Lercamen® efg 20/20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERKAMEN® ACF 20/20

Composition:

Active substances: lercanidipine, enalapril;

One film-coated tablet contains lercanidipine hydrochloride 20 mg (equivalent to lercanidipine 18.88 mg) and enalapril maleate 20 mg (equivalent to enalapril 15.29 mg);

Excipients:

Tablet core: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone (K30); sodium bicarbonate; magnesium stearate;

Film coating: 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: round, biconvex, film-coated tablets of orange color, 12 mm in diameter.

Pharmacotherapeutic group. ACE inhibitors and calcium channel blockers: enalapril and lercanidipine.

ATC code C09BB02.

Pharmacological Properties

Pharmacodynamics

Lerkamen® ACE is a combination medicinal product containing lercanidipine hydrochloride (a calcium channel blocker) and enalapril maleate (an ACE inhibitor), two antihypertensive agents with complementary mechanisms of action for controlling blood pressure in patients with essential hypertension.

Enalapril

Enalapril maleate is the maleic acid salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to blockade of the negative feedback mechanism of renin release) and decreased aldosterone secretion.

Since ACE is identical to kininase II, enalapril may also inhibit the breakdown of bradykinin, a potent vasodilator peptide. However, the therapeutic relevance of this mechanism remains unclear.

Although enalapril primarily reduces blood pressure by inhibiting the renin-angiotensin-aldosterone system, it is also effective in patients with low plasma renin levels.

In patients with arterial hypertension, enalapril administration reduces blood pressure in both supine and upright positions without significantly increasing heart rate.

Symptomatic orthostatic hypotension is rarely observed. In some patients, normalization of blood pressure occurs over several weeks of treatment. Abrupt discontinuation of enalapril does not lead to a sudden rise 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 usually observed within 1 hour, with maximal blood pressure reduction occurring 4–6 hours after administration. The duration of effect is dose-dependent; however, at recommended doses, antihypertensive and hemodynamic effects last for at least 24 hours.

Hemodynamic studies in patients with essential hypertension have demonstrated that blood pressure reduction is associated with decreased peripheral vascular resistance and increased cardiac output, with no significant change or only minimal change in heart rate. Following enalapril administration, renal blood flow increases, while glomerular filtration rate remains unchanged. There is no evidence of sodium and water retention. However, in patients with low glomerular filtration rate prior to treatment, these parameters generally improved.

In short-term clinical trials, enalapril administration in patients with and without diabetes mellitus and with kidney disease was associated with reduced albuminuria and decreased urinary excretion of IgG and total urinary protein.

The combined use of ACE inhibitors and angiotensin II receptor blockers has been evaluated in two large-scale, randomized, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).

ONTARGET was a trial conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial conducted in patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Therefore, the concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and incidence of stroke were higher in the aliskiren group compared to the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.

Lercanidipine

Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle. Its antihypertensive mechanism is based on direct relaxation of vascular smooth muscle, leading to a reduction in 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 vasodilation induced by lercanidipine develops gradually, acute arterial hypotension with reflex tachycardia is rarely observed in patients with arterial hypertension.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is primarily attributed to the (S)-enantiomer.

Enalapril/Lercanidipine

The combination of these two substances demonstrates an additive antihypertensive effect, resulting in greater blood pressure reduction than either component alone.

Lerkamen® ACE 20/20

In a randomized, double-blind, factorial-designed, placebo- and active comparator-controlled trial involving 1039 patients with moderate arterial hypertension (defined as seated diastolic blood pressure of 100–109 mm Hg and seated systolic blood pressure in the office < 180 mm Hg, and seated home diastolic blood pressure ≥ 85 mm Hg), patients receiving the combination of enalapril 20 mg/lercanidipine 20 mg achieved significantly greater reductions in seated office and home diastolic and systolic blood pressure compared to placebo (P < 0.001). With the 20 mg/20 mg combination therapy, clinically significant differences were observed in the change from baseline in seated office diastolic blood pressure (-15.2 mm Hg, n = 113) compared to monotherapy with enalapril 20 mg (-11.3 mm Hg, P = 0.004, n = 113) or lercanidipine 20 mg (-13.0 mm Hg, P = 0.092, n = 113). Similar differences in the change from baseline in seated office systolic blood pressure (-19.2 mm Hg) were observed compared to monotherapy with lercanidipine 20 mg (-13.0 mm Hg, P = 0.002) or enalapril 20 mg (-15.3 mm Hg, P = 0.055). Similar differences were also observed for home systolic and diastolic blood pressure values. A significant increase in response rates for seated diastolic blood pressure (75%) and seated systolic blood pressure (71%) was observed with the 20 mg/20 mg combination therapy compared to placebo (P < 0.001) and both monocomponents (P < 0.01). Blood pressure normalization was achieved in a higher proportion of patients receiving the 20 mg/20 mg combination therapy (42%) compared to those receiving placebo (22%).

