Coripren 20 mg/20 mg
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORIPREN 20 mg/20 mg (CORIPREN 20 mg/20 mg)
Composition:
Active substances: enalapril, lercanidipine;
one tablet contains: enalapril maleate 20 mg (corresponds to enalapril 15.29 mg), lercanidipine hydrochloride 20 mg (corresponds to lercanidipine 18.88 mg);
Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone (K 30), sodium bicarbonate, magnesium stearate;
coating: Opadry 02F23516;
content of Opadry 02F23516: hypromellose 5 cP, titanium dioxide (E 171), macrogol 6000, yellow iron oxide (E 172), talc, red iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: orange, round, biconvex, film-coated tablets, 12 mm in diameter.
Pharmacotherapeutic group.
ACE inhibitors and calcium channel blockers. Enalapril and lercanidipine.
ATC code C09BB02.
Pharmacological Properties.
Pharmacodynamics.
Coripren 20 mg/20 mg is a fixed-dose combination of an angiotensin-converting enzyme (ACE) inhibitor (enalapril 20 mg) and a calcium channel blocker (lercanidipine 20 mg) – two antihypertensive agents with complementary mechanisms of action for controlling blood pressure in patients with hypertension.
The combination of enalapril and lercanidipine produces an additive antihypertensive effect, resulting in greater blood pressure reduction than with either component administered alone.
Clinical studies have demonstrated that systolic blood pressure reduction is significantly greater with the fixed-dose combination of enalapril and lercanidipine compared to monotherapy. The difference in favor of the combination was 3.9 mm Hg with enalapril and 6.2 mm Hg with lercanidipine.
Clinical studies have also demonstrated that diastolic blood pressure reduction is significantly greater with the fixed-dose combination of enalapril and lercanidipine compared to monotherapy. The difference in favor of the combination was 3.9 mm Hg with enalapril and 2.2 mm Hg with lercanidipine.
Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids – L-alanine and L-pyrrolidine-α-carboxylic acid. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictor agent angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to reduced angiotensin II levels in plasma, resulting in increased plasma renin activity (due to removal of negative feedback on renin secretion) and reduced aldosterone secretion. Since ACE is identical to kininase II, enalapril may also inhibit the degradation of bradykinin, a potent vasodilator peptide. However, the role of this mechanism in the therapeutic effects of enalapril remains unclear.
Although the primary mechanism by which enalapril lowers blood pressure involves suppression of the renin-angiotensin-aldosterone system, enalapril exerts antihypertensive effects even in patients with low renin levels. Enalapril reduces blood pressure without significantly increasing heart rate in hypertensive patients both in the supine and upright positions. Symptomatic postural hypotension is rare. In some patients, several weeks of treatment may be required to achieve optimal blood pressure control. Abrupt discontinuation of enalapril does not lead to a rapid rebound increase in blood pressure.
Effective inhibition of ACE activity typically occurs within 2–4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive effect is generally observed within one hour, with maximal blood pressure reduction occurring 4–6 hours after administration. The duration of action is dose-dependent, but at recommended doses, the antihypertensive and hemodynamic effects last at least 24 hours.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was associated with decreased peripheral arterial resistance, increased cardiac output, and either minimal or no increase in heart rate.
After enalapril administration, renal blood flow increases, while glomerular filtration rate remains unchanged. Signs of sodium or water retention are not observed. However, in patients with low glomerular filtration rate prior to treatment, glomerular filtration rate typically increases.
In short-term studies in patients with diabetic and non-diabetic kidney disease, enalapril administration was associated with reduced albuminuria and decreased urinary excretion of IgG and total protein.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle cells. Its antihypertensive mechanism is based on direct relaxation of vascular smooth muscle, thereby reducing total peripheral resistance. Despite its short elimination half-life, lercanidipine exerts a prolonged antihypertensive effect due to its high membrane partition coefficient and lacks negative inotropic effects due to its high vascular selectivity.
Because the vasodilation produced by lercanidipine develops gradually, acute arterial hypotension with reflex tachycardia is rarely observed in hypertensive patients.
As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is primarily attributable to its (S)-enantiomer.
Pharmacokinetics.
No pharmacokinetic interactions were observed when enalapril and lercanidipine were co-administered.
Pharmacokinetics of Enalapril
Absorption. Enalapril is rapidly absorbed, with peak serum concentrations reached within one hour. The extent of absorption of enalapril maleate after oral administration is approximately 60%. Food in the gastrointestinal tract does not affect the absorption of enalapril.
Distribution. After absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat are reached 3–4 hours after oral administration of enalapril maleate. The effective half-life for accumulation of enalaprilat after multiple doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved within 4 days of treatment.
