Lercania

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERCANIA® (LERCANIA)

Composition:

Active substance: lercanidipine;

1 tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.4 mg, or lercanidipine hydrochloride 20 mg, equivalent to lercanidipine 18.8 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium starch glycolate (type A); povidone; colloidal anhydrous silicon dioxide; magnesium stearate;

film coating of 10 mg tablet: hypromellose, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172);

film coating of 20 mg tablet: hypromellose, titanium dioxide (E 171), macrogol, talc, red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablet: round, biconvex tablets, film-coated, pale yellow to yellow in color;

20 mg tablet: round, biconvex tablets, film-coated, pink to dark pink in color.

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

Pharmacological properties.

Pharmacodynamics.

Lercanidipine is a calcium antagonist of the dihydropyridine group. It inhibits the transmembrane influx of calcium into cardiomyocytes and vascular smooth muscle cells. The antihypertensive mechanism of action of lercanidipine is due to its direct vasorelaxant effect on vascular smooth muscles, thereby reducing total peripheral vascular resistance. Despite a short plasma half-life, lercanidipine exerts a prolonged antihypertensive effect owing to its high membrane partition coefficient. Due to its high vascular selectivity, the drug does not exert negative inotropic effects. Acute arterial hypotension with reflex tachycardia rarely occurs, thanks to the gradual onset of vasodilation following lercanidipine administration.

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

The clinical efficacy and safety of lercanidipine administered at doses of 10–20 mg once daily have been evaluated in a double-blind, placebo-controlled clinical trial (in which 1200 patients received lercanidipine and 603 patients received placebo) and in active-controlled and uncontrolled long-term clinical trials involving a total of 3676 hypertensive patients.

Most studies included patients with mild to moderate essential hypertension (including elderly patients and those 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 the clinical trials conducted to confirm therapeutic indications, a further small, uncontrolled but randomized study in patients with severe arterial hypertension (mean ± standard deviation of diastolic blood pressure 114.5 ± 3.7 mmHg) demonstrated blood pressure normalization in 40% of 25 patients receiving lercanidipine 20 mg once daily and in 56% of 25 patients receiving lercanidipine 10 mg twice daily. In a double-blind, randomized, placebo-controlled study in patients with isolated systolic hypertension, lercanidipine effectively reduced systolic blood pressure from a mean baseline value of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg.

Clinical studies in the pediatric population have not been conducted.

Pharmacokinetics.

Absorption

Lercanidipine is completely absorbed after oral administration at doses of 10–20 mg. Peak plasma concentrations of 3.30 ng/mL ± 2.09 SD and 7.66 ng/mL ± 5.90 SD, respectively, are reached approximately 1.5–3 hours after administration.

The two enantiomers of lercanidipine exhibit similar plasma concentration profiles: time to peak plasma concentration is identical, peak concentration and AUC values are on average 1.2 times higher for the S-enantiomer, and the elimination half-lives of both enantiomers are essentially the same. In vivo interconversion of enantiomers has not been observed.

Due to extensive first-pass metabolism in the liver, the absolute bioavailability of orally administered lercanidipine taken after food is approximately 10%. However, bioavailability decreases to about one-third of this value when administered to healthy volunteers on an empty stomach. If the drug is taken no later than 2 hours after a high-fat meal, its bioavailability increases fourfold. Therefore, lercanidipine should be taken before meals.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive. The extent of lercanidipine binding to serum proteins exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic impairment, the free fraction of the drug may increase.

Biotransformation

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

In vitro experiments using human liver microsomes indicate that lercanidipine slightly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its maximum plasma concentration achieved after a 20 mg dose. Furthermore, clinical drug interaction studies have demonstrated that lercanidipine does not alter plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate. Thus, when lercanidipine is used at therapeutic doses, inhibition of the biotransformation of drugs metabolized by CYP3A4 or CYP2D6 is not expected.

Elimination

Elimination occurs primarily via biotransformation. The mean terminal half-life is 8–10 hours, while the therapeutic effect lasts 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, lercanidipine plasma concentrations are not directly proportional to the administered dose (non-linear kinetics). Following doses of 10 mg, 20 mg, and 40 mg, observed peak plasma concentrations showed a ratio of 1:3:8, and the areas under the plasma concentration-time curves (AUC) showed a ratio of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, the bioavailability of lercanidipine increases with dose escalation.

Special patient groups

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction have been shown to be similar to those observed in the general patient population. In patients with severe renal dysfunction or those on dialysis, drug concentrations were higher (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as the drug is predominantly metabolized in the liver.

Clinical characteristics.

Indications.

Mild to moderate essential hypertension.

Contraindications.