Pharmacokinetics

No pharmacokinetic interaction was observed when enalapril and lercanidipine were administered concomitantly.

Enalapril

Absorption

After oral administration, enalapril is rapidly absorbed, and peak serum concentrations are reached within 1 hour. Based on urinary recovery, the extent of absorption of enalapril following oral administration as enalapril maleate is approximately 60%. Food does not affect the absorption of enalapril.

Distribution

Following absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur approximately 4 hours after oral administration of enalapril maleate. The effective elimination half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved by Day 4 of treatment. At therapeutic concentrations, enalaprilat binds to plasma proteins by no more than 60%.

Biotransformation

Apart from conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

Elimination

Enalaprilat is primarily eliminated via the kidneys. The main components in urine are enalaprilat (approximately 40% of the administered dose) and unchanged enalapril (approximately 20%).

Renal Dysfunction

Exposure to enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), the steady-state AUC of enalaprilat is approximately twice that in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately 8-fold. The effective elimination half-life of enalaprilat after multiple doses of enalapril maleate is prolonged at this level of renal impairment, and the time to reach steady-state concentration is increased (see section "Dosage and Administration"). Enalaprilat can be removed from systemic circulation by hemodialysis. Dialysis clearance is 62 mL/min.

Lactation

Four to six hours after a 20 mg oral dose, the peak concentration of enalapril in breast milk from five postpartum women averaged 1.7 µg/L (range: 0.54–5.9 µg/L). The average peak concentration of enalaprilat was 1.7 µg/L (range: 1.2–2.3 µg/L); peak concentrations occurred at varying times within 24 hours. Based on peak concentration data in breast milk, it is estimated that an exclusively breastfed infant receives no more than 0.16% of the maternal dose adjusted for body weight. In one woman taking 10 mg enalapril orally daily for 11 months, peak enalapril concentration (2 µg/L) occurred approximately 4 hours after dosing, and peak enalaprilat concentration (0.75 µg/L) occurred approximately 9 hours after dosing. Total daily amounts of enalapril and enalaprilat in breast milk were 1.44 µg/L and 0.63 µg/L, respectively. Four hours after a single 5 mg dose of enalapril in one patient and single 10 mg doses in two patients, enalaprilat levels in breast milk were below the limit of detection (< 0.2 µg/L); enalapril levels were not determined.

Lercanidipine

Absorption

Lercanidipine is completely absorbed after oral administration, and peak plasma concentrations are reached approximately 1.5–3 hours post-dose.

The two enantiomers of lercanidipine exhibit identical plasma concentration profiles: peak time is identical, and 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. In vivo interconversion of the two enantiomers does not occur.

Due to extensive first-pass metabolism, the absolute bioavailability of orally administered lercanidipine under fasting conditions is approximately 10%. However, bioavailability in healthy volunteers under fasting conditions decreases to one-third of this value.

Oral bioavailability of lercanidipine increases fourfold when administered 2 hours after a high-fat meal. Therefore, the medication should be taken before meals.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive.

Plasma protein binding of lercanidipine exceeds 98%. Because protein levels may be reduced in patients with severe renal or hepatic dysfunction, the concentration of free lercanidipine fractions may be higher.

Biotransformation

Lercanidipine is extensively metabolized by the CYP3A4 enzyme; no parent compound is detected in urine or feces. It is primarily converted into inactive metabolites, with approximately 50% of the dose excreted in urine.

In vitro experiments with human liver microsomes demonstrated that lercanidipine weakly inhibits two enzymes, CYP3A4 and CYP2D6, at concentrations 160 and 40 times higher, respectively, than peak plasma concentrations achieved after a 20 mg dose.

Additionally, interaction studies in humans showed that lercanidipine does not alter plasma levels of midazolam (a typical CYP3A4 substrate) or metoprolol (a typical CYP2D6 substrate). Therefore, clinically significant metabolic interactions with drugs metabolized by CYP3A4 or CYP2D6 are not expected when lercanidipine is used at therapeutic doses.

Elimination

Elimination occurs primarily via biotransformation. The mean terminal elimination half-life is 8–10 hours; due to high affinity for lipid membranes, therapeutic activity lasts up to 24 hours. No accumulation occurs with repeated dosing.

Linearity/Non-linearity

Plasma levels of lercanidipine after oral administration are not directly proportional to dose (non-linear kinetics). After administration of 10, 20, or 40 mg, observed peak plasma concentrations were in the ratio 1:3:8, and areas under the plasma concentration-time curve were in the ratio 1:4:18, suggesting progressive saturation of first-pass metabolism. Consequently, bioavailability increases with dose.