Across the entire therapeutic concentration range, approximately 60% of enalaprilat is protein-bound in plasma.
Metabolism. Apart from its conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.
Elimination. Excretion of enalaprilat is primarily renal. The main urinary components are enalaprilat, accounting for approximately 40% of the dose, and unchanged enalapril (approximately 20%).
The elimination half-life (T1/2) of enalapril after repeated oral administration is 11 hours.
Renal impairment. Exposure to enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal dysfunction (creatinine clearance 40–60 mL/min), the steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after a single 5 mg dose. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC is increased approximately 8-fold. The effective elimination half-life of enalaprilat is prolonged with this degree of renal impairment, and steady-state concentrations are delayed.
Enalapril can be removed from the circulation by hemodialysis. Dialysis clearance is 62 mL/min.
Pharmacokinetics of Lercanidipine
Absorption. Lercanidipine is completely absorbed after oral administration, with peak plasma levels achieved approximately 1.5–3 hours post-dose. The two enantiomers of lercanidipine exhibit identical plasma concentration profiles: time to peak concentration is identical, and both peak plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer. The elimination half-lives of the two enantiomers are essentially the same. No interconversion of the two enantiomers occurs in vivo.
Due to extensive first-pass metabolism, the absolute oral bioavailability of lercanidipine taken after food is approximately 10%. However, bioavailability decreases to one-third of this value when administered to healthy volunteers on an empty stomach. Oral bioavailability of lercanidipine increases 4-fold when administered no later than 2 hours after a high-fat meal. Therefore, the drug should be administered with food.
Distribution. Distribution from plasma to tissues and organs is rapid and extensive.
Protein binding in plasma exceeds 98%. Since protein levels are reduced in patients with severe renal or hepatic dysfunction, the free fraction of lercanidipine may be higher.
Metabolism. Lercanidipine is extensively metabolized by CYP3A4; no metabolites are detected in urine or feces. Lercanidipine is primarily converted into inactive metabolites, and approximately 50% of the dose is excreted in urine.
In vitro experiments with human liver microsomes showed that lercanidipine causes negligible inhibition of CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than the peak plasma level achieved after a 20 mg dose. Furthermore, human interaction studies showed that lercanidipine does not alter plasma levels of midazolam (a typical CYP3A4 substrate) or metoprolol (a typical CYP2D6 substrate). Therefore, lercanidipine at therapeutic doses is not expected to inhibit the biotransformation of drugs metabolized by CYP3A4 or CYP2D6.
Elimination. Elimination is primarily via biotransformation.
The mean terminal elimination half-life is estimated to be 8–10 hours. Due to its high affinity for lipid membranes, therapeutic activity persists for 24 hours. No accumulation occurs after repeated dosing.
Linearity/Non-linearity. After oral administration, plasma levels of lercanidipine are not directly proportional to dose (non-linear kinetics). After 10, 20, or 40 mg doses, the ratios of peak plasma concentrations were 1:3:8, and the ratios of AUCs (area under the plasma concentration-time curve) were 1:4:18, indicating progressive saturation of first-pass hepatic metabolism. Consequently, bioavailability increases with increasing dose.
Special patient populations. Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction are similar to those observed in the general patient population. Patients with severe renal dysfunction or those dependent on dialysis showed higher drug concentrations (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as it is primarily metabolized in the liver.
Clinical characteristics.
Indications.
Essential arterial hypertension.
Contraindications.
- Hypersensitivity to any angiotensin-converting enzyme (ACE) inhibitor, any dihydropyridine calcium channel blocker, or to any component of this medicinal product.
- History of angioedema associated with previous ACE inhibitor therapy.
- Hereditary or idiopathic angioedema.
- Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").
- Left ventricular outflow tract obstruction.
- Untreated congestive heart failure.
- Unstable angina or recent (within 1 month) myocardial infarction.
- Severe renal impairment (GFR < 30 mL/min), including patients on dialysis.
- Severe hepatic impairment.
Concomitant use:
- Strong inhibitors of CYP3A4;
- Cyclosporine;
- Grapefruit or grapefruit juice.
- Concomitant use with sacubitril/valsartan therapy. Enalapril should not be administered less than 36 hours after the last dose of sacubitril/valsartan.
- Concomitant use of Coripren 20 mg/20 mg with aliskiren-containing medicinal products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²).
Interaction with other medicinal products and other forms of interaction.
The antihypertensive effect of Coripren may be potentiated by other medicinal products that lower blood pressure, such as diuretics, β-blockers, α-blockers, etc. In addition, the following interactions have been observed with the use of one of the components of the combination product.