• Hypersensitivity to lercanidipine or to any component of the medicinal product.
• 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 (creatinine clearance < 30 mL/min), including patients on hemodialysis.
• Concomitant use with strong CYP3A4 inhibitors, cyclosporine, grapefruit or grapefruit juice.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated

Inhibitors of CYP3A4

Lercanidipine is metabolized by the CYP3A4 enzyme; therefore, inhibitors and inducers of this enzyme taken concomitantly with lercanidipine may affect the metabolism and elimination of lercanidipine. Interaction studies between lercanidipine and the potent CYP3A4 inhibitor ketoconazole demonstrated a marked increase in plasma lercanidipine levels (15-fold increase in AUC and 8-fold increase in maximum concentration of the S-enantiomer of lercanidipine).

Concomitant use of lercanidipine with CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided.

Cyclosporine

When lercanidipine and cyclosporine are used concomitantly, plasma levels of both substances increase. A study involving young healthy volunteers showed that administration of cyclosporine 3 hours after lercanidipine intake did not alter lercanidipine plasma levels, while cyclosporine AUC increased by 27%. However, concomitant administration of lercanidipine and cyclosporine leads to a 3-fold increase in lercanidipine plasma levels and a 21% increase in cyclosporine AUC.

Cyclosporine and lercanidipine should not be used together.

Grapefruit or grapefruit juice

As with other dihydropyridines, grapefruit juice slows down the metabolism of lercanidipine, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect. Grapefruit or grapefruit juice should not be consumed together with lercanidipine.

Concomitant use is not recommended

Inducers of CYP3A4

Lercanidipine should be used with caution concomitantly with CYP3A4 inducers such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, due to the possible reduction of the antihypertensive effect of lercanidipine. In such cases, more frequent monitoring of blood pressure is recommended.

Alcohol

Alcohol consumption should be avoided due to the potential potentiation of the vasodilatory effect of antihypertensive medicinal products.

Interactions requiring dose adjustment

Substrates of CYP3A4

Caution should be exercised when using lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics such as amiodarone, quinidine, and sotalol.

Midazolam

When 20 mg lercanidipine and midazolam were administered concomitantly to elderly volunteers, absorption of lercanidipine increased (approximately by 40%), while the rate of absorption decreased (tmax prolonged from 1.75 to 3 hours). Midazolam concentration remained unchanged.

Metoprolol

Concomitant administration of lercanidipine with metoprolol—a β-blocker primarily eliminated via the liver—does not alter the bioavailability of metoprolol but reduces the bioavailability of lercanidipine by 50%. This effect may be due to reduced hepatic blood flow caused by β-blockers and may therefore occur when used with other agents in this class. Thus, lercanidipine may be used with β-adrenergic blockers, but dose adjustment may be required.

Digoxin

When 20 mg lercanidipine was administered concomitantly to patients chronically taking β-methyldigoxin, no evidence of pharmacokinetic interaction was observed. However, an average increase of 33% in digoxin Cmax was observed, while AUC and renal clearance were not significantly altered. Patients receiving digoxin concomitantly should be closely monitored for signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

A study investigating interaction with fluoxetine (an inhibitor of CYP2D6 and CYP3A4) in volunteers aged 65 ± 7 years (mean ± SD) did not reveal any clinically significant change in the pharmacokinetics of lercanidipine.

Cimetidine

Concomitant administration of cimetidine at a dose of 800 mg per day does not cause significant changes in lercanidipine plasma concentration. However, caution should be exercised when using higher doses due to the potential for increased bioavailability and antihypertensive effect of lercanidipine.

Simvastatin

When lercanidipine 20 mg was administered concomitantly with 40 mg simvastatin, the AUC of lercanidipine was not significantly altered, while the AUC of simvastatin increased by 56% and that of its active metabolite, β-hydroxyacid, by 28%. Such changes are unlikely to be of clinical significance. No interaction between these agents is expected if lercanidipine is taken in the morning and simvastatin in the evening, as recommended for simvastatin.

Diuretics and ACE inhibitors

Lercanidipine may be used concomitantly with diuretics and angiotensin-converting enzyme (ACE) inhibitors.

Other medicinal products affecting blood pressure

As with all antihypertensive agents, an enhanced hypotensive effect may occur when lercanidipine is used concomitantly with other medicinal products affecting blood pressure, such as α-blockers used for symptomatic treatment of urinary bladder disorders, tricyclic antidepressants, and neuroleptics.

Conversely, a reduced antihypertensive effect may occur when used concomitantly with corticosteroids.

Special precautions for use.

Sinus node dysfunction

Lercanidipine should be used with caution in patients with sinus node dysfunction (without an implanted cardiac pacemaker).

Left ventricular dysfunction

Although hemodynamically controlled studies have not shown worsening of ventricular function, this medication should be prescribed with caution in patients with left ventricular dysfunction.

Ischemic heart disease

There have been hypotheses that certain short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischemic heart disease. Although Lercanidipine® is a long-acting formulation, this medicinal product should nevertheless be used with caution in such patients. Some dihydropyridines may rarely cause precordial pain or angina pectoris. Very rarely, in patients with pre-existing angina pectoris, an increase in frequency, duration, or severity of episodes may occur. Isolated cases of myocardial infarction have been reported.