Additional Information on Special Populations

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic impairment are similar to those in the general patient population. In patients with severe renal impairment or those undergoing dialysis, drug concentrations are higher (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as the drug is normally extensively metabolized in the liver.

Preclinical Safety Data

Combination of Enalapril and Lercanidipine

The potential toxicity of the combined enalapril and lercanidipine formulation was studied in rats: the drug was administered orally for 3 months, and two genotoxicity tests were performed. The toxicological profile of the combination product did not differ from that of the individual components when administered separately.

Separate data are available for the two components—enalapril and lercanidipine.

Enalapril

Preclinical data from traditional safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans.

Reproductive toxicity studies suggest that enalapril does not affect fertility or reproductive function in rats and has no teratogenic effects. However, when administered to female rats before mating and throughout pregnancy, increased offspring mortality was observed during lactation. The drug crosses the placenta and is excreted in milk. ACE inhibitors have been shown to adversely affect late fetal development, potentially leading to fetal death and cranial malformations. Additionally, fetotoxicity, delayed intrauterine development, and patent ductus arteriosus have been reported. These developmental abnormalities may be partly explained by the direct effect of ACE inhibitors on the fetal renin-angiotensin system, partly by maternal hypotension-induced ischemia, and reduced placental blood flow and oxygen and nutrient supply to the fetus.

Lercanidipine

Data from standard preclinical safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies indicate no special hazard for humans.

Significant effects observed in long-term studies in rats and dogs were directly or indirectly related to the known effects of high doses of calcium antagonists—i.e., consequences of excessive pharmacodynamic activity.

Lercanidipine treatment did not affect fertility or general reproductive function in rats; however, administration of high doses led to pre- and post-implantation loss and delayed intrauterine development. Teratogenic effects of lercanidipine were not observed in rats and rabbits, although teratogenicity of other dihydropyridine derivatives has been demonstrated in animal studies. High-dose lercanidipine (12 mg/kg/day) administered during delivery may cause dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their passage into milk has not been studied.

Clinical characteristics.

Indications.

Lerkamen® ACE 20/20 is indicated for the treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with 20 mg enalapril and 20 mg lercanidipine administered concomitantly as separate tablets.

Contraindications.

• Hypersensitivity to any angiotensin-converting enzyme (ACE) inhibitor or calcium channel blockers of the dihydropyridine class, or to any of the excipients (see section "Composition").
• History of angioedema associated with previous ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Obstruction of blood outflow from the left ventricle.
• Uncompensated heart failure.
• Unstable angina or within one month following myocardial infarction.
• Severe renal impairment (GFR < 30 mL/min), including patients on hemodialysis.
• Severe hepatic impairment.
• Concomitant use with:
  • potent CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction");
  • cyclosporine (see section "Interaction with other medicinal products and other forms of interaction");
  • grapefruit or grapefruit juice (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use in combination with sacubitril/valsartan therapy. Enalapril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Concomitant use of Lerkamen® ACE with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction.

The antihypertensive effect of Lerkamen® ACE may be enhanced by other medicinal products that lower blood pressure, such as diuretics, β-blockers, α-blockers, and other substances.

Additionally, the following interactions have been observed with each of the active substances in this medicinal product.

Enalapril maleate

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of developing angioedema (see section "Special precautions for use").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren is associated with an increased frequency of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

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 substances may lead to a significant increase in serum potassium concentration. Caution is advised when enalapril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of enalapril with the above-mentioned agents is not recommended. If such agents are co-administered due to documented hypokalemia, they should be used with caution and under frequent monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Diuretics (thiazide and loop diuretics)

Prior treatment with high doses of diuretics may lead to reduced blood volume and increase the risk of arterial hypotension at the initiation of enalapril therapy (see section "Special precautions for use"). Hypotensive effects may be minimized by discontinuing diuretics, increasing salt or fluid intake, or using a low initial dose 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 additional reduction of arterial blood pressure.

Lithium

Reversible increases in serum lithium concentrations and enhanced lithium toxicity have been observed during concomitant use of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase lithium levels and thereby enhance lithium toxicity when used with ACE inhibitors. Therefore, concomitant use of enalapril with lithium-containing medicinal products is not recommended. However, if such combination is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

Tricyclic antidepressants/antipsychotics/anesthetics/narcotics

Additional reduction in arterial blood pressure may occur when certain anesthetics, tricyclic antidepressants, or antipsychotics are used concomitantly with ACE inhibitors (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, may reduce the efficacy of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be diminished when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs (including selective COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium levels and may lead to worsening of renal function. These effects are usually reversible. In rare cases, acute renal failure may develop, particularly in patients with impaired renal function (e.g., elderly or dehydrated patients, including those receiving diuretic therapy). Therefore, concomitant use of these agents should be prescribed with caution, especially in patients with renal impairment. Adequate hydration should be ensured. Renal function should be monitored periodically, both after initiation and during continued combination therapy.