Enalapril maleate
Medicinal products that increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema.
mTOR inhibitors
Concomitant use of ACE inhibitors with racetodril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may lead to an increased risk of angioedema.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects, including hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent.
Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes
Serum potassium levels usually remain within normal limits; however, hyperkalemia may occur in some patients receiving enalapril. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution is required when enalapril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of enalapril with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, caution and frequent monitoring of serum potassium levels are required.
Cyclosporine
Hyperkalemia may occur during concomitant use of ACE inhibitors with cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin
Hyperkalemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended.
Diuretics (thiazide or loop diuretics)
Initiating enalapril therapy with high doses of diuretics may lead to reduced blood volume and risk of hypotension. Hypotensive effects can be minimized by discontinuing the diuretic, increasing fluid or salt intake, or using low doses of enalapril.
Other antihypertensive agents
Concomitant use of these agents may enhance the antihypertensive effect of enalapril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may result in further reduction of blood pressure.
Lithium
Concomitant use of lithium-containing medicinal products with ACE inhibitors has been associated with reversible increases in serum lithium concentration and lithium toxicity. Concomitant use of thiazide diuretics with ACE inhibitors may lead to elevated lithium levels and increased risk of lithium toxicity. Concomitant use of enalapril with lithium is not recommended; however, if such a combination is necessary, careful monitoring of serum lithium levels is required.
Tricyclic antidepressants/antipsychotics/anesthetics/narcotics
Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Concomitant use of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors produces additive effects on increasing serum potassium levels and may lead to worsening of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, particularly in patients with impaired renal function (e.g., elderly patients or patients with signs of dehydration, including those due to diuretic therapy). Therefore, the combination of these medicinal products should be prescribed with particular caution in patients with impaired renal function. Patients should receive adequate hydration, and special attention should be paid to monitoring renal function after initiation of concomitant therapy and periodically during treatment.
Gold-containing medicinal products
Rarely, patients receiving injectable gold-containing medicinal products (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including enalapril, have developed nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension).
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Antidiabetic medicinal products
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic medicinal products (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect, with a risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.
Alcohol
Alcohol enhances the antihypertensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics, and β-adrenoblockers
Enalapril can be safely taken concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, and β-adrenoblockers.
Lercanidipine
Contraindicated concomitant use
CYP3A4 inhibitors
Lercanidipine is known to be metabolized by the CYP3A4 enzyme; therefore, concomitant use of CYP3A4 inhibitors and inducers may affect the metabolism and elimination of lercanidipine.
A drug interaction study with ketoconazole, a strong CYP3A4 inhibitor, demonstrated a marked increase in plasma levels of lercanidipine (15-fold increase in the area under the concentration-time curve (AUC) and 8-fold increase in Cmax of the S-enantiomer of lercanidipine).
Concomitant use of lercanidipine with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided.
Cyclosporine
Increased plasma concentrations of both medicinal products have been observed when lercanidipine and cyclosporine are used together. A study in healthy young volunteers showed no changes in plasma levels of lercanidipine after administration of cyclosporine 3 hours after lercanidipine, but the AUC of cyclosporine increased by 27%. However, concomitant use of lercanidipine with cyclosporine resulted in a 3-fold increase in plasma levels of lercanidipine and a 21% increase in the AUC of cyclosporine.
Cyclosporine and lercanidipine should not be taken concomitantly (see section "Contraindications").
Grapefruit or grapefruit juice
As with other dihydropyridines, the metabolism of lercanidipine may be inhibited by grapefruit juice, leading to increased systemic availability and, consequently, enhanced antihypertensive effect.
Lercanidipine should not be taken with grapefruit or grapefruit juice (see section "Contraindications").
Not recommended for concomitant use
CYP3A4 inducers
Use of lercanidipine concomitantly with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin requires caution, as the antihypertensive effect of lercanidipine may be reduced. Therefore, blood pressure should be monitored more frequently than usual.
Alcohol
Alcohol consumption should be avoided, as it may enhance the effect of antihypertensive vasodilators.
Precautions for use, including dose adjustment
CYP3A4 substrates
Concomitant use of lercanidipine with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics (e.g., amiodarone, quinidine, sotalol) should be prescribed with caution.
Midazolam
In elderly volunteers, concomitant oral administration of 20 mg lercanidipine and midazolam led to enhanced absorption of lercanidipine (approximately 40%) and reduced absorption rate (Tmax increased from 1.75 to 3 hours). No changes in midazolam concentration were observed.
