Lernicor^® (Tablets) Instructions for Use

Marketing Authorization Holder

Aliym, JSC (Russia)

Contact Information

Aliym, JSC (Russia)

ATC Code

C08CA13 (Lercanidipine)

Active Substance

Lercanidipine (Rec.INN registered by WHO)

Dosage Forms

	Lernicor®	Film-coated tablets, 10 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 50, 56, 60, 84 or 112 pcs.
		Film-coated tablets, 20 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 50, 56, 60, 84 or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex; on cross-section, the core is light yellow.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (sodium starch glycolate), povidone K30, magnesium stearate.

Shell composition Opadry II 85F38107 yellow (polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, aluminum lake based on quinoline yellow dye, red iron oxide dye).

7 pcs. – contour cell packaging (1) – cardboard packs.
7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (3) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
14 pcs. – contour cell packaging (1) – cardboard packs.
14 pcs. – contour cell packaging (2) – cardboard packs.
14 pcs. – contour cell packaging (3) – cardboard packs.
14 pcs. – contour cell packaging (4) – cardboard packs.
28 pcs. – contour cell packaging (1) – cardboard packs.
28 pcs. – contour cell packaging (2) – cardboard packs.
28 pcs. – contour cell packaging (3) – cardboard packs.
28 pcs. – contour cell packaging (4) – cardboard packs.

Film-coated tablets pink, round, biconvex; on cross-section, the core is light yellow.

Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (sodium starch glycolate), povidone K30, magnesium stearate.

Shell composition Opadry II 85F34555 pink (polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, aluminum lake based on Allura Red AC dye, aluminum lake based on Sunset Yellow FCF dye, aluminum lake based on azorubine dye).

7 pcs. – contour cell packaging (1) – cardboard packs.
7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (3) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
14 pcs. – contour cell packaging (1) – cardboard packs.
14 pcs. – contour cell packaging (2) – cardboard packs.
14 pcs. – contour cell packaging (3) – cardboard packs.
14 pcs. – contour cell packaging (4) – cardboard packs.
28 pcs. – contour cell packaging (1) – cardboard packs.
28 pcs. – contour cell packaging (2) – cardboard packs.
28 pcs. – contour cell packaging (3) – cardboard packs.
28 pcs. – contour cell packaging (4) – cardboard packs.

Clinical-Pharmacological Group

Selective class II calcium channel blocker

Pharmacotherapeutic Group

“Slow” calcium channel blocker

Pharmacological Action

Lercanidipine is a selective blocker of slow calcium channels, a derivative of 1,4-dihydropyridine, inhibits the transmembrane flow of calcium ions into vascular smooth muscle cells.

Lercanidipine is a racemic mixture of (+)-R- and (-)S- enantiomers. The antihypertensive effect of lercanidipine is primarily due to the S-enantiomer. The mechanism of the antihypertensive action of lercanidipine is due to a direct relaxing effect on vascular smooth muscle cells, resulting in a decrease in total peripheral resistance. Despite the relatively short plasma half-life, Lercanidipine has a prolonged antihypertensive effect due to its high membrane distribution coefficient. Due to high vascular selectivity, it does not have a negative inotropic effect. Acute arterial hypotension with reflex tachycardia rarely occurs due to the gradual development of vasodilation when taking lercanidipine.

Lercanidipine is metabolically neutral and does not significantly affect the content of lipoproteins and apolipoproteins in the blood serum, and does not change the lipid profile in patients with arterial hypertension.

Pharmacokinetics

Absorption

Lercanidipine is completely absorbed after oral administration. The maximum plasma concentration (C_max) is reached in 1.5-3 hours and is 3.3±2.09 ng/ml and 7.66±5.90 ng/ml after taking 10 and 20 mg of lercanidipine, respectively.

The (+)-R- and (-)S- enantiomers of lercanidipine demonstrate a similar pharmacokinetic profile: they have the same time to reach maximum concentration (T_max), the same half-life (T_1/2); C_max and area under the concentration-time curve (AUC) values are 1.2 times higher for the (-)S-enantiomer. Interconversion of enantiomers was not observed in in vivo experiments.

During the “first pass” through the liver, the absolute bioavailability of lercanidipine when taken orally after a meal is approximately 10%; when taken on an empty stomach, the bioavailability value decreases by 1/3. When lercanidipine is taken no later than 2 hours after a fatty meal, its bioavailability increases 4 times, so Lercanidipine should not be taken after a meal. With oral use of lercanidipine, its plasma concentration is not directly proportional to the dose taken (nonlinear kinetics). Saturation of presystemic metabolism occurs gradually. Thus, bioavailability increases with increasing dose.

Distribution

Distribution from plasma to tissues and organs occurs quickly and extensively. Binding to plasma proteins exceeds 98%.

Metabolism and excretion

Lercanidipine is metabolized with the participation of the CYP3A4 isoenzyme to form inactive metabolites.