Gold preparations

Rare nitritoid-like reactions, including facial flushing, nausea, vomiting, and arterial hypotension, have been reported during concomitant use of ACE inhibitors, including enalapril, with injectable gold preparations (sodium aurothiomalate).

Sympathomimetics

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Antidiabetic agents

Epidemiological studies suggest that concomitant use of ACE inhibitors with antidiabetic agents (insulin, oral hypoglycemic agents) may reduce blood glucose levels, increasing the risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combined therapy and in patients with renal impairment (see sections "Special precautions for use" and "Adverse reactions").

Alcohol

Alcohol may enhance the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers

Concomitant use of enalapril with acetylsalicylic acid (in cardiologic doses), thrombolytics, and β-blockers is not associated with risk.

Lercanidipine

Concomitant use is contraindicated

CYP3A4 inhibitors

Lercanidipine is metabolized by the CYP3A4 enzyme, and therefore concomitant administration of CYP3A4 inhibitors may affect the metabolism and excretion of lercanidipine.

In a drug interaction study with ketoconazole, a potent CYP3A4 inhibitor, a significant increase in plasma concentrations of lercanidipine was observed (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 potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) is contraindicated (see section "Contraindications").

Cyclosporine

Increased plasma concentrations of both lercanidipine and cyclosporine have been observed after concomitant use. A study in young healthy volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, plasma levels of lercanidipine were unchanged, but cyclosporine AUC increased by 27%. When lercanidipine and cyclosporine were administered simultaneously, a 3-fold increase in plasma lercanidipine levels and a 21% increase in cyclosporine AUC were observed.

Cyclosporine and lercanidipine should not be used together (see section "Special precautions for use").

Grapefruit or grapefruit juice

As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit or grapefruit juice, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect.

Lercanidipine should not be taken with grapefruit or grapefruit juice (see section "Contraindications").

Concomitant use not recommended

CYP3A4 inducers

Caution is advised when lercanidipine is used concomitantly with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) and rifampicin, as the antihypertensive effect of lercanidipine may be reduced, and blood pressure should be monitored more frequently than usual (see section "Special precautions for use").

Alcohol

Alcohol consumption should be avoided as it may enhance the vasodilatory effect of antihypertensive agents (see section "Special precautions for use").

Safety measures, including dose adjustment

CYP3A4 substrates

Caution is advised when lercanidipine is co-administered with other CYP3A4 substrates such as terfenadine, astemizole, or class III antiarrhythmics (e.g., amiodarone, quinidine, sotalol).

Midazolam

In elderly volunteers, concomitant oral administration of 20 mg midazolam increased lercanidipine absorption (by approximately 40%) but decreased its absorption rate (tmax increased from 1.75 to 3 hours). Midazolam concentration was unchanged.

Metoprolol

Concomitant use of lercanidipine and metoprolol (a β-blocker primarily eliminated via the liver) did not alter the bioavailability of metoprolol, but the bioavailability of lercanidipine was reduced by 50%. This effect may be due to reduced hepatic blood flow caused by β-blockers and may also occur with other agents in this class. Therefore, lercanidipine can be safely used concomitantly with β-adrenergic blockers, but dose adjustment may be necessary.

Digoxin

Concomitant use of 20 mg lercanidipine in patients chronically receiving β-methyldigoxin did not reveal any pharmacokinetic interaction. However, a 33% increase in digoxin Cmax (mean maximum concentration) was observed, while no significant changes occurred in AUC or renal clearance. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for possible signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

A drug interaction study of lercanidipine with fluoxetine, an inhibitor of CYP2D6 and CYP3A4, conducted in healthy volunteers aged 65 ± 7 years (mean ± standard deviation), did not reveal any clinically significant modification of lercanidipine pharmacokinetics.

Cimetidine

Concomitant use of cimetidine 800 mg daily did not cause significant changes in lercanidipine plasma levels; however, caution is required with higher cimetidine doses, as bioavailability and thus the antihypertensive effect of lercanidipine may be increased.

Simvastatin

When lercanidipine 20 mg was repeatedly administered concomitantly with 40 mg simvastatin, AUC of lercanidipine changed insignificantly, while AUC of simvastatin increased by up to 56% and AUC of its main metabolite, β-hydroxy acid, by up to 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 drugs in this class.

Warfarin

Concomitant administration of 20 mg lercanidipine on an empty stomach did not alter the pharmacokinetics of warfarin in healthy volunteers.

Diuretics and ACE inhibitors

Lercanidipine can be safely used concomitantly with diuretics and ACE inhibitors.