Metoprolol
When lercanidipine was used concomitantly with metoprolol—a beta-blocker primarily eliminated by the liver—bioavailability of metoprolol was unchanged, while bioavailability of lercanidipine decreased by 50%. This effect may be due to reduced hepatic blood flow caused by β-adrenoblockers and may therefore occur with other agents of this class. However, lercanidipine can be safely used concomitantly with β-adrenoblockers, although dose adjustment may be required.
Digoxin
Concomitant use of 20 mg lercanidipine in patients on long-term treatment with beta-methyldigoxin showed no signs of pharmacokinetic interaction. However, in healthy volunteers, a mean increase in digoxin Cmax of 33% was observed, while AUC and renal clearance were not significantly altered. When digoxin is used concomitantly, careful monitoring for clinical signs of digoxin toxicity is required.
Concomitant use with other medicinal products
Fluoxetine
In a drug interaction study with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) involving healthy volunteers aged 65 ± 7 years (mean ± SD), no clinically significant changes in the pharmacokinetics of lercanidipine were observed.
Cimetidine
Concomitant use of cimetidine at a dose of 800 mg daily did not cause significant changes in plasma levels of lercanidipine, but caution should be exercised with higher doses, as bioavailability of lercanidipine and its antihypertensive effect may increase.
Simvastatin
When lercanidipine 20 mg was repeatedly administered concomitantly with simvastatin 40 mg, the AUC of lercanidipine was not significantly altered, while the AUC of simvastatin increased by 56% and that of its main active metabolite (β-hydroxy acid) by 28%. Such changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as recommended for this medicinal product.
Warfarin
Concomitant use of 20 mg lercanidipine on an empty stomach in healthy volunteers did not alter the pharmacokinetics of warfarin.
Diuretics and ACE inhibitors
Lercanidipine has been safely used with diuretics and ACE inhibitors.
Other medicinal products affecting blood pressure
As with all antihypertensive agents, an enhanced antihypertensive effect may occur when lercanidipine is used with other agents affecting blood pressure, such as alpha-blockers for urinary symptoms, tricyclic antidepressants, and neuroleptics. A reduced antihypertensive effect may be observed when used concomitantly with corticosteroids.
Children
Drug interaction studies have been conducted only in adults.
Special precautions for use.
Symptomatic hypotension.
Symptomatic hypotension is rare in patients with uncomplicated hypertension. In patients with arterial hypertension receiving enalapril, symptomatic hypotension occurs more frequently if they have reduced circulating blood volume, for example, due to diuretic therapy, a salt-free diet, dialysis, diarrhea, or vomiting. Symptomatic hypotension has been observed in patients with heart failure (with or without renal impairment). Symptomatic hypotension is likely possible in patients with severe heart failure, particularly when receiving high doses of loop diuretics, in the presence of hyponatremia, or functional renal impairment. In such patients, therapy should be initiated under medical supervision, and patients must strictly adhere to the treatment regimen whenever the dose of enalapril and/or diuretics is changed. Similar precautions are necessary for patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.
If arterial hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of isotonic saline solution. A transient hypotensive response is not a contraindication to further administration of the drug at an appropriate dose. Treatment may be continued without complications after blood pressure has increased due to restoration of fluid volume. In some patients with heart failure and normal or low blood pressure, additional reduction in systemic arterial pressure may occur during enalapril therapy. This effect may be anticipated and is generally not a reason to discontinue treatment. If arterial hypotension becomes symptomatic, dose reduction and/or discontinuation of diuretics and/or enalapril may be necessary.
Sinus node dysfunction.
Lercanidipine should be administered with caution to patients with sinus node dysfunction (unless a cardiac pacemaker has been implanted).
Left ventricular dysfunction.
Despite the absence of deterioration in ventricular function observed during controlled hemodynamic studies, the drug should be used cautiously in patients with left ventricular dysfunction.
Ischemic heart disease.
It is likely that the use of certain short-acting dihydropyridines may be associated with an increased cardiovascular risk in patients with ischemic heart disease. Although lercanidipine is a prolonged-release agent, it should be used with caution in such patients. Rarely, the use of some dihydropyridines may cause precordial pain or angina. Very rarely, patients with pre-existing angina may experience increased frequency, duration, or severity of such episodes. Isolated cases of myocardial infarction have been reported.
Use in renal impairment.
Particular caution is required when prescribing enalapril to patients with mild to moderate renal impairment. Regular monitoring of serum potassium and creatinine levels during enalapril therapy is an essential part of medical care for these patients. Reports of renal failure associated with enalapril use have primarily involved patients with severe heart failure or underlying kidney disease, including renal artery stenosis. If diagnosed promptly and managed appropriately, enalapril-induced renal failure is usually reversible. In some patients with arterial hypertension and no prior kidney disease, combining enalapril with a diuretic may lead to increased blood urea and serum creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, the possibility of renal artery stenosis should be considered.