About 50% of the administered dose is excreted by the kidneys (about 50% is excreted by the intestine). Elimination occurs mainly through biotransformation. The average T_1/2 is 8-10 hours. The duration of therapeutic action is 24 hours.

No accumulation of lercanidipine is observed upon repeated oral administration.

Pharmacokinetics in special clinical cases

The pharmacokinetics of lercanidipine in elderly patients, patients with renal failure (creatinine clearance (CrCl) greater than 30 ml/min) and patients with mild to moderate hepatic impairment have been shown to be similar to the pharmacokinetics observed in the general patient population.

In patients with severe renal and/or hepatic impairment, due to decreased plasma protein concentration, the free fraction of lercanidipine may increase.

In patients with renal failure (CrCl less than 30 ml/min) and in patients on hemodialysis, plasma concentrations of lercanidipine were higher (approximately 70%).

In patients with moderate and severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to increase, since Lercanidipine is metabolized mainly in the liver.

Indications

• Grade 1-2 arterial hypertension.

ICD codes

Dosage Regimen

Orally, at least 15 minutes before meals, preferably in the morning, without chewing, with a sufficient amount of water.

The recommended dose of the drug is 10 mg once a day. Depending on the individual tolerance of the drug by the patient, the dose can be increased to 20 mg. If necessary, increasing the daily dose to 20 mg is carried out 2 weeks after starting the drug.

The therapeutic dose is selected gradually, since the maximum antihypertensive effect develops approximately 2 weeks after starting the drug.

It is unlikely that the effectiveness of the drug will increase with a dose increase above 20 mg/day, while the risk of side effects increases.

Pharmacokinetic profile and clinical study data show that in elderly patients, no dose adjustment of lercanidipine is required. However, caution should be exercised at the initial stage of treatment in this group of patients.

In the presence of renal failure (CrCl greater than 30 ml/min) or mild or moderate hepatic impairment, the initial dose is 10 mg, then the dose is carefully increased to 20 mg/day. The antihypertensive effect may be enhanced in patients with mild or moderate hepatic impairment and may require dose adjustment (reduction).

Adverse Reactions

Possible adverse reactions are listed below in descending order of frequency: common (<1/10, >1/100), uncommon (<1/100, >1/1000), rare (<1/1000, >1/10,000), very rare (<1/10,000), including isolated reports.

Nervous system disorders uncommon – headache, dizziness; rare – drowsiness.

Cardiovascular system disorders uncommon – palpitations, tachycardia, flushing; rare – angina pectoris, chest pain; very rare – syncope, myocardial infarction, pronounced decrease in blood pressure, in patients with angina pectoris, an increase in the frequency, duration and severity of attacks is possible.

Gastrointestinal disorders rare – nausea, dyspepsia, diarrhea, epigastric pain, vomiting; very rare – reversible increase in liver transaminase activity, gingival hyperplasia.

Respiratory, thoracic and mediastinal disorders very rare – chest pain.

Skin and subcutaneous tissue disorders rare – skin rash.

Musculoskeletal and connective tissue disorders rare – myalgia.

Renal and urinary disorders rare – polyuria; very rare – pollakiuria (increased frequency of urination).

Immune system disorders very rare – hypersensitivity reactions.

General disorders and administration site conditions uncommon – peripheral edema; rare – asthenia, increased fatigue.

Contraindications

• Hypersensitivity to lercanidipine, other dihydropyridine derivatives or any component of the drug;
• Untreated chronic heart failure;
• Unstable angina;
• Left ventricular outflow tract obstruction;
• Period within 1 month after myocardial infarction;
• Severe hepatic impairment;
• Severe renal failure (CrCl less than 30 ml/min);
• Concomitant use with potent CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin);
• Concomitant use with cyclosporine;
• Concomitant use with grapefruit juice;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Pregnancy;
• Breastfeeding period;
• Use in women of childbearing potential not using reliable methods of contraception;
• Age under 18 years (efficacy and safety have not been studied).

With caution renal failure (CrCl greater than 30 ml/min) and/or mild to moderate hepatic impairment, elderly age, sick sinus syndrome (without a pacemaker), coronary artery disease, left ventricular dysfunction.

Use in Pregnancy and Lactation

The use of lercanidipine during pregnancy and breastfeeding, as well as in women of childbearing potential without reliable contraception, is contraindicated.

Preclinical studies did not reveal a teratogenic effect of lercanidipine in rats and rabbits; reproductive function in rats was unchanged.

Due to the lack of clinical experience with the use of lercanidipine during pregnancy and breastfeeding and since it is known that other dihydropyridine derivatives have had a teratogenic effect in animals, Lercanidipine is not recommended for use during pregnancy and in women of childbearing potential not using reliable methods of contraception.

Due to the high lipophilicity of lercanidipine, its penetration into breast milk can be assumed, therefore Lercanidipine is not recommended for use during breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

With caution mild to moderate hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl less than 30 ml/min).

With caution renal failure (CrCl greater than 30 ml/min).

Pediatric Use

Contraindicated in children under 18 years of age (efficacy and safety have not been studied).