Other medicinal products affecting blood pressure

As with other antihypertensive agents, enhanced hypotensive effects may occur when lercanidipine is used concomitantly with other medicinal products affecting blood pressure, such as α-blockers used for urinary symptoms, tricyclic antidepressants, or neuroleptics. Conversely, attenuated antihypertensive effects may occur with concomitant use of corticosteroids.

Children

Interaction studies have been conducted only in adults.

Special precautions for use.

Symptomatic arterial hypotension

Symptomatic arterial hypotension rarely occurs in patients with uncomplicated arterial hypertension. When treating patients with hypertension using enalapril, the risk of symptomatic hypotension increases if fluid and electrolyte balance is disturbed and fluid loss occurs, for example, after diuretic therapy, salt-restricted diet, dialysis, diarrhea, or vomiting (see section "Interaction with other medicinal products and other forms of interaction"). Symptomatic hypotension has been observed in patients with heart failure (with or without concomitant renal impairment). It occurs more frequently in patients with more severe heart failure, particularly those receiving high doses of loop diuretics, with hyponatremia, or impaired renal function. Treatment of such patients should be initiated under medical supervision, and this monitoring should continue during dose adjustments of enalapril and/or diuretics. The same recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular accident.

In case of arterial hypotension, the patient should be placed in a supine position, and if necessary, intravenous infusion of physiological saline solution should be administered. Reversible hypotensive effect is not a contraindication for further use of the drug, which may be continued after blood pressure has increased following volume repletion.

In some patients with heart failure and normal or low blood pressure, enalapril may cause additional blood pressure reduction. This effect is expected and usually not a reason to discontinue therapy. If arterial hypotension becomes symptomatic, dose reduction and/or discontinuation of diuretic and/or enalapril may be necessary.

Sinus node dysfunction

Lercanidipine should be prescribed with caution to patients with sinus node dysfunction if a pacemaker has not been implanted.

Left ventricular dysfunction

Although hemodynamically controlled studies have not revealed any ventricular dysfunction, lercanidipine should be used with caution in patients with left ventricular dysfunction.

Ischemic heart disease

It is presumed that the use of certain short-acting dihydropyridine derivatives may be associated with increased cardiovascular risk in patients with ischemic heart disease. Although lercanidipine is a long-acting agent, caution is required when prescribing it to such patients.

In rare cases, the use of some dihydropyridine derivatives may cause precordial pain or angina. Very rarely, in patients with existing angina attacks, their frequency, duration, and severity may increase. Isolated cases of myocardial infarction are possible (see section "Adverse reactions").

Use in renal impairment

Particular caution is required when using enalapril in patients with mild or moderate renal impairment. Routine monitoring of these patients should include regular assessment of serum potassium and creatinine levels. Reports of renal impairment associated with enalapril use have primarily involved patients with severe heart failure or underlying kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, enalapril-induced renal impairment is reversible. In some patients with arterial hypertension and no prior kidney disease, combined use of enalapril and diuretics may lead to increased blood urea and creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be necessary. In such cases, the possibility of renal artery stenosis should be considered (see section "Special precautions for use. Renovascular hypertension").

Renovascular hypertension

The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of arterial hypotension and renal failure. In such cases, renal dysfunction may occur with only minor changes in serum creatinine concentration. Treatment of such patients should be initiated under close medical supervision, using low doses and cautious dose titration, with regular monitoring of renal function.

Kidney transplantation

There is no experience with the use of lercanidipine and enalapril in patients who have recently undergone kidney transplantation. Therefore, the use of Lerкамen® АРF in such patients is not recommended.

Hepatic impairment

The antihypertensive effect of lercanidipine may be enhanced in patients with impaired liver function. Rarely, when using ACE inhibitors, a syndrome may develop, beginning with cholestatic jaundice or hepatitis, which rapidly progresses to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or a marked increase in liver enzymes while taking ACE inhibitors should discontinue the drug and receive appropriate treatment.

Peritoneal dialysis

Lercanidipine intake has been associated with dialysate cloudiness in patients undergoing peritoneal dialysis. Cloudiness is due to increased triglyceride concentration in the effluent dialysate. Although the mechanism of this phenomenon is not fully understood, cloudiness resolves soon after discontinuation of lercanidipine. This feature should be considered, as dialysate cloudiness may be mistakenly interpreted as infectious peritonitis, potentially leading to unnecessary hospitalization and empirical antibiotic therapy.

Neutropenia/Agranulocytosis

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and no special risk factors. Enalapril should be used with particular caution in patients with vasculitis, those receiving immunosuppressive agents, allopurinol, procainamide, or in the presence of several of these risk factors, especially with pre-existing renal impairment. Severe infections resistant to antibiotic therapy have developed in some patients. Regular monitoring of the leukocyte count is recommended when using enalapril in such patients, and patients should be instructed to report any signs of infection to their physician.