Renovascular hypertension.
Patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney are particularly susceptible to developing arterial hypotension or renal failure during therapy with ACE inhibitors. Renal dysfunction may occur even with minimal changes in serum creatinine levels. In these patients, therapy should be initiated under close medical supervision, starting with low doses and cautious dose titration, with regular monitoring of renal function.
Kidney transplantation.
There is no experience with the use of lercanidipine or enalapril in patients who have recently undergone kidney transplantation. Therefore, treatment of these patients with Koripren is not recommended.
Hepatic impairment.
The antihypertensive effect of lercanidipine may be enhanced in patients with impaired liver function. Rarely, treatment with ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to rapidly progressive necrotizing hepatitis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevations in liver enzymes during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate treatment.
Peritoneal dialysis.
The use of lercanidipine has been associated with turbidity of peritoneal effluent in patients undergoing peritoneal dialysis. The turbidity is due to increased triglyceride concentration in the peritoneal exudate. Although the mechanism is unknown, this effect tends to resolve shortly after discontinuation of lercanidipine. This association should be taken into account to avoid misdiagnosing peritoneal effluent turbidity as infectious peritonitis, which could lead to unnecessary hospitalization and empirical antibiotic therapy.
Neutropenia/agranulocytosis.
Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been observed in patients treated with ACE inhibitors, including enalapril. In patients with normal renal function and no special risk factors, neutropenia occurs rarely. Enalapril should be used with particular caution in patients with vascular collagenosis, those undergoing immunosuppressive therapy, those receiving allopurinol or procainamide, or those with multiple risk factors, especially if renal impairment is present. Serious infections, occasionally unresponsive to intensive antibiotic therapy, have been observed in some of these patients. When enalapril is used in such patients, regular monitoring of the leukocyte count is recommended, and patients should be instructed to report any signs of infection to their physician.
Hypersensitivity/angioedema.
Cases of angioedema (Quincke's edema) involving the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including enalapril. This may occur at any time during treatment. In such cases, enalapril must be discontinued immediately. Patients should remain under close medical supervision until discharge from the hospital to ensure complete resolution of symptoms. Even if swelling is limited to the tongue without respiratory distress, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.
Very rare fatal outcomes of angioedema, including laryngeal or tongue edema, have been reported. Patients with swelling of the tongue, glottis, or larynx may develop airway obstruction, particularly if they have a history of airway surgery.
If angioedema of the tongue, glottis, or larynx may lead to airway obstruction, immediate appropriate treatment is required, including subcutaneous administration of 1:1000 adrenaline solution (0.3 mL to 0.5 mL), and/or measures to secure airway patency. Reports indicate that the incidence of Quincke's edema is significantly higher in patients of African descent compared to patients of other races when treated with ACE inhibitors. Patients with a history of angioedema unrelated to ACE inhibitor use may have a higher risk of developing angioedema when receiving an ACE inhibitor.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of enalapril. Treatment with enalapril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise). Patients already receiving ACE inhibitors should initiate treatment with racecadotril, mTOR inhibitors (sirolimus, everolimus, temsirolimus), or vildagliptin with caution.
Anaphylactoid reactions during hymenoptera venom desensitization.
Life-threatening anaphylactoid reactions rarely occur during desensitization therapy for hymenoptera venom when used concomitantly with an ACE inhibitor. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each desensitization session.
Anaphylactoid reactions during LDL apheresis.
Life-threatening anaphylactoid reactions rarely occur during low-density lipoprotein (LDL) apheresis using dextran sulfate when used concomitantly with an ACE inhibitor. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.
Hypoglycemia.
Careful monitoring of blood glucose levels is required during the first month of ACE inhibitor therapy in diabetic patients receiving oral antidiabetic agents or insulin.
Cough.
Cough may occur with the use of ACE inhibitors. It is typically a non-productive, persistent cough that resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery/anesthesia.
During major surgery or anesthesia with agents that lower blood pressure, enalapril inhibits the formation of angiotensin II, which may lead to compensatory renin secretion. If arterial hypotension develops via this mechanism, it can be corrected by physically increasing circulating blood volume.
Serum potassium.
ACE inhibitors may cause hyperkalemia, as their action suppresses aldosterone release. The effect is usually mild in patients with normal renal function. However, hyperkalemia may occur in patients with renal impairment and/or in patients receiving potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, or co-trimoxazole (trimethoprim/sulfamethoxazole), and particularly with aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored.
Lithium.
