Lercamen® 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERKAMENâ20 (LERKAMENâ 20)

Composition:

Active substance: lercanidipine;

One film-coated tablet contains lercanidipine hydrochloride 20 mg, equivalent to lercanidipine 18.8 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K 30, magnesium stearate;

Coating: ready-made mixture for film coating containing: hypromellose, talc, titanium dioxide (E 171), macrogol 6000, iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink, round, biconvex, film-coated tablets with a score line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. Dihydropyridine derivatives. ATC code C08CA13.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle cells. The antihypertensive mechanism of action of lercanidipine is due to its direct relaxant effect on vascular smooth muscle, resulting in a reduction of total peripheral vascular resistance.

Pharmacodynamic effects

Despite the short elimination half-life of lercanidipine, it exerts a prolonged antihypertensive effect due to its high membrane partition coefficient and lacks negative inotropic action owing to its high vascular selectivity. Since the vasodilation induced by lercanidipine hydrochloride occurs 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 its (S)-enantiomer.

Clinical efficacy and safety

The clinical efficacy and safety of lercanidipine at doses ranging from 10 to 20 mg once daily were evaluated in a double-blind, placebo-controlled clinical study (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo), as well as in active-controlled and long-term uncontrolled clinical studies involving 3676 patients with arterial hypertension.

Most clinical trials were conducted in patients with mild to moderate essential arterial hypertension (including elderly patients and patients with diabetes mellitus), who received lercanidipine either as monotherapy or in combination with angiotensin-converting enzyme (ACE) inhibitors, diuretics, or beta-blockers.

In addition to clinical studies conducted to confirm therapeutic indications, another small uncontrolled but randomized study in patients with severe arterial hypertension (mean ± standard deviation of diastolic blood pressure was 114.5 ± 3.7 mm Hg) showed that blood pressure normalized in 40% of 25 patients receiving lercanidipine hydrochloride 20 mg once daily, and in 56% of 25 patients receiving 10 mg twice daily.

In a double-blind, randomized, controlled study comparing lercanidipine hydrochloride with placebo in patients with isolated systolic hypertension, lercanidipine effectively reduced systolic blood pressure from a mean baseline value of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.

Pediatric population

No clinical trials have been conducted in children.

Pharmacokinetics.

Absorption

Lercanidipine hydrochloride is completely absorbed after oral administration of 10–20 mg, with peak plasma concentrations of 3.30 ± 2.09 ng/mL and 7.66 ± 5.90 ng/mL, respectively, reached within 1.5–3 hours after intake.

The two enantiomers of lercanidipine exhibit a similar plasma concentration profile: time to peak plasma concentration is identical, peak plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer, and the elimination half-life of both enantiomers is mainly comparable. Interconversion of enantiomers was not observed in in vivo studies.

Due to extensive first-pass metabolism in the liver, the absolute bioavailability of orally administered lercanidipine hydrochloride is approximately 10% when taken after a meal, and decreases to one-third of this value when administered to healthy volunteers on an empty stomach.

The bioavailability of lercanidipine hydrochloride after oral administration increases fourfold if taken no sooner than 2 hours after a high-fat meal; therefore, lercanidipine hydrochloride should be taken before meals.

Distribution

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

The extent of lercanidipine binding to plasma proteins exceeds 98%. Since plasma protein levels may be reduced in patients with severe renal or hepatic impairment, the free fraction of the drug may be increased.

Biotransformation

Lercanidipine hydrochloride is actively metabolized by the CYP3A4 enzyme; unchanged drug is not detected in urine or feces. It is primarily converted into inactive metabolites, and approximately 50% of the administered dose is excreted in the urine.

In vitro experiments with human liver microsomes have demonstrated that lercanidipine weakly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its peak plasma concentrations achieved after a 20 mg dose. Furthermore, interaction studies in humans have shown that lercanidipine does not alter plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate. Therefore, clinically significant effects on the biotransformation of drugs metabolized by CYP3A4 or CYP2D6 are not expected when lercanidipine hydrochloride is used at therapeutic doses.

Elimination

Elimination occurs primarily via biotransformation.

The mean elimination half-life is 8–10 hours, and the therapeutic effect lasts for 24 hours due to the high degree of lercanidipine binding to cellular membrane lipids. No accumulation occurs with repeated administration.