Hypersensitivity/Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported during treatment with ACE inhibitors, particularly enalapril. This swelling may develop at any time during treatment. In such cases, enalapril should be discontinued immediately; the patient should remain under medical supervision until all symptoms have completely resolved. Even if swelling affects only the tongue without concomitant respiratory distress, prolonged observation is necessary, as treatment with antihistamines and corticosteroids may be insufficient.

Rare cases of death due to laryngeal or lingual angioedema have been reported. When swelling involves the tongue, glottis, or larynx, there is an increased risk of airway obstruction, particularly in patients who have undergone airway surgery.

If swelling extends to the tongue, glottis, or larynx and may cause airway obstruction, immediate appropriate treatment should be initiated, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3 mL – 0.5 mL) and/or measures to ensure airway patency.

Angioedema occurs more frequently in patients of African descent compared to other patients receiving ACE inhibitors.

Patients with a history of angioedema of other etiology belong to a high-risk group for this complication when prescribed ACE inhibitors (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of enalapril. Enalapril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving ACE inhibitors.

Anaphylactoid reactions during desensitization therapy against Hymenoptera venom

Life-threatening anaphylactoid reactions rarely occur when using ACE inhibitors concurrently with desensitization therapy against Hymenoptera venom. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization therapy.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Life-threatening anaphylactoid reactions rarely occur when using ACE inhibitors concurrently with LDL apheresis using dextran sulfate. Such reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis procedure.

Hypoglycemia

In patients with diabetes receiving oral antidiabetic agents or insulin, careful monitoring for hypoglycemia is required at the beginning of ACE inhibitor therapy, especially during the first month of combination therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough

Cough has been reported during treatment with ACE inhibitors. The cough is usually non-productive and resolves after discontinuation of the drug. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.

Surgery/Anesthesia

During major surgical procedures or anesthesia with agents causing arterial hypotension, enalapril inhibits the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension occurs that can be explained by these interaction mechanisms, it may be corrected by increasing fluid volume.

Serum potassium

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. This effect is usually minor in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), and particularly 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 levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Lithium

The combination of lithium and enalapril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade therapy is absolutely necessary, it should be conducted only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not indicated in patients with diabetic nephropathy.

CYP3A4 inducers

CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin may reduce serum levels of lercanidipine, potentially resulting in lower than expected efficacy of lercanidipine (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences

As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in patients of African descent compared to patients of other races, possibly due to a higher prevalence of low renin levels in this population.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Lactation

Lerкамen® АРF is not recommended for use during lactation (see section "Use during pregnancy or breastfeeding").

Children

The safety and efficacy of this combined medicinal product in children have not been established in controlled studies.

Alcohol

Alcohol consumption should be avoided as it may enhance the vasodilatory antihypertensive effect of medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

This medicinal product contains lactose. Patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not use Lerкамen® АРF.

Sodium

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Enalapril

The use of ACE inhibitors (enalapril) is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). The use of ACE inhibitors (enalapril) is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk 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. Women planning pregnancy should have their ACE inhibitor therapy replaced with alternative antihypertensive therapy with an established safety profile for use during pregnancy, except when ACE inhibitor therapy is considered necessary. When pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and alternative therapy initiated if necessary.

The use of ACE inhibitors during the second and third trimesters of pregnancy causes fetotoxic effects in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) (see section "*Preclinical safety data"). Oligohydramnios may occur in the mother, likely as a manifestation of impaired fetal renal function, potentially leading to limb contractures, craniofacial deformities, and pulmonary hypoplasia. Ultrasound examination should be performed in pregnant women who have received an ACE inhibitor 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. Teratogenic effects were not observed in animal studies (see section "Preclinical safety data"), 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 are not using effective contraception (see section "Special precautions for use").

Combination of enalapril and lercanidipine

There is insufficient or no data on the use of enalapril maleate/lercanidipine hydrochloride in pregnant women. Animal studies are insufficient to draw conclusions on reproductive toxicity (see section "Preclinical safety data").

In view of the above, the medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Breastfeeding

Enalapril

Some pharmacokinetic data show very low concentrations of enalapril in breast milk (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 cardiovascular system and renal function) and the lack of clinical experience, enalapril therapy is not recommended in breastfeeding mothers of premature infants or infants in the first weeks of life. Breastfeeding of older infants may allow the mother to take Lerкамen® АРF only if absolutely necessary and under medical supervision for monitoring adverse reactions in the infant.

Lercanidipine

There are no data on the excretion of lercanidipine/metabolites in breast milk. Risk to newborns/infants cannot be excluded. Lercanidipine should not be used during breastfeeding.