Concomitant use of lithium and enalapril is generally not recommended.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute kidney injury). Therefore, dual blockade with ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If such combination therapy is considered absolutely necessary, it should be administered only under specialist supervision with close monitoring of renal function, blood pressure, and electrolyte levels. ACE inhibitors and angiotensin II receptor blockers should not be used with aliskiren in patients with diabetic nephropathy.
CY P3A4 inducers.
Inducers of CYP3A4, such as anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin, may reduce serum levels of lercanidipine, potentially resulting in lower than expected efficacy.
Ethnic differences.
As with other ACE inhibitors, enalapril is undoubtedly less effective in reducing blood pressure in patients of African descent compared to Caucasian patients, likely due to lower plasma renin levels commonly observed in patients of African descent with arterial hypertension.
Alcohol.
Alcohol intake should be avoided, as this combination may potentiate the vasodilatory hypotensive effects.
Lactose.
The medicinal product contains lactose. Koripren should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy.
Enalapril.
The use of ACE inhibitors (enalapril) is not recommended during the first trimester of pregnancy. ACE inhibitors (enalapril) are contraindicated during the second and third trimesters of pregnancy.
Epidemiological data on teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy do not allow definitive conclusions; however, a small increased risk cannot be excluded. Pregnant women or women planning pregnancy should have their ACE inhibitor therapy replaced with alternative antihypertensive agents with an established safety profile during pregnancy, except when ACE inhibitor therapy is considered life-saving. When pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy initiated if necessary.
It is known that ACE inhibitor use during the second and third trimesters of pregnancy is toxic to the human fetus (impaired renal function, oligohydramnios, delayed skull ossification) and to the newborn (renal failure, arterial hypotension, hyperkalemia). In the mother, oligohydramnios may occur, likely as a manifestation of impaired fetal renal function, potentially leading to limb contractures, craniofacial deformities, and pulmonary hypoplasia. If an ACE inhibitor is used during the second trimester of pregnancy, ultrasound examination should be performed to assess fetal renal function and skull ossification. Newborns whose mothers received ACE inhibitors should be monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Lercanidipine.
There are no data on the use of lercanidipine in pregnant women.
Animal studies have not shown teratogenic effects of lercanidipine, although such effects have been observed with other dihydropyridine compounds.
Lercanidipine is not recommended for use in pregnant women or women of childbearing potential who are not using effective contraception.
Combination of enalapril and lercanidipine.
There is insufficient or no data on the use of enalapril maleate/lercanidipine hydrochloride in pregnant women. Animal studies on reproductive toxicity are inadequate.
Koripren should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
Breastfeeding.
Enalapril.
Limited pharmacokinetic data show that enalapril is present in breast milk at very low concentrations (see section "Pharmacokinetics"). Although low concentrations of ACE inhibitors are not clinically significant, due to the hypothetical risk of adverse reactions in infants (effects on the cardiovascular system and renal function) and the lack of clinical experience with Koripren, enalapril therapy is not recommended in breastfeeding mothers of premature infants or newborns in the first weeks of life. Breastfeeding mothers of older infants may use Koripren only if absolutely necessary and under medical supervision for adverse reactions in the infant.
Lercanidipine.
There are no data on the excretion of lercanidipine in breast milk, but a risk to infants cannot be excluded. Therefore, lercanidipine should not be used during breastfeeding.
Combination of enalapril and lercanidipine.
Koripren should not be used during breastfeeding.
Fertility.
Cases have been reported in which some patients receiving calcium channel blockers developed reversible biochemical changes in the sperm head, potentially affecting fertilization. In cases of repeated failed attempts at in vitro fertilization and in the absence of other explanations, the use of calcium channel blockers should be considered as a possible cause.
Ability to affect reaction speed when driving or operating machinery.
The effect of Koripren and its components on reaction speed when driving or operating machinery is negligible. However, the possible development of dizziness, asthenia, fatigue, and rarely somnolence should be taken into account.
Method of Administration and Dosage.
The tablets are taken orally. The recommended dose is 1 tablet once daily. The medication should be taken in the morning, at least 15 minutes before breakfast. This drug should not be taken with grapefruit juice.
Geriatric patients. Dosage selection depends on renal function status.
Dosage in renal impairment: Coripren 20 mg/20 mg is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) or in patients undergoing hemodialysis. Particular caution is required at the beginning of treatment in patients with mild to moderate renal impairment.
Dosage in hepatic impairment. Coripren 20 mg/20 mg is contraindicated in patients with severe hepatic impairment. Particular caution is required at the beginning of treatment in patients with mild to moderate hepatic impairment.
Children.
The efficacy and safety of Coripren for use in children have not been established. The drug is not used in pediatric practice.
Overdose.
