow.
In comparative studies, initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared to placebo.
Clinical Efficacy and Safety
Patients with Stable IHD
An international, multicenter, randomized, double-blind, placebo-controlled clinical trial, EUROPA, lasting 4 years, has been reported. The study included patients with confirmed ischemic heart disease (IHD) and without clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients received perindopril as an addition to standard therapy with antiplatelet agents, lipid-lowering drugs, and β-blockers.
The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and/or cardiac arrest followed by successful resuscitation. Treatment with perindopril 8 mg once daily was reported to result in an absolute reduction in the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6]; p < 0.001). In patients with a history of myocardial infarction and/or revascularization, an absolute reduction in the primary endpoint of 2.2% was observed, corresponding to a relative risk reduction of 22.4% (95% CI [12.0; 31.6]; p < 0.001) compared to placebo.
Use in Children
Safety and efficacy of perindopril in children and adolescents (under 18 years of age) have not been established.
An open-label clinical study involving 62 children aged 2 to 15 years, who received perindopril at a mean dose of 0.07 mg/kg with glomerular filtration rate >30 mL/min/1.73 m², has been reported. The dose was individually adjusted and increased up to a maximum of 0.135 mg/kg/day depending on patient status and blood pressure response. The mean duration of the study was 44 months. Systolic and diastolic blood pressure remained stable in patients previously treated with other antihypertensive agents and decreased in those not previously treated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children was consistent with the known safety profile of perindopril.
Pharmacokinetics
Absorption
After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The half-life of perindopril in plasma is 1 hour.
Perindopril is a prodrug. 27% of the total administered perindopril is detected in blood as the active metabolite—perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak plasma concentration of perindoprilat is reached 3–4 hours after drug administration.
Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril tert-butylamine is recommended to be taken once daily in the morning before a meal.
A linear relationship between perindopril dose and plasma concentration is observed.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, primarily to ACE, but this value is dose-dependent.
Elimination
Perindoprilat is excreted in urine. The terminal half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of starting treatment.
Special Patient Groups
Elimination of perindoprilat is slowed in elderly patients, as well as in patients with heart or renal failure. Dose adjustment is recommended for patients with renal impairment based on the degree of impairment (creatinine clearance).
Dialysis clearance of perindoprilat – 70 mL/min
Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required in these patients.
Clinical characteristics
Indications
Perindopril-Darnitsia medicinal product is indicated:
- for treatment:
- of arterial hypertension;
- of heart failure;
- for prevention:
- of recurrent stroke in patients with cerebrovascular disease;
- of cardiovascular complications in patients with documented stable ischemic heart disease.
Long-term treatment reduces the risk of myocardial infarction and heart failure (based on EUROPA study results).
Contraindications
- Hypersensitivity to the active substance or to any of the excipients of the medicinal product, or to any other angiotensin-converting enzyme (ACE) inhibitor;
- history of angioedema after taking an ACE inhibitor;
- idiopathic or hereditary angioedema;
- concomitant administration with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (GFR < 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 planned pregnancy (see section "Use during pregnancy or breastfeeding");
- concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use");
- 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");
- paediatric population.
Interaction with other medicinal products and other forms of interaction
Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to use of a single agent affecting the RAAS.
Medicinal products causing hyperkalaemia
Certain medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalaemia. Therefore, concomitant use of Perindopril-Darnitsia with the above-mentioned agents is not recommended. If concomitant use is necessary, they should be used with caution and serum potassium levels should be monitored frequently.
Contraindicated combinations
Concomitant use of perindopril with aliskiren is contraindicated in patients with diabetes mellitus and in patients with renal impairment due to increased risk of hyperkalaemia, renal dysfunction, cardiovascular morbidity, and mortality (see section "Contraindications"). It is not recommended in all other patient groups (see section "Special precautions for use").
In case of extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as high-flux dialysis or haemofiltration membranes (e.g. polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulfate, the risk of severe anaphylactoid reactions is increased (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-Darnitsia. Treatment with Perindopril-Darnitsia 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
Concomitant use of ACE inhibitors and angiotensin receptor blockers. Clinical data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of hypotension, syncope, hyperkalaemia, and renal dysfunction (including acute renal failure) compared to monotherapy with RAAS-affecting agents. Dual blockade (i.e. combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered in individual cases under strict monitoring of renal function, potassium levels, and blood pressure.