Linearity/Non-linearity

After oral administration, plasma concentrations of lercanidipine hydrochloride are not directly proportional to the administered dose (non-linear kinetics). Following single doses of 10, 20, or 40 mg, observed peak plasma concentrations showed a ratio of 1:3:8, and plasma concentration-time AUC ratios were 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, the bioavailability of lercanidipine 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 in the general population. In patients with severe renal dysfunction or undergoing hemodialysis, drug concentrations were higher (approximately 70%). In patients with moderate or severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as it is primarily metabolized in the liver.

Preclinical safety data

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

Safety pharmacology studies in animals showed no effects on the autonomic nervous system, central nervous system, or gastrointestinal function at antihypertensive doses.

Significant findings 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 is not genotoxic and shows no carcinogenic risk.

Lercanidipine had no effect on fertility or general reproductive performance in rats.

Treatment with lercanidipine had no effect on teratogenicity in rats and rabbits; however, in rats, administration of high doses led to pre- and post-implantation loss and delayed intrauterine development.

Administration of high doses of lercanidipine hydrochloride (12 mg/kg/day) during parturition may cause dystocia. The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion into milk have not been studied.

Metabolites were not evaluated separately in toxicological studies.

Clinical characteristics.

Indications.

Mild to moderate essential hypertension.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").
• Left ventricular outflow tract obstruction.
• Untreated congestive heart failure.
• Unstable angina or recent myocardial infarction (within the last month).
• Severe hepatic impairment.
• Severe renal impairment (GFR < 30 mL/min), including patients undergoing dialysis.
• Concomitant use with strong CYP3A4 inhibitors, cyclosporine, grapefruit, or grapefruit juice (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated

CYP3A4 inhibitors

Lercanidipine is known to be metabolized by the CYP3A4 enzyme; therefore, CYP3A4 inhibitors administered concomitantly with lercanidipine may affect its metabolism and elimination.

Interaction studies with ketoconazole, a strong CYP3A4 inhibitor, showed a significant increase in plasma concentrations of lercanidipine (15-fold increase in AUC [area under the curve] and 8-fold increase in Cmax of the S-lercanidipine enantiomer).

Concomitant use of lercanidipine with CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, and clarithromycin should be avoided (see section "Contraindications").

Cyclosporine

Increased plasma concentrations of both lercanidipine and cyclosporine have been observed when administered concomitantly. A study in young healthy volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, plasma concentrations of lercanidipine remained unchanged, while cyclosporine AUC increased by 27%. However, concomitant administration of lercanidipine and cyclosporine resulted in a 3-fold increase in plasma lercanidipine concentrations and a 21% increase in cyclosporine AUC.

Cyclosporine and lercanidipine should not be used together (see section "Contraindications").

Grapefruit or grapefruit juice

As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit or grapefruit juice, leading to increased systemic availability of lercanidipine and enhanced hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section "Contraindications").

Concomitant use is not recommended

CYP3A4 inducers

Lercanidipine should be used with caution when co-administered with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) and rifampicin, as the antihypertensive effect may be reduced. Blood pressure should be monitored more frequently than usual (see section "Special precautions for use").

Alcohol

Alcohol intake should be avoided, as it may potentiate the effect of vasodilating antihypertensive drugs (see section "Special precautions for use").

Safety measures, including dose adjustment

CYP3A4 substrates

Caution should be exercised when administering lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and Class III antiarrhythmics (e.g., amiodarone, quinidine, sotalol).

Midazolam

Concomitant administration of midazolam and lercanidipine 20 mg in elderly volunteers resulted in increased absorption of lercanidipine (approximately 40%) and delayed absorption rate (Tmax increased from 1.75 to 3 hours), while midazolam concentrations remained unchanged.

Metoprolol

Concomitant administration of lercanidipine and metoprolol (a β-blocker primarily metabolized by the liver) did not alter the bioavailability of metoprolol, whereas the bioavailability of lercanidipine decreased by 50%. This effect may be related to reduced hepatic blood flow caused by β-blockers and may also occur with other drugs in this class. Therefore, lercanidipine can be used with β-blockers without restriction, but dose adjustment may be required.

Digoxin

Concomitant administration of lercanidipine 20 mg to patients on chronic β-methyldigoxin therapy revealed no pharmacokinetic interaction. However, a 33% increase in digoxin Cmax was observed, while no significant changes in AUC or renal clearance occurred. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

Interaction studies with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) conducted in volunteers aged 65 ± 7 years (mean ± standard deviation) showed no clinically significant changes in lercanidipine pharmacokinetics.

Cimetidine

Concomitant administration of cimetidine at a daily dose of 800 mg did not cause significant changes in lercanidipine plasma concentrations. However, caution is advised at higher doses, as increased bioavailability and antihypertensive effect of lercanidipine may occur.

