Coripren 10 mg/10 mg
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORIPREN 10 mg/10 mg (CORIPREN 10 mg/10 mg)
Composition:
Active substances: enalapril; lercanidipine;
One tablet contains enalapril maleate 10 mg (corresponds to enalapril 7.64 mg) and lercanidipine hydrochloride 10 mg (corresponds to lercanidipine 9.44 mg);
Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone (K 30), sodium bicarbonate, magnesium stearate; coating: white opadry 02F29056;
content of white opadry 02F29056: hypromellose 5cP (E 646), titanium dioxide (E 171), talc, macrogol 6000.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white, round, biconvex, film-coated tablets.
Pharmacotherapeutic group.
ACE inhibitors and calcium channel blockers: enalapril and lercanidipine.
ATC code C09BB02.
Pharmacological properties.
Pharmacodynamics.
Coripren 10 mg/10 mg is a fixed combination of an ACE inhibitor (enalapril 10 mg) and a calcium channel blocker (lercanidipine 10 mg), two antihypertensive compounds with complementary mechanisms of action for controlling blood pressure in patients with hypertension.
Clinical studies have demonstrated that systolic pressure reduction was greater with the fixed combination of enalapril and lercanidipine than with monotherapy. The difference was 5.4 mm Hg.
Clinical studies have demonstrated that diastolic pressure reduction was greater with the fixed combination of enalapril and lercanidipine than with monotherapy. The difference was 2.8 mm Hg.
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 a reduction in 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 vasodepressor 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 is considered to be 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 standing 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 rise in blood pressure.
Effective inhibition of ACE activity usually 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 maximum blood pressure reduction occurring 4–6 hours after administration. The duration of effect is dose-dependent, but at recommended doses, the hypotensive and hemodynamic effects last at least 24 hours.
In hemodynamic studies of patients with essential hypertension, blood pressure reduction was accompanied by decreased peripheral arterial resistance with increased cardiac output and 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, the glomerular filtration rate usually increases.
In short-term studies of patients with diabetes and non-diabetic patients with kidney disease, administration of enalapril was associated with reduced albuminuria and decreased urinary excretion of IgG and total protein.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane influx of calcium into cardiac muscle and smooth muscle. The mechanism of its antihypertensive action 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 does not exhibit negative inotropic effects due to its high vascular selectivity.
Because vasodilation induced 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 due to its (S)-enantiomer.
Pharmacokinetics.
No pharmacokinetic interactions were observed when enalapril and lercanidipine were administered concomitantly.
Pharmacokinetics of enalapril
Absorption. Enalapril is rapidly absorbed; peak serum concentration occurs within one hour. The extent of absorption of enalapril maleate after oral administration is approximately 60%. The presence of 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 concentration of enalaprilat occurs 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.
Within the entire therapeutic concentration range, 60% of enalaprilat is bound to serum proteins.
Metabolism: Apart from 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 not undergoing transformation or metabolism (approximately 20%).
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 5 mg once-daily dose. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), the AUC is approximately 8 times higher. The effective elimination half-life of enalaprilat after multiple doses of enalapril is prolonged in such degrees of renal impairment, and the time to reach steady-state concentration is increased.
Enalaprilat can be removed from the circulation by hemodialysis. The dialysis clearance of enalaprilat is 62 mL/min.
Pharmacokinetics of lercanidipine
Absorption. Lercanidipine is completely absorbed after oral administration, and peak plasma levels are reached approximately 1.5–3 hours after intake. The two enantiomers of lercanidipine show identical plasma concentration profiles: time to peak concentration is the same; 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 mainly similar. In vivo, interconversion of the two enantiomers does not occur.
Due to extensive first-pass metabolism, the absolute oral bioavailability of lercanidipine taken after food is approximately 10%. However, bioavailability in healthy volunteers taking the drug on an empty stomach decreases to one-third of the above value. The bioavailability of lercanidipine after oral administration increases 4-fold when administered no later than 2 hours after a high-fat meal. Therefore, the drug should be administered before meals.
Distribution. Distribution from plasma to tissues and organs is rapid and extensive.
Protein binding exceeds 98%. Since protein levels are reduced in patients with severe renal or hepatic dysfunction, the concentration of free lercanidipine fractions 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 exhibits negligible inhibition of the two enzymes CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher than the peak plasma level achieved after a 20 mg dose. Additionally, 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 administration 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 high affinity for lipid membranes, therapeutic activity lasts for 24 hours. No accumulation occurs after repeated dosing.