Estramustine. Increased risk of adverse reactions such as angioedema.
Co-trimoxazole (trimethoprim/sulfamethoxazole). Increased risk of hyperkalaemia in patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) (see section "Special precautions for use").
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts. Hyperkalaemia (including fatal cases) may occur, particularly in patients with renal impairment (additive hyperkalaemic effect). These medicinal products are not recommended for concomitant use with Perindopril-Darnitsia (see section "Special precautions for use"). However, if concomitant use is necessary, they should be used with caution and plasma potassium levels should be closely monitored.
Lithium. Concomitant use of ACE inhibitors with lithium preparations may lead to reversible increases in plasma lithium concentrations and, consequently, an increased risk of lithium toxicity. Concomitant use of Perindopril-Darnitsia with lithium preparations is not recommended. If such combination is necessary, plasma lithium levels must be closely monitored (see section "Special precautions for use").
Concomitant use requiring special attention
Antidiabetic agents (insulin, oral hypoglycaemic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and hypoglycaemic agents (insulin, oral hypoglycaemic agents) may enhance the hypoglycaemic effect, increasing the risk of hypoglycaemia. This phenomenon is most likely to occur during the first weeks of combination therapy and in patients with renal impairment.
Baclofen. Enhanced antihypertensive effect. Blood pressure should be monitored and antihypertensive dosage adjusted if necessary.
Diuretics. In patients receiving diuretics, especially those with impaired water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effect can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake prior to starting Perindopril-Darnitsia. Treatment should be initiated with low doses and gradually increased.
In arterial hypertension, if a diuretic has previously been prescribed and may have caused fluid/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later), or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.
In chronic heart failure on background of diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors, the following should be considered:
- Risk of hyperkalaemia (possibly fatal) exists if recommendations for use of this combination are not followed, particularly in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic.
- Before initiating this combination, absence of hyperkalaemia and renal impairment should be confirmed.
- Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.
NSAIDs, including acetylsalicylic acid ≥ 3 g/day. Concomitant use of ACE inhibitors with NSAIDs such as acetylsalicylic acid (at anti-inflammatory doses), COX-2 inhibitors, or non-selective NSAIDs may reduce the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of renal dysfunction, including acute renal failure, and elevate plasma potassium levels, particularly in patients with a history of renal impairment. This combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored immediately after initiation and periodically thereafter.
Racecadotril. ACE inhibitors (e.g. perindopril) may cause angioedema. This risk increases when used concomitantly with racecadotril (a medicinal product used for treatment of acute diarrhoea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus). Increased risk of angioedema in patients receiving concomitant mTOR inhibitors (see section "Special precautions for use").
Concomitant use requiring some attention
Antihypertensive agents and vasodilators. Concomitant use of antihypertensive agents may enhance the hypotensive effect of Perindopril-Darnitsia. Concomitant use with nitrates (e.g. nitroglycerin) or other vasodilators may lead to additional blood pressure reduction.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). In patients receiving a combination of a gliptin and an ACE inhibitor, there may be an increased risk of angioedema due to the gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV).
Concomitant use of certain anaesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
Gold preparations. Nitrate-like reactions (symptoms: facial flushing, nausea, vomiting, and hypotension) are rarely observed in patients receiving ACE inhibitors, including perindopril, concomitantly with injectable gold preparations (sodium aurothiomalate).
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates. Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, beta-blockers, and/or nitrates.
Special precautions for use
Stable ischemic heart disease
If an episode of unstable angina (of any severity) occurred during the first month of treatment with Perindopril-Darnitsya, carefully weigh the risk/benefit ratio before deciding on continuing therapy.
Arterial hypotension
ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less common in patients with uncomplicated hypertension and is more likely to occur in patients with hypovolemia, those receiving diuretics, those on a low-salt diet, patients undergoing dialysis, patients with diarrhea or vomiting, or patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic arterial hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have a history of hyponatremia, or have functional renal impairment. To reduce the risk of symptomatic arterial hypotension, patients should be under close medical supervision during initiation of therapy and dose titration (see sections "Dosage and administration" and "Side effects"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.
In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication for further use of the medicinal product, which can usually be continued without difficulty after restoration of blood volume and increase in blood pressure.
In some patients with congestive heart failure and normal or low blood pressure, Perindopril-Darnitsya may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may be necessary.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
Like other ACE inhibitors, Perindopril-Darnitsya should be administered with caution to patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).