During the post-marketing period, cases of intentional overdose with enalapril/lercanidipine at doses ranging from 100 to 1000 mg for each of these drugs have been reported. Hospitalization was required in such cases. Reported symptoms (reduction in systolic blood pressure, bradycardia, anxiety, somnolence, and flank pain) may also have been related to concomitant intake of high doses of other medications (e.g., beta-blockers).
Symptoms of overdose. The most characteristic symptom of enalapril overdose is hypotension (occurring approximately 6 hours after drug intake), associated with simultaneous blockade of the RAAS and stupor. Symptoms related to ACE inhibitor overdose may include vascular shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough. Serum enalaprilat levels 100 and 200 times higher than usual have been observed after administration of therapeutic doses of enalapril at 300 mg and 440 mg, respectively.
As with other dihydropyridines, lercanidipine overdose may cause excessive peripheral vasodilation leading to marked hypotension and reflex tachycardia. However, with extremely high doses, peripheral selectivity may be lost, resulting in bradycardia. The most commonly reported adverse reactions associated with overdose were hypotension, dizziness, headache, and palpitations.
Treatment of overdose. Recommended treatment for enalapril overdose is intravenous infusion of physiological saline. If hypotension occurs, the patient should be placed in a supine position with low elevation of the head. Intravenous administration of angiotensin II and/or catecholamines may be used if available. If the drug was recently ingested, measures to remove enalapril maleate from the body should be taken (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from the bloodstream by hemodialysis. A cardiac pacemaker is indicated in cases of bradycardia resistant to therapy. Vital functions, serum electrolyte levels, and serum creatinine should be monitored continuously.
In cases of lercanidipine overdose with development of severe hypotension, bradycardia, and loss of consciousness, cardiovascular support with intravenous atropine may be beneficial to prevent bradycardia.
Due to the prolonged pharmacological effect of lercanidipine, the patient who has taken an excessive dose should be monitored for at least 24 hours. There is no information regarding the effectiveness of dialysis. Because the drug is highly lipophilic, plasma lercanidipine levels are not informative regarding the degree of overdose. Dialysis is ineffective.
Adverse reactions.
The safety of the drug Coripren was evaluated in five double-blind controlled clinical trials and in two long-term open extension phases. Overall, 1141 patients received the drug at doses of 10 mg/10 mg, 20 mg/10 mg, and 20 mg/20 mg. Adverse reactions observed during treatment with Coripren correspond to those observed with the individual active substances of this drug. The most frequently occurring adverse reactions during treatment with Coripren are cough (4.03%), dizziness (1.67%), and headache (1.67%).
The table below presents the adverse reactions identified in clinical trials of the drug administered at doses of 10 mg/10 mg, 20 mg/10 mg, and 20 mg/20 mg, for which a causal relationship with the drug administration has been established. Adverse reactions are listed by MedDRA system organ classes and according to the following frequency categories: very common (> 1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).
| Blood and lymphatic system |
|
| Uncommon: |
Thrombocytopenia |
| Rare: |
Decreased hemoglobin levels |
| Immune system |
|
| Rare: |
Increased sensitivity |
| Metabolism and nutrition |
|
| Uncommon: |
Hyperkalemia |
| Psychiatric |
|
| Uncommon: |
Anxiety |
| Nervous system |
|
| Common: |
Dizziness, headache |
| Uncommon: |
Postural dizziness |
| Ear and labyrinth disorders |
|
| Uncommon: |
Spatial disorientation (vertigo) |
| Rare: |
Tinnitus |
| Cardiac |
|
| Uncommon: |
Tachycardia, palpitations |
| Vascular disorders |
|
| Uncommon: |
Hyperemia, hypotension |
| Rare: |
Vascular insufficiency |
| Respiratory, thoracic and mediastinal |
|
| Common: |
Cough |
| Rare: |
Dry throat, oropharyngeal pain |
| Gastrointestinal |
|
| Uncommon: |
Abdominal pain, constipation, nausea |
| Rare: |
Dyspepsia, lip swelling, speech disorders, diarrhea, dry mouth, gingivitis |
| Hepatobiliary |
|
| Uncommon: |
Elevated ALT levels, elevated AST levels |
| Skin and subcutaneous tissue |
|
| Uncommon: |
Redness of the skin |
| Rare: |
Angioedema, facial swelling, dermatitis, rash, urticaria |
| Musculoskeletal and connective tissue |
|
| Uncommon: |
Joint pain (arthralgia) |
| Renal and urinary |
|
| Uncommon: |
Increased frequency of urination (polyuria) |
| Rare: |
Nocturia, polyuria |
| Reproductive system and breast |
|
| Rare: |
Erectile dysfunction |
| General disorders and administration site conditions |
|
| Uncommon: |
Asthenia, fatigue, feeling of warmth, peripheral edema |
Adverse reactions reported in only one patient were classified as "isolated".