Linearity/Non-linearity. After oral administration of lercanidipine, plasma levels are not directly proportional to dose (non-linear kinetics). After administration of 10, 20, or 40 mg, the ratios of peak plasma concentrations were 1:3:8, and the area under the plasma concentration–time curve (AUC) ratios were 1:4:18, indicating progressive saturation of the first-pass hepatic effect. Accordingly, bioavailability increases with increasing dose.
Special patient populations. Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic impairment have been shown to be similar to those observed in the general patient population. Patients with severe renal impairment or patients dependent on dialysis demonstrated 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 or 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").
- Obstruction of outflow from the left ventricle.
- Uncompensated 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 used less than 36 hours after the last dose of sacubitril/valsartan.
- Concomitant use of Coripren 10 mg/10 mg with aliskiren-containing products in patients with diabetes mellitus 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 were observed with one of the components of the combination product.
Enalapril maleate
Medicinal products increasing 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 racadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the 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 combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects, including hypotension, hyperkalemia, and renal dysfunction (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 and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as the potassium-sparing diuretic amiloride. Therefore, combination of enalapril with the above-mentioned agents is not recommended. If concomitant use is indicated, caution and frequent monitoring of serum potassium levels are required.
Cyclosporine
Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin
Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.
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 hypotensive 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 increase lithium levels and the risk of lithium toxicity. Concomitant use of enalapril with lithium is not recommended, but if such a combination is necessary, careful monitoring of serum lithium levels should be performed.
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.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effects 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 causes additive effects on increasing serum potassium levels and may lead to worsening 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 those with dehydration, including due to diuretic therapy). Therefore, the combination of these agents 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 preparations
Rarely, patients receiving injectable gold-containing preparations (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 agents
Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic medicinal products (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.
Alcohol
Alcohol enhances the hypotensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics, and β-adrenoblockers
Enalapril can be safely taken concomitantly with acetylsalicylic acid (at cardiologic 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 lercanidipine levels (15-fold increase in the area under the concentration-time curve (AUC) of the drug and 8-fold increase in Cmax of the S-lercanidipine eutomer).
Concomitant use of lercanidipine with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided.
Cyclosporine
Increased plasma concentrations of both agents have been observed when lercanidipine and cyclosporine are used together. A study in healthy young volunteers showed no changes in lercanidipine plasma levels after cyclosporine administration 3 hours after lercanidipine, but cyclosporine AUC increased by 27%. However, concomitant use of lercanidipine with cyclosporine resulted in a 3-fold increase in lercanidipine plasma levels and a 21% increase in cyclosporine AUC.
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 hypotensive 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 selection
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 resulted in enhanced absorption of lercanidipine (approximately 40% increase) 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, whereas 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 necessary.
Digoxin
Concomitant administration of 20 mg lercanidipine in patients on long-term treatment with beta-methyl-digoxin 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 recommended.
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 lercanidipine pharmacokinetics were observed.
Cimetidine
Concomitant use of cimetidine at a dose of 800 mg per day did not cause significant changes in lercanidipine plasma levels, but caution should be exercised with higher doses, as bioavailability of lercanidipine and its hypotensive effect may increase.
Simvastatin
When 20 mg lercanidipine was repeatedly administered concomitantly with 40 mg simvastatin, the AUC of lercanidipine was not significantly altered, whereas the AUC of simvastatin increased by 56% and that of its main active metabolite (β-hydroxyacid) by 28%. Such changes are unlikely to have clinical significance. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as recommended for this drug.
Warfarin
Concomitant administration 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 increased hypotensive 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 hypotensive effect may occur with concomitant use of 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, e.g., 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 in patients with severe heart failure, particularly when receiving high doses of loop diuretics, 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.
In case of arterial hypotension, 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 blood pressure may occur during enalapril therapy. This effect may be anticipated and generally is 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 is implanted).
Left ventricular dysfunction.
Although controlled hemodynamic studies have not shown worsening of ventricular function, the drug should be used with caution 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. Continuous monitoring of serum potassium and creatinine levels during enalapril therapy is 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. When diagnosed promptly and managed appropriately, enalapril-induced renal failure is usually reversible. In some patients with arterial hypertension and no prior kidney disease, combination of enalapril with a diuretic may cause increased serum urea and creatinine. Dose reduction of enalapril and/or discontinuation of the diuretic may be required. In such cases, renal artery stenosis should be considered.
Renovascular hypertension.
Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney are particularly susceptible to developing arterial hypotension or renal failure during therapy with ACE inhibitors. Renal function impairment 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, along with 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 ACE inhibitors and receive appropriate treatment.
Peritoneal dialysis.
The use of lercanidipine has been associated with turbidity of peritoneal effluent in patients undergoing peritoneal dialysis. Turbidity is caused by 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 considered to avoid misdiagnosing turbidity of peritoneal effluent 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, during immunosuppressive therapy, during treatment with allopurinol or procainamide, or in the presence of several of these risk factors, especially if renal impairment is present. Serious infections, rarely 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 inform their physician of any signs of infection.
Hypersensitivity/angioedema.
Cases of angioedema (Quincke's edema) with swelling of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitor therapy, including enalapril. This may occur at any time during treatment. In such cases, enalapril must be discontinued immediately. Patients should remain under close observation until discharge from 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 rarely, fatal outcomes of angioedema, including laryngeal or tongue edema, have been reported. Patients with swelling of the tongue, glottis, or larynx may experience airway obstruction, particularly if they have a history of airway surgery.
If swelling of the tongue, glottis, or larynx may lead to airway obstruction, appropriate treatment must be initiated immediately, 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 non-Caucasian race receiving ACE inhibitors compared to patients of other races. Patients with a history of angioedema unrelated to ACE inhibitor use may have a much higher risk of developing angioedema when receiving an ACE inhibitor.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to 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, racecadotril, mTOR inhibitors (sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment). Patients already receiving ACE inhibitors should start treatment with racecadotril, mTOR inhibitors (sirolimus, everolimus, temsirolimus), or vildagliptin with caution.
Anaphylactoid reactions during desensitization to hymenoptera venom.
Life-threatening anaphylactoid reactions rarely occur during desensitization therapy for insect venom when combined with ACE inhibitor use. 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 combined with ACE inhibitor use. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis session.
Hypoglycemia.
Close monitoring of blood glucose levels is required during the first month of ACE inhibitor therapy in diabetic patients receiving oral hypoglycemic agents or insulin.
Cough.
Cough may occur with the use of ACE inhibitors. It is usually non-productive and persistent, resolving after discontinuation of therapy. ACE inhibitor-induced cough should also 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 due to this mechanism, it can be corrected by physical expansion of 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, in patients with renal impairment and/or those taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, or co-trimoxazole (trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients taking ACE inhibitors, and serum potassium and renal function should be monitored.
Lithium.
Combination 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 renal failure). Therefore, dual blockade with ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. If use of these combinations is considered absolutely necessary, such therapy should be conducted only under specialist supervision and with careful 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.
CY3A4 inducers.
CY3A4 inducers 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 non-Caucasian race compared to patients of Caucasian race, likely due to lower plasma renin levels frequently observed in non-Caucasian patients with arterial hypertension.
Alcohol.
Alcohol intake should be avoided, as this combination may potentiate the action of vasodilating antihypertensive agents.
Lactose.
The medicinal product contains lactose. Koripren should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy.
Enalapril.
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 the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy do not allow definitive conclusions; however, a slight increase in risk cannot be excluded. Pregnant 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. Upon diagnosis of pregnancy, ACE inhibitor therapy should be discontinued immediately, and alternative therapy initiated if necessary.
It is known that use of ACE inhibitors during the second and third trimesters of pregnancy is toxic to the human fetus (impaired renal function, oligohydramnios, delayed ossification of skull bones) and to the newborn (renal failure, arterial hypotension, hyperkalemia). In the mother, oligohydramnios may develop, possibly as a manifestation of impaired fetal renal function, which may lead 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 took ACE inhibitors should be monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Lercanidipine.
Data on the use of lercanidipine in pregnant women are lacking.
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 reproductive age who do not use effective contraception.
Combination of enalapril and lercanidipine.
Data on the use of enalapril maleate/lercanidipine hydrochloride in pregnant women are insufficient or lacking. 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 drug, 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 theoretical risk of adverse reactions in infants (effects on cardiovascular system and renal function), and due to insufficient clinical experience with Koripren, enalapril therapy is not recommended in breastfeeding mothers of preterm infants or newborns in the first weeks of life. Breastfeeding in older infants may be permitted only if absolutely necessary and under medical supervision for adverse reactions in the infant.
Lercanidipine
Data on the excretion of lercanidipine in breast milk are lacking, but 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 experienced reversible biochemical changes in the sperm head, potentially negatively affecting fertilization. In cases of repeated unsuccessful in vitro fertilization attempts with no other explanation, 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.