Renal impairment
In case of renal impairment (creatinine clearance < 60 mL/min), the initial dose of Perindopril-Darnitsya should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently adjusted depending on the patient's response to treatment. Monitoring of potassium and creatinine levels is standard practice for such patients (see section "Side effects").
In patients with symptomatic heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration in renal function, in some cases resulting in acute renal failure, which is usually reversible.
In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with ACE inhibitors has been associated with increases in blood urea and serum creatinine levels, which usually return to normal after discontinuation of treatment. This is particularly relevant in patients with renal impairment. The risk of severe arterial hypotension and renal failure is increased in patients with concomitant renovascular hypertension. Treatment of such patients should be initiated under close medical supervision, starting with low doses and cautious dose titration.
Due to these precautions, diuretic therapy may lead to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril tert-butylamine.
In some patients with arterial hypertension who had no evidence of renovascular disease before treatment initiation, administration of perindopril, particularly in combination with diuretics, may cause increases in blood urea and serum creatinine, which are usually mild and transient. The likelihood of such adverse reactions is higher in patients with impaired renal function. In such cases, dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may be necessary.
Patients undergoing hemodialysis
Anaphylactoid reactions have occurred in patients undergoing hemodialysis with high-flux polyacrylonitrile membranes while receiving concomitant ACE inhibitor therapy. Therefore, for such patients, it is necessary to consider using a different type of dialysis membrane or a different class of antihypertensive medicinal products.
Patients after kidney transplantation
Experience with the use of Perindopril-Darnitsya in patients after recent kidney transplantation surgery is lacking.
Renovascular hypertension
In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). The use of diuretics may be a contributing factor. Impaired renal function may be accompanied by 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, mucous membranes, tongue, glottis, and/or larynx have been reported in patients during treatment with ACE inhibitors, including perindopril tert-butylamine (see section "Side effects"). This may occur at any time during treatment. In such cases, the medicinal product must be discontinued immediately and appropriate monitoring of the patient should be instituted until symptoms completely resolve. In isolated cases where swelling is limited to the face and lips, the condition usually improves without treatment. Administration of antihistamine medicinal products may be helpful in reducing symptoms.
Angioedema involving laryngeal edema may be fatal. If swelling involves the tongue, glottis, or larynx, causing airway obstruction, emergency treatment must be initiated immediately, including possible administration of adrenaline and/or securing airway patency. Patients should remain under close medical supervision until symptoms have completely resolved and the condition is stabilized.
Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").
Rare cases of intestinal angioedema have been reported in patients during treatment with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or 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 confirmed by abdominal computed tomography, ultrasound, or surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema must be excluded in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors.
Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
In patients receiving concomitant mTOR inhibitors, there may be an increased risk of developing angioedema (including airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of other neutral endopeptidase (NEP) inhibitors, such as racecadotril, and ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, before initiating NEP inhibitor therapy (e.g., racecadotril) in patients receiving perindopril, a careful benefit/risk assessment should be performed.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.
Anaphylactoid reactions during desensitization therapy
Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing preparations. These reactions can be avoided by temporarily discontinuing the ACE inhibitor, but may recur if provocation tests are performed carelessly.
Hepatic impairment
Rare cases of a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis (sometimes fatal) have been reported during ACE inhibitor therapy. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes during ACE inhibitor therapy should discontinue the drug, undergo appropriate medical evaluation, and receive treatment (see section "Side effects").
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagenosis, during immunosuppressive therapy, with allopurinol or procainamide, or in combination of these risk factors, especially in the presence of impaired renal function. Serious infections, occasionally unresponsive to intensive antibiotic therapy, may develop in such patients. If perindopril is prescribed to such patients, periodic monitoring of white blood cell counts is recommended; patients should also be informed to report any signs of infection (sore throat, fever).
Racial characteristics
ACE inhibitors are more frequently associated with angioedema in black patients than in patients of other races. Like other ACE inhibitors, perindopril is less effective in reducing blood pressure in black patients compared to patients of other races, possibly due to lower plasma renin levels in black patients with hypertension.
Cough
Cough has been reported during therapy with ACE inhibitors.
The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. Cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.