Combination of enalapril and lercanidipine

In view of the above, Lerкамen® АРF is not recommended for use during breastfeeding.

Fertility

Clinical data on lercanidipine are lacking. Cases have been reported in which some patients receiving calcium channel blockers developed reversible biochemical changes in the sperm head that could negatively affect fertilization. In cases of repeated unsuccessful attempts at in vitro fertilization and in the absence of other explanations, the possibility that calcium channel blockers may have contributed to these failures should be considered.

Ability to influence reaction speed when driving vehicles or operating machinery.

Lerкамen® АРF has a minor influence on the ability to drive vehicles or operate machinery. However, caution is advised, as dizziness, asthenia, fatigue, and rarely somnolence may occur (see section "Adverse reactions").

Method of Administration and Dosage

Lerkamen® ACF 20/20

Adult patients whose blood pressure is adequately controlled with enalapril 20 mg and lercanidipine 20 mg administered simultaneously as separate tablets may be switched to the combined medicinal product Lerkamen® ACF 20/20.

Dosage

The recommended dose is one tablet once daily, taken at least 15 minutes before a meal.

Elderly Patients

Dosage depends on the patient's renal function (see below "Patients with Renal Impairment").

Patients with Renal Impairment

Lerkamen® ACF is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) or those undergoing hemodialysis (see sections "Contraindications" and "Special Warnings and Precautions for Use"). Caution should be exercised when administering the drug to patients with mild or moderate renal impairment.

Patients with Hepatic Impairment

Lerkamen® ACF is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering the drug to patients with mild or moderate hepatic impairment.

Method of Administration

Precautions during administration or handling of this medicinal product:

• The drug should preferably be taken in the morning, at least 15 minutes before breakfast;
• This drug should not be taken with grapefruit juice (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Contraindications").

Children

The use of Lerkamen® ACF in children for the treatment of arterial hypertension is not recommended.

Overdose

In post-marketing experience, several cases of intentional overdose requiring hospitalization have been reported following ingestion of enalapril/lercanidipine at doses ranging from 100 to 1000 mg of each substance. Symptoms reported (reduced systolic pressure, bradycardia, restlessness, somnolence, and flank pain) may have resulted from concomitant use of other medicinal products in high doses (e.g., β-blockers).

Symptoms of Enalapril and Lercanidipine Overdose Separately

The most prominent signs of enalapril overdose reported to date are marked hypotension beginning approximately six hours after tablet ingestion, associated with blockade of the renin-angiotensin system and stupor. In cases of ACE inhibitor overdose, symptoms may include acute circulatory failure, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalaprilat levels following ingestion of 300 mg and 440 mg of enalapril were 100 and 200 times higher, respectively, than levels typically observed after therapeutic doses.

As with other dihydropyridines, lercanidipine overdose causes marked peripheral vasodilation with profound hypotension and reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, resulting in bradycardia and negative inotropic effects. The most common adverse reactions associated with overdose were hypotension, dizziness, headache, and palpitations.

Treatment in Case of Enalapril and Lercanidipine Overdose Separately

In cases of enalapril overdose, intravenous infusion of physiological saline is recommended. If arterial hypotension develops, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines should be considered if possible. If treatment is initiated immediately after tablet ingestion, measures to remove enalapril maleate from the gastrointestinal tract should be taken (e.g., by inducing emesis, gastric lavage, administration of adsorbents, or sodium sulfate). Enalaprilat can be removed from the systemic circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In cases of persistent bradycardia, therapy with a cardiac pacemaker is indicated. Vital signs, serum electrolyte concentrations, and creatinine levels should be monitored continuously.

Clinically significant hypotension following lercanidipine administration requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated lower limbs, and monitoring circulating fluid volume and urine output. Due to the prolonged pharmacological action of lercanidipine, cardiovascular status should be monitored for at least 24 hours. Since the drug has a high protein-binding capacity, dialysis is unlikely to be effective. Patients expected to experience moderate to severe intoxication should be observed under strict medical supervision.

Adverse reactions.

Short description of the safety profile

The safety of Lercamen® ACF was evaluated in five double-blind controlled clinical studies and in two long-term open-label extension phases. Overall, 1,141 patients received Lercamen® ACF. The adverse effects of this combined therapy correspond to the adverse effects typical of the individual components of the drug when used separately. The most commonly occurring adverse reactions during treatment with Lercamen® ACF are cough (4.03%), dizziness (1.67%), and headache (1.67%).

Short description of adverse reactions in table form

The table below lists adverse reactions reported during clinical trials of Lercamen® ACF that have a clear causal relationship, classified by MedDRA organ systems and frequency of occurrence. 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); not known (cannot be estimated based on available data).

Adverse effects that occurred in only one patient are listed with a frequency of "rarely".