Simvastatin

When lercanidipine 20 mg was repeatedly co-administered with 40 mg simvastatin, the AUC of lercanidipine changed insignificantly, while the AUC of simvastatin increased by 56% and the AUC of its active metabolite, β-hydroxy acid, increased by 28%. Such changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as recommended for this medicinal product.

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 blood pressure-affecting drugs such as alpha-blockers (used for urinary symptoms), tricyclic antidepressants, and neuroleptics. Conversely, reduced antihypertensive effects may occur with concomitant use of corticosteroids.

Special precautions for use.

Sinus node weakness syndrome

Extreme caution is required when administering lercanidipine to patients with sinus node weakness syndrome who do not have a cardiac pacemaker implanted.

Left ventricular dysfunction

Lercanidipine should be administered with caution in patients with left ventricular dysfunction, despite the fact that hemodynamically controlled studies have not revealed any disturbances in ventricular function.

Ischemic heart disease

It is believed that certain short-acting dihydropyridines are associated with an increased cardiovascular risk in patients with ischemic heart disease. Although lercanidipine is a long-acting agent, it should still be used with caution in such patients.

Some dihydropyridines may, in isolated cases, provoke chest pain or angina. Very rarely, patients with pre-existing angina may experience an increase in the frequency, duration, and severity of angina attacks. In individual cases, myocardial infarction may occur (see section "Adverse reactions").

Use in renal or hepatic impairment

Particular caution is required when treating patients with mild to moderate renal dysfunction. Although the usual recommended dose of 10 mg daily is generally well tolerated in these patients, dose escalation to 20 mg daily should be approached cautiously. The antihypertensive effect of the drug may be enhanced in patients with moderate hepatic impairment; therefore, dose adjustment may be necessary in such cases.

Lercanidipine is contraindicated in patients with severe hepatic or severe renal impairment (GFR < 30 mL/min), including patients undergoing hemodialysis (see sections "Dosage and administration" and "Contraindications").

Peritoneal dialysis

Administration of lercanidipine has been associated with dialysate clouding in patients undergoing peritoneal dialysis. Clouding is due to elevated triglyceride levels in the effluent dialysate. Although the mechanism of this phenomenon is not fully understood, the clouding resolves shortly after discontinuation of lercanidipine. This feature should be taken into account, as dialysate clouding may be mistakenly interpreted as infectious peritonitis, potentially leading to unnecessary hospitalization and empirical antibiotic therapy.

CYP3A4 inducers

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

Alcohol

Concomitant alcohol intake should be avoided, as it may enhance the vasodilatory antihypertensive effect of the drug (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

This medicinal product contains lactose and therefore should not be administered to patients with rare hereditary conditions such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

One 20 mg film-coated tablet contains 60 mg of lactose monohydrate.

Sodium

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

Paediatric population

The safety and efficacy of lercanidipine in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of lercanidipine during pregnancy are lacking. Animal studies have not revealed teratogenic effects (see preclinical safety data), although such effects have been observed with other dihydropyridine derivatives. LERKAMEN® is not recommended for use during pregnancy or in women of childbearing potential who are not using contraception.

Breastfeeding

It is unknown whether lercanidipine or its metabolites pass into human breast milk. Risk to newborns or infants cannot be excluded. LERKAMEN® should not be taken during breastfeeding.

Fertility

Clinical data on lercanidipine are lacking. Cases have been reported in which calcium channel blockers caused reversible biochemical changes in the sperm head in some patients, potentially affecting the fertilization process. In cases of repeated unsuccessful in vitro fertilization attempts without other explanations, calcium channel blockers should be considered as a possible cause.

Ability to influence reaction speed when driving or operating machinery.

LERKAMEN® has a negligible influence on the ability to drive or operate machinery. However, caution is advised, as dizziness, asthenia, fatigue, and rarely somnolence may occur.

Method of Administration and Dosage

Method of Administration

Lercanidipine should be taken in the morning, at least 15 minutes before breakfast.

This medicinal product must not be taken with grapefruit juice (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Dosage. The recommended dose is 10 mg once daily, taken at least 15 minutes before a meal. The dose may be increased to 20 mg depending on individual patient response. Dose titration should be gradual, as the maximum antihypertensive effect may not be achieved until 2 weeks after initiation of treatment.

In some patients in whom blood pressure is not adequately controlled with a single antihypertensive agent, combination therapy with lercanidipine hydrochloride and a β-blocker (atenolol), a diuretic (hydrochlorothiazide), or an angiotensin-converting enzyme inhibitor (captopril or enalapril) may be appropriate.

