Lerkamen® 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERKAMEN®10

Composition:

Active substance: lercanidipine;

One film-coated tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.4 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K30, magnesium stearate; coating: ready-made mixture for film coating consisting of hypromellose, talc, titanium dioxide (E 171), polyethylene glycol, iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets with a break line on one side. The break line is intended only for breaking the tablet to facilitate swallowing and is not intended for dividing the tablet into equal doses.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular action. 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. Its antihypertensive effect is due to direct vasorelaxant action on vascular smooth muscles, resulting in reduced total peripheral 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 activity owing to its high vascular selectivity. Since vasodilation induced by lercanidipine hydrochloride develops gradually, acute 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 attributable to its (S)-enantiomer.

Clinical efficacy and safety

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

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

In addition to the clinical trials conducted to confirm the therapeutic indications, another small uncontrolled but randomized study was performed in patients with severe hypertension (mean ± standard deviation of diastolic blood pressure was 114.5 ± 3.7 mm Hg). In this study, blood pressure normalized in 40% of 25 patients receiving lercanidipine hydrochloride 20 mg once daily and in 56% of 25 patients receiving lercanidipine hydrochloride 10 mg twice daily. In a double-blind, randomized, controlled study in patients with systolic hypertension, lercanidipine hydrochloride effectively reduced systolic blood pressure from a mean of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.

Pediatric population

Clinical studies in children have not been conducted.

Pharmacokinetics.

Absorption

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

The two enantiomers of lercanidipine exhibit a similar plasma concentration profile: time to peak 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 essentially the same. Interconversion of enantiomers was not observed in in vivo studies.

Due to high first-pass metabolism, the absolute bioavailability of lercanidipine hydrochloride administered after food intake is approximately 10%, and it decreases to one-third of this value when administered to healthy volunteers in the fasting state.

The bioavailability of lercanidipine hydrochloride after oral administration increases fourfold when taken no later 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 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, inhibition of biotransformation of drugs metabolized by CYP3A4 or CYP2D6 is not expected when lercanidipine hydrochloride is used at therapeutic doses.

Elimination

Elimination occurs 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 was observed after repeated administration.

Linearity/non-linearity

After oral administration of lercanidipine hydrochloride, plasma concentrations are not directly proportional to the administered dose (non-linear kinetics). After administration of 10, 20, and 40 mg, the observed peak plasma concentrations had a ratio of 1:3:8, and the area under the plasma concentration-time curve (AUC) had a ratio of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, bioavailability increases with dose escalation.

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 normally extensively metabolized in the liver.

Preclinical safety data

Data from standard preclinical safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies indicate no special hazard to 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., resulting from excessive pharmacodynamic activity.

Lercanidipine is not genotoxic and does not exhibit carcinogenic potential.

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

Treatment with lercanidipine showed no teratogenic effects in rats and rabbits; however, administration of high doses in rats led to pre- and post-implantation mortality and delayed intrauterine development.

Administration of high doses of lercanidipine hydrochloride (12 mg/kg/day) during labor may lead to dystocia. Distribution of lercanidipine and/or its metabolites in pregnant animals and their passage into breast milk has 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»).
• Outflow tract obstruction from the left ventricle.
• Untreated congestive heart failure.
• Unstable angina or recent myocardial infarction (within the past month).
• Severe hepatic impairment.
• Severe renal impairment (GFR < 30 mL/min), including patients on 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.

Contraindications for concomitant use

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 the strong CYP3A4 inhibitor ketoconazole 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-enantiomer of lercanidipine).

Concomitant use of lercanidipine with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (see section «Contraindications»).

Cyclosporine

Increased plasma concentrations have been observed for both lercanidipine and cyclosporine when administered together. A study conducted in young healthy volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, lercanidipine plasma concentration remained unchanged, while cyclosporine AUC increased by 27%. However, concomitant administration of lercanidipine and cyclosporine results in a threefold increase in lercanidipine plasma concentration 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, 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

Concomitant use of lercanidipine with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution, as antihypertensive efficacy 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 potentiate the effects of vasodilating antihypertensive agents (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 such as amiodarone, quinidine, and sotalol.

Midazolam

Concomitant administration of midazolam and lercanidipine at a dose of 20 mg in elderly volunteers resulted in approximately a 40% increase in lercanidipine absorption and a slower absorption rate (3 hours instead of 1.75 hours to reach maximum concentration). Midazolam concentration was not altered.

Metoprolol

Concomitant administration of lercanidipine and metoprolol (a β-blocker primarily eliminated via 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 occur with other agents 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 showed no pharmacokinetic interaction. However, an average increase of 33% in digoxin Cmax was observed, while AUC and renal clearance were not significantly altered. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for possible signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

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

Cimetidine

Concomitant administration of cimetidine at a daily dose of 800 mg does not cause significant changes in lercanidipine blood concentration; however, higher doses should be used with caution, as they may increase lercanidipine bioavailability and antihypertensive effect.

Simvastatin

When lercanidipine hydrochloride 20 mg was administered repeatedly and concomitantly with simvastatin 40 mg, the AUC of lercanidipine changed only slightly, whereas the AUC of simvastatin increased by 56% and the AUC of the active β-hydroxyacid metabolite 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 agents affecting blood pressure, such as alpha-blockers for relief of urinary symptoms, tricyclic antidepressants, and neuroleptics. Conversely, reduced antihypertensive effect may occur with concomitant use of corticosteroids.