Adverse reactions related to the individual active substances of the medicinal product.
Adverse reactions reported during the use of either of the individual components (enalapril or lercanidipine) may potentially occur with the combined medicinal product, even if they were not observed during clinical trials or in the post-marketing period.
Enalapril
The adverse reactions associated with enalapril use are listed below.
Blood and lymphatic system disorders:
Uncommon: anaemia (including aplastic and haemolytic forms);
Isolated: neutropenia, decreased haemoglobin, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune disorders.
Endocrine system disorders:
Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolism and nutrition disorders:
Uncommon: hypoglycaemia.
Psychiatric disorders:
Common: depression;
Uncommon: confusion, nervousness;
Isolated: abnormal dreams, sleep disturbances.
Nervous system disorders:
Very common: dizziness;
Common: headache, faintness, taste disturbance;
Uncommon: somnolence, paraesthesia, vertigo.
Eye disorders:
Very common: blurred vision.
Cardiac disorders:
Common: chest pain, arrhythmia, tachycardia;
Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, probably due to severe arterial hypotension in patients at risk (see section "Special precautions for use").
Vascular disorders:
Common: hypotension (including orthostatic hypotension);
Uncommon: flushing, orthostatic hypotension.
*The incidence was comparable to that observed in placebo and active control groups in clinical trials.
Respiratory, thoracic and mediastinal disorders:
Very common: cough;
Common: dyspnoea;
Uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma;
Isolated: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders:
Very common: nausea;
Common: diarrhoea, abdominal pain;
Uncommon: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcer;
Isolated: stomatitis/aphthous stomatitis, glossitis;
Rare: angioedema of the intestine.
Hepatobiliary disorders:
Isolated: hepatic failure, hepatocellular or cholestatic hepatitis (including necrosis), cholestasis (including jaundice).
Skin and subcutaneous tissue disorders:
Common: rash, hypersensitivity/angioedema of the face, extremities, lips, tongue, glottis and/or larynx;
Uncommon: hyperhidrosis, pruritus, urticaria, alopecia;
Isolated: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.
A symptom complex which may include some or all of the following symptoms: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, presence of antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations.
Renal and urinary disorders:
Uncommon: renal failure, renal impairment, proteinuria;
Isolated: oliguria.
Musculoskeletal and connective tissue disorders:
Uncommon: muscle cramps.
Reproductive system and breast disorders:
Uncommon: impotence;
Isolated: gynaecomastia.
General disorders:
Very common: asthenia;
Common: fatigue;
Uncommon: malaise, fever.
Laboratory test abnormalities:
Common: hyperkalaemia, increased creatinine levels;
Uncommon: increased blood urea nitrogen, hyponatraemia;
Isolated: increased liver enzymes, increased serum bilirubin levels.
Lercanidipine
The most frequently reported adverse reactions during clinical studies and post-marketing experience are headache, dizziness, peripheral oedema, tachycardia, palpitations and flushing.
Immune system disorders:
Rare: hypersensitivity.
Nervous system disorders:
Common: headache;
Uncommon: dizziness;
Isolated: somnolence, faintness.
Cardiac disorders:
Common: tachycardia, palpitations;
Isolated: angina pectoris.
Vascular disorders:
Common: flushing;
Uncommon: hypotension.
Gastrointestinal disorders:
Uncommon: nausea, dyspepsia, abdominal pain.
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus;
Isolated: urticaria;
Not known: angioedema1.
Musculoskeletal and connective tissue disorders:
Uncommon: myalgia.
Renal and urinary disorders:
Uncommon: polyuria;
Isolated: pollakiuria.
General disorders:
Common: peripheral oedema;
Uncommon: asthenia, increased fatigue;
Isolated: chest pain.
1Spontaneously reported adverse reactions in the post-marketing period.
Some dihydropyridines may rarely cause precordial pain or angina pectoris. Very rarely, in patients with a history of angina, an increase in frequency, duration or severity of attacks may occur. There have been reports of isolated cases of myocardial infarction.
Lercanidipine does not affect blood glucose levels or serum lipid levels.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging to protect from light and moisture at a temperature not exceeding 25 °C.
Keep out of the reach and sight of children.
Packaging.
14 tablets in a blister. 2 or 4 blisters in a cardboard box.
Prescription category. Prescription only.
Manufacturer.
Recordati Industria Chimica e Farmaceutica S.p.A., Italy.
Manufacturer's address and place of business.
Via M. Civitali 1, 20148 Milan, Italy.