Description of individual adverse reactions

The frequency of individual recorded adverse reactions commonly observed during monotherapy with enalapril and lercanidipine is presented in the table below, based on data from a double-blind, randomized, factorial clinical study.

Additional information on individual components

Adverse reactions reported with the use of one of the components (enalapril or lercanidipine) may also be potential adverse reactions of Lerkamen® ACE, even if they were not observed during clinical trials or in the post-marketing period.

Enalapril individually

Enalapril may cause the following adverse reactions.

Disorders of the blood and lymphatic system

Uncommon: anaemia (including aplastic and haemolytic).

Rare: neutropenia, decreased haemoglobin concentration, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine system disorders

Unknown frequency: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Uncommon: hypoglycaemia (see section "Special precautions for use").

Psychiatric disorders

Common: depression.

Uncommon: confusion, increased excitability, insomnia.

Rare: pathological dreams, sleep disorders.

Nervous system disorders

Very common: dizziness.

Common: headache, syncope, taste disturbances.

Uncommon: somnolence, paraesthesia, vertigo.

Eye disorders

Very common: blurred vision.

Ear and labyrinth disorders

Uncommon: tinnitus.

Cardiac disorders

Common: chest pain, arrhythmia, angina pectoris, tachycardia.

Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, likely secondary to severe hypotension in patients at risk (see section "Special precautions for use").

* Incidence compared to placebo and active control groups in clinical trials.

Vascular disorders

Common: hypotension (including orthostatic hypotension).

Uncommon: flushing, orthostatic hypotension.

Rare: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders

Very common: cough.

Common: dyspnoea.

Uncommon: rhinorrhoea, sore throat or hoarseness, bronchospasm/asthma.

Rare: 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 ulcers.

Rare: stomatitis/aphthous ulcers, glossitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders

Rare: liver failure, hepatitis (hepatocellular or cholestatic), hepatitis with necrosis, cholestasis (including with jaundice).

Skin and subcutaneous tissue disorders

Common: rash, hypersensitivity/angioedema (cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported (see section "Special precautions for use")).

Uncommon: hyperhidrosis, pruritus, urticaria, alopecia.

Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A symptom complex has been described which may include: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive ANA titre, elevated ESR, eosinophilia and leukocytosis. Skin rash, photosensitivity or other skin disorders may occur.

Musculoskeletal, connective tissue and bone disorders

Uncommon: muscle cramps.

Renal and urinary disorders

Uncommon: renal dysfunction, renal failure, proteinuria.

Rare: oliguria.

Reproductive system and breast disorders

Uncommon: impotence.

Rare: gynaecomastia.

General disorders

Very common: asthenia.

Common: fatigue.

Uncommon: weakness, fever.

Investigations

Common: hyperkalaemia, increased serum creatinine concentration.

Uncommon: increased blood urea concentration, hyponatraemia.

Rare: increased liver enzyme activity, increased serum bilirubin levels.

Lercanidipine individually

In controlled clinical studies and during the post-marketing period, the most commonly reported adverse reactions were: peripheral oedema, headache, flushing, tachycardia and palpitations.

Immune system disorders

Rare: hypersensitivity.

Nervous system disorders

Common: headache.

Uncommon: dizziness.

Rare: somnolence, syncope.

Cardiac disorders

Common: tachycardia, palpitations.

Rare: angina pectoris.

Vascular disorders

Common: flushing.

Uncommon: hypotension.

Gastrointestinal disorders

Uncommon: nausea, dyspepsia, upper abdominal pain.

Rare: vomiting, diarrhoea.

Not known: gingival hyperplasia¹, cloudy peritoneal dialysate¹.

Hepatic disorders

Not known: increased serum transaminase levels¹.

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus.

Rare: urticaria.

Not known: angioedema¹.

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

Renal and urinary disorders

Uncommon: polyuria.

Rare: pollakiuria.

General disorders

Common: peripheral oedema.

Uncommon: asthenia, fatigue.

Rare: chest pain.

¹ Adverse reactions reported from spontaneous reports in the post-marketing period.

Some dihydropyridine derivatives may rarely cause precordial pain or angina. Very rarely, in patients with pre-existing angina, an increase in frequency, duration and severity of attacks may occur. In isolated cases, myocardial infarction may develop.

Lercanidipine has no negative effect on blood glucose or serum lipid levels.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorised is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 25 °C. Protect from light and moisture by storing in the original packaging. Keep out of the reach of children.

Packaging. 14 film-coated tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Recordati Industria Chimica e Farmaceutica S.p.A.

Address of the manufacturer and location of its place of business.

Via Matteo Civitali, 1 – 20148 Milan (MI), Italy.

Marketing Authorisation Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorisation Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.

Under licence from RECORDATI