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Particular caution should be exercised when prescribing lercanidipine to patients with sick sinus syndrome (without a pacemaker). Although hemodynamically controlled studies have not revealed worsening of ventricular function when taking lercanidipine, caution should be exercised when prescribing lercanidipine to patients with left ventricular dysfunction. It has been suggested that taking some dihydropyridines may be associated with a risk of increased angina attacks in patients with coronary artery disease. Therefore, in such patients, therapy with lercanidipine should be carried out with particular caution.

Effect on ability to drive vehicles and operate machinery

Since dizziness, asthenia, increased fatigue and, in rare cases, drowsiness may occur during therapy with the drug, patients should exercise particular caution when driving vehicles and engaging in other potentially hazardous activities that require high speed of psychomotor reactions during the period of drug use.

Overdose

Symptoms presumably, in case of an overdose of lercanidipine, symptoms similar to those of an overdose of other dihydropyridine derivatives will be observed – peripheral vasodilation with a pronounced decrease in blood pressure and reflex tachycardia.

Treatment symptomatic. In case of a pronounced decrease in blood pressure, loss of consciousness, cardiovascular therapy is indicated; for bradycardia – intravenous administration of atropine.

There are data on 3 cases of overdose when taking lercanidipine in doses of 150 mg, 280 mg and 800 mg for suicidal purposes.

In the case of taking 150 mg of lercanidipine + alcohol (an unknown amount), drowsiness was observed. Treatment: gastric lavage, intake of activated charcoal.

In the case of taking 280 mg of lercanidipine + 5.6 mg of moxonidine, the following symptoms were observed: cardiogenic shock, severe myocardial ischemia, mild renal failure. Treatment: cardiac glycosides, diuretics (furosemide), high doses of catecholamines, plasma substitutes.

In the case of taking 800 mg of lercanidipine, nausea and a pronounced decrease in blood pressure were observed. Treatment: intake of activated charcoal and a laxative, intravenous dopamine.

In all cases of overdose, all patients survived. Information on the effectiveness of dialysis for lercanidipine is not available. Most likely, due to the high binding of lercanidipine to plasma proteins, dialysis may be ineffective.

Drug Interactions

Lercanidipine can be used simultaneously with beta-blockers, diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors).

When used concomitantly with metoprolol, the bioavailability of lercanidipine decreases by 50%. This effect may also occur with concomitant use with other beta-blockers, so dose adjustment of lercanidipine may be required to achieve a therapeutic effect with this combination. Lercanidipine is metabolized with the participation of the CYP3A4 isoenzyme, therefore inhibitors and inducers of this isoenzyme, when used concomitantly, can affect the metabolism and excretion of lercanidipine. Concomitant use of lercanidipine with potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is not recommended.

Concomitant use of cyclosporine and lercanidipine is not recommended, as an increase in the plasma concentration of both substances is observed.

Caution should be exercised when lercanidipine is used concomitantly with other CYP3A4 substrates (terfenadine, astemizole, class III antiarrhythmic drugs, e.g., amiodarone, quinidine).

When lercanidipine 20 mg is used concomitantly with midazolam, the bioavailability of lercanidipine in elderly patients may increase by approximately 40%.

Lercanidipine should be prescribed with caution concomitantly with CYP3A4 inducers, for example, anticonvulsants (phenytoin, carbamazepine) and rifampicin, as a decrease in the antihypertensive effect is possible. Regular monitoring of blood pressure (BP) is necessary.

When lercanidipine 20 mg was used concomitantly in patients constantly taking beta-methyldigoxin, no pharmacokinetic interaction was noted, while in healthy volunteers treated with digoxin, an increase in the C_max value for digoxin by an average of 33% was observed after taking 20 mg of lercanidipine on an empty stomach, while the AUC (area under the concentration-time curve) and renal clearance changed insignificantly. It is necessary to monitor for signs of digoxin intoxication in patients taking digoxin and Lercanidipine concomitantly.

Concomitant use of lercanidipine with cimetidine (up to 800 mg) does not cause significant changes in the plasma concentration of lercanidipine. With high doses of cimetidine, the bioavailability and antihypertensive effect of lercanidipine may increase.

With the simultaneous use of lercanidipine (20 mg) and simvastatin (40 mg), the AUC value for simvastatin increased by 56%, and the same value for its active metabolite, beta-hydroxy acid, increased by 28%. Taking the drugs at different times of the day (Lercanidipine in the morning, simvastatin in the evening) can avoid unwanted interaction.

With the simultaneous use of 20 mg of lercanidipine and warfarin in healthy volunteers, no changes in the pharmacokinetics of warfarin were observed.

Concomitant use with fluoxetine (an inhibitor of CYP2D6 and CYP3A4) in elderly patients did not cause clinically significant changes in the pharmacokinetics of lercanidipine.

It is possible to enhance the antihypertensive effect with the simultaneous intake of grapefruit juice and lercanidipine.

Ethanol may potentiate the antihypertensive effect of lercanidipine.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.