Special precautions for use.

Sinus node dysfunction

Lercanidipine should be used with caution in patients with sinus node dysfunction who do not have a cardiac pacemaker implanted.

Left ventricular dysfunction

Use 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 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 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 should be exercised when treating patients with mild to moderate renal impairment. Although the usual recommended dose of 10 mg daily may be well tolerated, dose escalation to 20 mg daily should be approached cautiously.

Antihypertensive effect may be enhanced in patients with moderate hepatic impairment; therefore, dose adjustment may be required in such cases.

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

Peritoneal dialysis

Use of lercanidipine has been associated with turbidity of peritoneal effluent in patients undergoing peritoneal dialysis. The turbidity is related to increased triglyceride concentration in the peritoneal effluent. Although the mechanism is unknown, the turbidity resolves shortly after discontinuation of lercanidipine. This association should be taken into account, as turbidity of peritoneal effluent 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 efficacy (see section «Interaction with other medicinal products and other forms of interaction»).

Alcohol

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

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

One 10 mg film-coated tablet contains 30 mg of lactose monohydrate.

Sodium

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

Paediatric population

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

Use during pregnancy or lactation.

Pregnancy

There are no data on the use of lercanidipine in pregnant women. Animal studies did not reveal teratogenic effects (see preclinical safety data), but such effects have been observed with other dihydropyridine derivatives. LERKAMEN® is not recommended during pregnancy or in women of childbearing potential who are not using contraception.

Breast-feeding

It is unknown whether lercanidipine/metabolites are excreted in human breast milk. Risk to newborns/infants cannot be excluded. LERKAMEN® should not be used during breast-feeding.

Fertility

Clinical data on lercanidipine are lacking. In some patients treated with calcium channel blockers, reversible biochemical changes in the sperm head have been reported, which may negatively affect fertilization. In cases of repeated failed attempts at in vitro fertilization and in the absence of 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 effect on the ability to drive or operate machinery. However, caution is advised, as dizziness, asthenia, fatigue, and in rare cases somnolence, may occur.

Method of Administration and Dosage

Method of Administration

Precautions to be followed when taking the medicinal product or handling it:

• The medicinal product should be taken preferably in the morning, at least 15 minutes before breakfast.
• This medicinal product should not be taken with grapefruit juice (see sections «Contraindications», «Interaction with other medicinal products and other forms of interaction»).

Dosage

The recommended dose is 10 mg orally 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 starting treatment.

For some individuals in whom blood pressure cannot be adequately controlled with a single antihypertensive agent, combination therapy with lercanidipine hydrochloride together with 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, it is unlikely that higher doses will provide greater efficacy; however, the frequency of adverse effects may increase.

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

Patients with renal or hepatic impairment: Extreme caution is required when initiating treatment in patients with mild to moderate renal or hepatic dysfunction. Although these patients generally tolerate the drug well, increasing the daily dose to 20 mg should be done 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 impairment or severe renal impairment (GFR < 30 mL/min), including patients on dialysis (see sections «Contraindications» and «Special Warnings and Precautions for Use»).

Children

Lercanidipine is not recommended for use in children (under 18 years of age) due to lack of clinical experience.

Overdose

From post-marketing experience with lercanidipine, several cases of overdose have been reported (dose range from 30–40 mg to 800 mg, including suicide attempt reports).

Symptoms

As with other dihydropyridines, overdose with lercanidipine leads to excessive peripheral vasodilation resulting in marked arterial hypotension and reflex tachycardia. However, when very high doses are administered, loss of peripheral selectivity may occur, leading to bradycardia and negative inotropic effects. The most commonly reported adverse reactions associated with overdose were arterial hypotension, dizziness, headache, and palpitations.

Treatment

Patients with clinically significant arterial hypotension require active cardiovascular support, including frequent monitoring of cardiac and respiratory function, placement in a supine position with elevated legs, monitoring of circulating fluid volume and diuresis. Due to the prolonged pharmacological effect of lercanidipine, monitoring of the cardiovascular system is essential for at least 24 hours. Since the drug is highly protein-bound, dialysis is unlikely to be effective. In cases of suspected moderate or severe poisoning, patients should be monitored in an intensive care unit.

Adverse Reactions

Overall Safety Profile

The safety of lercanidipine administered at doses of 10 to 20 mg once daily has been evaluated in a double-blind, placebo-controlled clinical trial involving 1200 patients receiving lercanidipine and 603 patients receiving placebo, as well as in long-term, non-controlled clinical studies with an active comparator drug involving 3676 patients with arterial hypertension treated with lercanidipine.

The adverse reactions most frequently reported during clinical trials and post-marketing surveillance are peripheral edema, headache, facial flushing, tachycardia, and palpitations.

Adverse Reaction Table

The table below lists adverse reactions reported during clinical trials and post-marketing experience worldwide, for which there is a reasonable causal relationship to lercanidipine administration. These reactions are classified by organ systems 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 from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

1 Adverse reactions reported spontaneously during post-marketing surveillance worldwide.

Description of selected adverse reactions

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

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

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all 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.

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

Storage conditions. No special storage conditions required. Keep the medicinal product in the original packaging. Store out of reach of children!

Packaging. 7, 14, or 15 tablets per blister; 1 blister with 7 tablets, or 1 or 2 blisters with 14 tablets, or 4 or 6 blisters with 15 tablets in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's location and address of the place of business.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A., Luxembourg.

Address of the Marketing Authorization Holder.

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