Since the dose-response curve is steep and plateaus at doses of 20–30 mg, higher doses are unlikely to provide greater efficacy, while the incidence of adverse effects may increase.

Elderly patients: Although pharmacokinetic data and clinical experience suggest that dose adjustment is not required, particular attention and caution should be exercised at the beginning of treatment in elderly patients.

Patients with renal or hepatic impairment: Particular caution is required when initiating treatment in patients with mild to moderate renal or hepatic impairment. Although such patients generally tolerate the drug well, dose escalation to 20 mg should be performed cautiously. The antihypertensive effect may be enhanced in patients with hepatic impairment; therefore, dose adjustment may be necessary.

Lercanidipine hydrochloride is contraindicated in patients with severe hepatic or severe renal impairment (GFR < 30 mL/min), including patients undergoing dialysis (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Children. The use of lercanidipine in children under 18 years of age is not recommended due to lack of clinical experience.

Overdose.

During the post-marketing period, several cases of lercanidipine overdose have been reported (ranging from 30–40 mg to 800 mg), including a suicide attempt.

Symptoms

As with overdose of other dihydropyridines, lercanidipine overdose causes excessive peripheral vasodilation leading to marked arterial hypotension and reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, resulting in bradycardia and negative inotropic effects. The most commonly reported adverse reactions associated with overdose include arterial hypotension, dizziness, headache, and palpitations.

Treatment

Clinically significant arterial hypotension resulting from overdose requires active cardiovascular support, including measures such as monitoring of cardiac and respiratory function, elevation of the limbs, maintenance of circulating fluid volume, and diuresis.

Due to the prolonged pharmacological effect of lercanidipine, cardiovascular monitoring should be continued for at least 24 hours. Because of the high degree of protein binding of the drug, dialysis is expected to be ineffective. In cases of suspected moderate to severe poisoning, the patient should be observed in an intensive care unit.

Adverse Reactions

General Safety Profile

The safety of lercanidipine administered at doses of 10 to 20 mg once daily was evaluated in a double-blind, placebo-controlled clinical study (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo), as well as in active-controlled and uncontrolled long-term clinical studies with an active comparator drug involving 3676 patients with arterial hypertension who received lercanidipine.

The most commonly reported adverse reactions observed during clinical studies and post-marketing surveillance were: peripheral edema, headache, flushing, tachycardia, and palpitations.

Adverse Reaction Table

The table below lists adverse reactions for which a causal relationship with the use of the drug has been established based on clinical studies and post-marketing surveillance conducted in various countries worldwide.

These reactions are classified by organ system according to MedDRA and by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (frequency cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

MedDRA System Organ Class	Common	Uncommon	Rare	Unknown
Immune system disorders			hypersensitivity
Nervous system disorders	headache	dizziness	somnolence, syncope
Cardiac disorders	tachycardia, palpitations		angina pectoris
Vascular disorders	flushing	arterial hypotension
Gastrointestinal disorders		dyspepsia, nausea, upper abdominal pain	vomiting, diarrhea	gingival hyperplasia1, turbid peritoneal effluent1
Hepatobiliary disorders				elevation of serum transaminases1
Skin and subcutaneous tissue disorders		rash, pruritus	urticaria	angioedema1
Connective tissue, musculoskeletal and bone disorders		myalgia
Renal and urinary disorders		polyuria	pollakiuria
General disorders and administration site conditions	peripheral edema	asthenia, fatigue	chest pain

1 Adverse reactions identified during the post-marketing period based on spontaneous reports from various countries worldwide.

Description of selected adverse reactions

In placebo-controlled clinical trials, the incidence of peripheral edema was 0.9% with lercanidipine at doses of 10 to 20 mg and 0.83% with placebo. In the overall study population, including long-term clinical trials, the incidence reached up to 2%.

Lercanidipine is unlikely to have a negative effect on blood glucose levels or serum lipid levels.

Some dihydropyridines rarely may cause chest pain or angina. Very rarely, in patients with pre-existing angina, the frequency, duration, or severity of attacks may increase. Isolated cases of myocardial infarction may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link:

https://aisf.dec.gov.ua or via the company's website https://www.berlin-chemie.ua

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Store in the original packaging in a place inaccessible to children.

Packaging.

1 blister strip containing 7 film-coated tablets; 1, 2, or 4 blister strips containing 14 film-coated tablets; 6 or 9 blister strips containing 10 film-coated tablets, and the instruction for medical use in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and site of operations.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

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