Patients whose blood pressure is not adequately controlled with 10 mg of lercanidipine as monotherapy may increase the lercanidipine dose to 20 mg or switch to treatment with the fixed-dose combination medicine Coripren 10 mg/10 mg.
Individual dose titration may be recommended. Transition from monotherapy to a fixed combination may also be considered if clinically appropriate.
The tablets are administered orally. The recommended dose is 1 tablet once daily.
The medicinal product should preferably be taken in the morning, at least 15 minutes before breakfast. This medicine should not be taken with grapefruit juice.
Elderly patients. Treatment of patients depends on renal function status.
Dosage in renal impairment: Coripren 10 mg/10 mg is contraindicated in patients with severe renal function impairment (creatinine clearance < 30 mL/min) and in patients undergoing hemodialysis. Particular caution should be exercised at the beginning of treatment in patients with mild to moderate renal impairment.
Dosage in hepatic impairment. Coripren 10 mg/10 mg is contraindicated in patients with severe hepatic impairment. Particular caution should be exercised 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 medicine 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 of each of these medicines have been reported. Hospitalization was required in such cases. Reported symptoms (reduction in systolic blood pressure, bradycardia, anxiety, somnolence, and flank pain) could also be related to concomitant intake of high doses of other medicines (e.g., beta-blockers).
Symptoms of enalapril and lercanidipine overdose. The most characteristic symptom of enalapril overdose is hypotension (occurring approximately 6 hours after drug intake) associated with 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 levels of enalaprilat up to 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 common adverse reactions associated with overdose were hypotension, dizziness, headache, and palpitations.
Treatment of enalapril and lercanidipine 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 head elevation. Intravenous administration of angiotensin II and/or catecholamines may be used. If the drug was recently ingested, measures should be taken to eliminate enalapril maleate from the body (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Enalaprilat can be removed from the bloodstream by hemodialysis. The use of a cardiac pacemaker is indicated in bradycardia resistant to therapy. Vital signs, serum electrolyte levels, and serum creatinine levels should be continuously monitored.
In cases of lercanidipine overdose, if severe hypotension, bradycardia, or loss of consciousness develops, cardiovascular support may be beneficial, including intravenous administration of atropine to prevent bradycardia.
Due to the prolonged pharmacological effect of lercanidipine, patients who have taken an excessive dose should be monitored for at least 24 hours. There is no information on the effectiveness of dialysis. Because the drug is highly lipophilic, plasma levels of lercanidipine are not informative regarding the degree of overdose. Dialysis is ineffective.
Adverse reactions.
The safety of Coripren was evaluated in five double-blind controlled clinical studies 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 Coripren administration correspond to those seen with the individual active ingredients of this drug used separately. The most frequently occurring adverse reactions during Coripren treatment 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 drug administration has been established. Adverse reactions are listed by MedDRA system organ classes and categorized according to frequency as follows: 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: |
Hypersensitivity |
| 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 failure |
| 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 component (enalapril or lercanidipine) of the medicinal product individually may also potentially occur with the combined preparation, even if they were not observed during clinical trials or the post-marketing period.
Enalapril
The adverse reactions associated with enalapril administration 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.
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, loss of consciousness, taste disturbances;
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: angioneurotic intestinal oedema.
Hepatobiliary disorders:
Isolated: hepatic failure, hepatocellular or cholestatic hepatitis, 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 symptomatic 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 changes:
Common: hyperkalaemia, increased creatinine levels;
Uncommon: increased blood urea, hyponatraemia;
Isolated: increased liver enzyme levels, increased serum bilirubin levels.
Lercanidipine
The most frequently reported adverse reactions during clinical studies and post-marketing experience are headache, dizziness, peripheral oedema, tachycardia, increased heart rate, and flushing.
Immune system disorders:
Rare: hypersensitivity.
Nervous system disorders:
Common: headache;
Uncommon: dizziness;
Isolated: somnolence, loss of consciousness.
Cardiac disorders:
Common: tachycardia, increased heart rate;
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.
1Spontaneous reports of adverse reactions during the post-marketing period.
Some dihydropyridines may rarely cause precordial pain or angina. Very rarely, in patients with a history of angina, an increase in frequency, duration, and 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. 1, 2 or 4 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Recordati Industria Chimica e Farmaceutica S.p.A., Italy.
Address of the manufacturer and location of business operations.
Via M. Civitali 1, 20148 Milan, Italy.