Surgery / anesthesia
The medicinal product may block the secondary formation of angiotensin II in response to compensatory renin release in patients undergoing surgery or during anesthesia with hypotensive agents. The medicinal product should be discontinued one day before surgery. If arterial hypotension occurs and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.
Hyperkalemia
Increased serum potassium concentration has been observed in some patients during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal impairment, impaired renal function, advanced 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, potassium-containing salt substitutes, or other medicinal products that increase serum potassium concentration (e.g., heparin). Concomitant 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 serum potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of these agents is considered necessary, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").
Patients with diabetes mellitus
Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").
Lithium
Concomitant use of lithium and perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Potassium-sparing medicinal products, potassium-containing dietary supplements, or potassium-containing salt substitutes
Concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Dual blockade of the RAAS
Reports exist of arterial hypotension, syncope, stroke, hyperkalemia, and renal impairment (including acute renal failure), particularly with concomitant use of medicinal products affecting the RAAS. Combination of an ACE inhibitor with an angiotensin II receptor blocker (ARB) or with aliskiren, due to dual blockade of the RAAS, is not recommended.
Concomitant use with aliskiren is contraindicated in patients with diabetes mellitus and in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
If dual blockade of the RAAS with two RAAS blockers is considered absolutely necessary, it may only be performed under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents acting via inhibition of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.
Important information on excipients
This medicinal product contains 59.0 mg/118.0 mg monohydrate lactose. It should not be administered to patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency. Use with caution in patients with diabetes mellitus.
Use during pregnancy or breastfeeding
Pregnancy. Use of ACE inhibitors is contraindicated during pregnancy (see section "Contraindications"). The medicinal product must not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment, the medicinal product must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.
Epidemiological data on the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; therefore, a small increase in risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
If a woman took an ACE inhibitor during the second trimester of pregnancy, the infant should undergo ultrasound assessment of renal and skull bone function. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for possible arterial hypotension.
Period of breastfeeding. Use of perindopril tert-butylamine during breastfeeding is not recommended due to lack of data on its passage into breast milk. During breastfeeding, it is advisable to prescribe an alternative treatment with a better-investigated safety profile, especially during breastfeeding of a newborn or premature infant.
Fertility. No effect on reproductive capacity or fertility has been observed.
Ability to influence reaction speed when driving or operating machinery
Perindopril tert-butylamine does not have a direct effect on the ability to drive or operate machinery. However, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or during concomitant use with other antihypertensive medicinal products. As a result, the ability to drive or operate machinery may be reduced.
Method of Administration and Dosage
For oral use.
Perindopril-Darnitsia tablets of 4 mg and 8 mg may be divided in half to achieve doses of 2 mg and 4 mg, respectively.
The tablets are recommended to be taken once daily in the morning before meals.
Dosage should be individually adjusted depending on blood pressure levels (see section "Special Instructions").
Arterial Hypertension
Perindopril tert-butylamine may be prescribed as monotherapy or in combination with antihypertensive drugs of other classes.
The recommended initial dose is 4 mg once daily in the morning.
In patients with high activity of the renin-angiotensin-aldosterone system (RAAS) (particularly patients with renovascular hypertension, fluid and electrolyte imbalance, cardiac decompensation, or severe hypertension), excessive reduction in blood pressure may occur after the first dose. Such patients should start treatment with a dose of 2 mg under medical supervision.
The dose may be increased to 8 mg once daily after one month of treatment.
Symptomatic arterial hypotension may occur at the beginning of perindopril tert-butylamine therapy; this is more likely in patients concurrently taking diuretics. Treatment with perindopril should be initiated cautiously in such patients, as they may have a deficit of water and/or salt.
If possible, diuretic therapy should be discontinued 2–3 days before starting treatment with perindopril tert-butylamine (see section "Special Instructions").
In hypertensive patients in whom discontinuation of diuretics is not feasible, treatment should be initiated with a dose of 2 mg. Renal function and serum potassium levels should be monitored in these patients. Further dose escalation of perindopril tert-butylamine should be based on blood pressure response. If necessary, diuretic therapy may be resumed.
In elderly patients, treatment should be initiated with a dose of 2 mg, which may be increased to 4 mg after one month of treatment, and subsequently, if necessary, to 8 mg, depending on renal function (see Table 1).
