Lerkamen^® (Tablets) Instructions for Use

ATC Code

C08CA13 (Lercanidipine)

Active Substance

Lercanidipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

“Slow” calcium channel blocker. Antihypertensive drug

Pharmacotherapeutic Group

Calcium channel blockers; selective calcium channel blockers with predominant vascular action; dihydropyridine derivatives

Pharmacological Action

Selective blocker of slow calcium channels with a predominant effect on blood vessels, a dihydropyridine derivative. It inhibits the transmembrane flow of calcium ions into vascular smooth muscle cells. 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 vascular resistance.

Despite a relatively short plasma half-life, Lercanidipine has a prolonged antihypertensive effect due to its high membrane distribution coefficient. Due to its 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 a racemic mixture of the (+)R- and (-)S-enantiomers. The antihypertensive effect of lercanidipine is primarily due to the S-enantiomer.

The duration of the therapeutic effect is 24 hours.

Pharmacokinetics

Lercanidipine is completely absorbed after oral administration. The maximum plasma concentration 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 mg 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 plasma concentration, the same half-life; the maximum plasma concentration and area under the curve values are 1.2 times higher for the (-)S-enantiomer. Interconversion of enantiomers was not observed in in vivo experiments.

Due to the first-pass effect 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 one third. When lercanidipine is taken no later than 2 hours after a fatty meal, its bioavailability increases 4-fold, so the drug should not be taken after meals. With oral administration of lercanidipine, its plasma concentration is not directly proportional to the dose taken (non-linear kinetics). Saturation of presystemic metabolism occurs gradually. Thus, bioavailability increases with increasing dose.

Distribution from plasma to tissues and organs occurs rapidly and extensively. Plasma protein binding exceeds 98%.

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 intestinally). Elimination occurs mainly through biotransformation. The mean half-life is 8-10 hours. No accumulation of lercanidipine is observed upon repeated oral administration.

The pharmacokinetics of lercanidipine in elderly patients, patients with renal impairment (creatinine clearance 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 renal impairment (creatinine clearance less than 30 ml/min) and in patients on hemodialysis, plasma concentrations of lercanidipine were higher (approximately 70%).

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 moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely increased since Lercanidipine is metabolized primarily in the liver.

Indications

• Essential hypertension of mild to moderate severity.

ICD codes

Dosage Regimen

Tablets

Take orally, at least 15 minutes before meals, preferably in the morning. Prescribed at 10 mg once a day. Depending on the individual tolerance of the drug by the patient, the dose can be increased to 20 mg.

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 no dose adjustment is required in elderly patients. However, caution should be exercised at the initial stage of treatment with the drug in this group of patients.

Caution should be exercised when used in patients with mild to moderate renal and hepatic impairment.

In renal impairment (creatinine clearance 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 dose adjustment (reduction) may be required.

In renal impairment (creatinine clearance less than 30 ml/min) and severe hepatic impairment, the use of the drug is contraindicated.

Adverse Reactions

Possible side effects are listed below in descending order of frequency: common (<1/10, ≥1/100), uncommon (<1/100, ≥1/1000), rare (<1/1000, ≥1/10000), very rare (<1/10000), 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, 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.

Skin and subcutaneous tissue disorders: rare – skin rash.

Musculoskeletal and connective tissue disorders: rare – myalgia.

Renal and urinary disorders: rare – polyuria.

Immune system disorders: very rare – hypersensitivity reactions.

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

There have been reports of the following very rare (<1/10000) adverse events: myocardial infarction, gingival hyperplasia, reversible increase in liver transaminase activity, marked decrease in blood pressure, pollakiuria (increased frequency of urination), chest pain.

Contraindications

• Untreated heart failure;
• Unstable angina;
• Obstruction of vessels originating from the left ventricle of the heart;
• The period within 1 month after myocardial infarction;
• Severe hepatic impairment;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Concomitant use with CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin);
• Concomitant use with cyclosporine;
• Concomitant intake with grapefruit juice;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Pregnancy;
• Period of lactation (breastfeeding);
• Use in women of childbearing potential not using reliable methods of contraception;
• Children and adolescents under 18 years of age (efficacy and safety have not been studied);
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other dihydropyridine derivatives.

Use with caution in renal (creatinine clearance greater than 30 ml/min) and/or mild to moderate hepatic impairment, in elderly patients, with sick sinus syndrome (without a pacemaker), coronary artery disease, left ventricular dysfunction.

Use in Pregnancy and Lactation

Preclinical studies did not reveal a teratogenic effect of lercanidipine in rats and rabbits; the reproductive function of 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 the drug is not recommended for use during breastfeeding.

Use in Hepatic Impairment

Use with caution in mild to moderate hepatic impairment.

Contraindicated in severe hepatic impairment.

Use in Renal Impairment

Use with caution in renal impairment (creatinine clearance greater than 30 ml/min).

Contraindicated in severe renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Effect on ability to drive vehicles and operate machinery

Since dizziness, asthenia, fatigue, and in rare cases, drowsiness may occur during therapy with lercanidipine, 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.

Drug Interactions

Lercanidipine can be used simultaneously with beta-blockers, diuretics, and ACE inhibitors.

When used concomitantly with metoprolol, the bioavailability of lercanidipine decreases by 50%. This effect may also occur with concomitant use of 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 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).

With the simultaneous use of lercanidipine at a dose of 20 mg with midazolam, the bioavailability of lercanidipine in elderly patients may increase by approximately 40%.

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

With the simultaneous use of lercanidipine at a dose of 20 mg in patients constantly taking beta-methyldigoxin, no pharmacokinetic interaction was noted, while in healthy volunteers treated with digoxin, an increase in the maximum plasma concentration of digoxin by an average of 33% was observed after taking 20 mg of lercanidipine on an empty stomach, while the area under the curve and renal clearance changed insignificantly. It is necessary to monitor for signs of digoxin intoxication in patients taking digoxin and Lercanidipine simultaneously.

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 area under the curve value for simvastatin increased by 56%, and the same value for its active metabolite, β-hydroxy acid, increased by 28%. Undesirable interaction can be avoided by taking the drugs at different times of the day (Lercanidipine in the morning, simvastatin in the evening).

With the simultaneous use of lercanidipine at a dose of 20 mg 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.

Enhancement of the antihypertensive effect is possible with the simultaneous intake of grapefruit juice and lercanidipine.

Ethanol may potentiate the antihypertensive effect of lercanidipine.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.