Heart Failure
In patients with heart failure, perindopril tert-butylamine is usually prescribed concomitantly with a potassium-wasting diuretic and/or digoxin and/or a β-blocker. Treatment should be initiated under close medical supervision with an initial dose of 2 mg taken in the morning. After 2 weeks, if well tolerated, the dose should be increased to 4 mg once daily. The dose should be individually adjusted according to the patient's clinical status.
Patients with severe heart failure and other high-risk patients (those with impaired renal function and predisposition to electrolyte disturbances, or those receiving concomitant therapy with diuretics and/or vasodilators) should start treatment under close medical supervision (see section "Special Instructions").
In patients at high risk of symptomatic arterial hypotension (those with electrolyte deficiency, with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy), these conditions should be corrected, if possible, prior to initiating the drug. Blood pressure, renal function, and serum potassium levels must be carefully monitored both before and during treatment (see section "Special Instructions").
Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease
The recommended initial dose is 2 mg (½ tablet of Perindopril-Darnitsia 4 mg) once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg (1 tablet of Perindopril-Darnitsia 4 mg) once daily in the morning.
If, after 2 weeks of treatment with Perindopril-Darnitsia 4 mg, additional blood pressure control is required, indapamide may be added at a dose of 1 tablet daily. Treatment may be initiated at any time from 2 weeks to several years after the initial stroke.
Prevention of Cardiovascular Complications in Patients with Documented Stable Ischemic Heart Disease
Treatment with Perindopril-Darnitsia should be initiated at a dose of 4 mg (1 tablet daily, in the morning). After 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 8 mg.
In elderly patients, treatment should be initiated with a dose of 2 mg (½ tablet of Perindopril-Darnitsia 4 mg) once daily in the morning; after one week, the dose should be increased to 4 mg (1 tablet of Perindopril-Darnitsia 4 mg); after 2 weeks, depending on renal function, the dose should be increased to 8 mg (Perindopril-Darnitsia 8 mg, 1 tablet daily) (see Table 1). Dose escalation is possible only if the previous dose is well tolerated.
Special Patient Groups
Dosing in patients with renal impairment should be based on creatinine clearance as specified in Table 1.
Table 1
Dosage Adjustment in Renal Impairment
| Creatinine clearance (mL/min) |
Recommended dosage |
| ClCR ≥ 60 |
4 mg once daily |
| 30 < ClCR < 60 |
2 mg once daily |
| 15 < ClCR < 30 |
2 mg every other day |
| Patients undergoing hemodialysis1 |
|
| ClCR < 15 |
2 mg on dialysis day |
1 The dialysis clearance of perindoprilat is 70 mL/min. For patients undergoing hemodialysis, the dose should be administered after hemodialysis.
Patients with hepatic insufficiency
Dose adjustment of the medicinal product is not required in patients with hepatic insufficiency (see sections "Pharmacokinetics" and "Special precautions for use").
Children
The efficacy and safety of the drug in children have not been studied; therefore, Perindopril-Darnitsya is not recommended for use in pediatric patients.
Overdose
Information regarding perindopril overdose is limited. Possible symptoms associated with angiotensin-converting enzyme (ACE) inhibitors overdose include arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, etc.
In case of overdose, intravenous administration of 0.9% sodium chloride solution (9 mg/mL) is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low head elevation. Infusion of angiotensin II and/or intravenous administration of catecholamines should be provided if possible. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions for use"). In case of treatment-resistant bradycardia, cardiac pacing is indicated. Continuous monitoring of vital signs, serum electrolytes, and creatinine concentration is required.
Adverse reactions
The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.
The most commonly observed adverse reactions during clinical trials with perindopril were: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, skin rashes, muscle cramps, asthenia.
Patients should be advised to consult a physician if symptoms of depression, anuria/oliguria, hot flushes, darkening of urine, nausea, vomiting, muscle cramps, or confusion occur, particularly signs suggestive of syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Adverse effects observed during clinical trials and in the post-marketing period with perindopril are listed in Table 2 according to frequency of occurrence: 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).
Table 2
| MedDRA System Organ Classes |
Adverse Reactions |
Frequency |
| Eye disorders |
vision disturbance |
common |
| Ear and labyrinth disorders |
tinnitus |
common |
| Respiratory, thoracic and mediastinal disorders |
cough |
common |
| dyspnoea |
common |
|
| bronchospasm |
uncommon |
|
| eosinophilic pneumonia |
very rare |
|
| rhinitis |
very rare |
|
| Gastrointestinal disorders |
abdominal pain |
common |
| constipation |
common |
|
| diarrhoea |
common |
|
| taste disturbance (dysgeusia) |
common |
|
| dyspepsia |
common |
|
| nausea |
common |
|
| vomiting |
common |
|
| dry mouth |
uncommon |
|
| pancreatitis |
very rare |
|
| Hepatobiliary disorders |
cytolytic or cholestatic hepatitis (see section "Special warnings and precautions for use") |
very rare |
| Renal and urinary disorders |
renal failure |
uncommon |
| acute renal failure |
rare |
|
| anuria/oliguria |
rare |
|
| Endocrine disorders |
syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
rare |
| Metabolism and nutrition disorders |
hypoglycaemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use") |
uncommon |
| hyperkalaemia, reversible upon discontinuation of the drug (see section "Special warnings and precautions for use") |
uncommon |
|
| hyponatraemia |
uncommon |
|
| Nervous system disorders |
dizziness |
common |
| headache |
common |
|
| paraesthesia |
common |
|
| vertigo |
common |
|
| sleepiness |
uncommon |
|
| syncope |
uncommon |
|
| confusion |
very rare |
|
| Psychiatric disorders |
mood changes |
uncommon |
| sleep disorders |
uncommon |
|
| depression |
uncommon |
|
| Cardiac disorders |
palpitations |
uncommon |
| tachycardia |
uncommon |
|
| angina pectoris (see section "Special warnings and precautions for use") |
very rare |
|
| arrhythmia |
very rare |
|
| myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients (see section "Special warnings and precautions for use") |
very rare |
|
| Vascular disorders |
hypotension (and associated symptoms) |
common |
| vasculitis |
uncommon |
|
| stroke may occur due to excessive reduction in blood pressure in high-risk patients (see section "Special warnings and precautions for use") |
very rare |
|
| Raynaud's phenomenon |
frequency not known |
|
| hot flushes |
rare |
|
| Blood and lymphatic system disorders |
eosinophilia |
uncommon |
| agranulocytosis or pancytopenia |
very rare |
|
| decreased haemoglobin and haematocrit levels |
very rare |
|
| leukopenia/neutropenia |
very rare |
|
| haemolytic anaemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency (see section "Special warnings and precautions for use") |
very rare |
|
| thrombocytopenia |
very rare |
|
| Immune system disorders |
hypersensitivity reactions, including anaphylactoid reactions (see section "Special warnings and precautions for use") |
uncommon |
| Skin and subcutaneous tissue disorders |
pruritus |
common |
| skin rashes |
common |
|
| urticaria (see section "Special warnings and precautions for use") |
uncommon |
|
| angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section "Special warnings and precautions for use") |
uncommon |
|
| photosensitivity reactions |
uncommon |
|
| pemphigoid |
uncommon |
|
| worsening of psoriasis symptoms |
rare |
|
| hyperhidrosis |
uncommon |
|
| multiforme erythema |
very rare |
|
| Musculoskeletal and connective tissue disorders |
muscle cramps |
common |
| arthralgia |
uncommon |
|
| myalgia |
uncommon |
|
| Reproductive system and breast disorders |
erectile dysfunction |
uncommon |
| General disorders |
asthenia |
common |
| chest pain |
uncommon |
|
| malaise |
uncommon |
|
| peripheral oedema |
uncommon |
|
| hyperthermia |
uncommon |
|
| Investigations |
increased blood urea levels |
uncommon |
| increased plasma creatinine |
uncommon |
|
| increased plasma bilirubin levels |
rare |
|
| increased liver enzymes |
rare |
|
| Injury, poisoning and procedural complications |
falls |
uncommon |
Clinical trials
During the randomized period of the EUROPA study, information was collected only on serious adverse reactions. A small number of patients (0.3%) experienced serious adverse reactions. In the perindopril treatment group, hypotension was observed in 6 patients, angioneurotic edema in 3 patients, and sudden cardiac arrest in 1 patient. Among patients who discontinued the study, 6.0% (n = 366) reported cough, arterial hypotension, or any other intolerance to perindopril, compared with 2.1% (n = 129) of patients receiving placebo.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.
Packaging
10 tablets in a blister pack; 3 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Pharmaceutical Company "Darnytsia".
Manufacturer's address and location of its business operations
13, Borispilska Street, Kyiv, 02093, Ukraine.