Peritoneal dialysis

The use of lercanidipine has been associated with turbidity of peritoneal exudate in patients undergoing peritoneal dialysis. This turbidity is due to elevated triglyceride concentrations in the peritoneal exudate. Although the mechanism is not known, this effect tends to resolve shortly after discontinuation of lercanidipine. This effect should be taken into account to avoid situations where turbidity of the peritoneal exudate may be mistakenly interpreted as infectious peritonitis, leading to unnecessary hospitalization and empirical antibiotic therapy.

Lactose

Lercania® contains lactose. If a patient has been diagnosed with intolerance to certain sugars, they should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

There is no clinical experience with the use of lercanidipine during pregnancy. Animal studies have not revealed teratogenic effects, but such effects have been observed with other dihydropyridine compounds. Lercanidipine is not recommended for use in pregnant women or women of childbearing potential who are not using effective contraception.

It is not definitively known whether lercanidipine or its metabolites are excreted in human breast milk. Therefore, risk to the infant cannot be excluded. Lercanidipine should not be used during breastfeeding.

Fertility

Clinical data on the effect of lercanidipine on fertility are lacking. Available data indicate reversible biochemical changes in the sperm head that may affect fertilizing capacity in patients treated with calcium channel blockers. In cases of repeated unsuccessful in vitro fertilization and in the absence of other explanations, the use of calcium channel blockers should be considered as a possible cause.

Ability to affect reaction speed when driving or operating machinery.

The effect of lercanidipine on the ability to drive or operate machinery is negligible. However, the possibility of dizziness, weakness, increased fatigue, and rarely somnolence, should be taken into account.

Dosage and Administration

The recommended dose is 10 mg orally once daily, taken at least 15 minutes before a meal. Depending on the individual patient's response to treatment, the dose may be increased to 20 mg.

Dosage titration should be gradual, as maximum antihypertensive effect develops within 2 weeks of treatment.

For patients whose blood pressure is not adequately controlled on monotherapy with antihypertensive agents, Lercanium® may be added to treatment regimens that include β-adrenoblockers (atenolol), diuretics (hydrochlorothiazide), or ACE inhibitors (captopril or enalapril).

Since the dose–response curve plateaus within the dose range of 20–30 mg, it is unlikely that efficacy will increase with higher doses, whereas the risk of adverse effects may rise.

Elderly patients.

According to pharmacokinetic and clinical study data, Lercanium® can be administered to elderly patients without specific dose adjustment; however, treatment initiation in elderly patients should be under medical supervision.

Patients with renal or hepatic impairment.

Treatment with Lercanium® in patients with mild to moderate renal or hepatic impairment should be initiated under medical supervision. The standard recommended dose of 00 mg is generally well tolerated in these subgroups, but dose escalation to 20 mg requires caution.

In patients with hepatic impairment, an enhanced antihypertensive effect of the drug may occur, necessitating dose adjustment.

Lercanidipine is contraindicated in patients with severe hepatic dysfunction or severe renal impairment (creatinine clearance < 30 mL/min), including patients on hemodialysis.

Administration instructions.

It should be noted that:

• the drug should preferably be taken in the morning, at least 15 minutes before breakfast;
• this medicinal product must not be taken with grapefruit juice.

Children.

The safety and efficacy of this medicinal product in children (under 18 years of age) have not been studied; there are no data on use in pediatric patients.

Overdose.

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

Symptoms. By analogy with other dihydropyridines, overdose with lercanidipine is expected to cause excessive peripheral vasodilation, marked arterial hypotension, and reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, potentially leading to bradycardia and negative inotropic effects. The most common adverse reactions associated with overdose are hypotension, dizziness, headache, and palpitations.

Treatment. In cases of severe arterial hypotension, active cardiovascular support measures are required, including careful monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated legs, fluid status monitoring, and urine output assessment. Due to the prolonged pharmacological effect of lercanidipine, cardiovascular monitoring of patients after overdose is necessary for at least 24 hours. Because of lercanidipine's high protein binding, dialysis may be ineffective. Patients with expected moderate or severe intoxication should be monitored in an intensive care setting.

Adverse Reactions

According to data from clinical studies and post-marketing use, the most commonly reported adverse reactions are peripheral edema, headache, flushing, tachycardia, and palpitations.

The table below lists adverse reactions reported during clinical studies and post-marketing use of the drug worldwide, for which a causal relationship with the drug has been reasonably established. Adverse reactions are listed by MedDRA (Medical Dictionary for Regulatory Activities) system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, reactions are listed in order of decreasing severity.

1Adverse reactions from spontaneous reports during post-marketing use worldwide.

Lercanidipine does not negatively affect blood glucose levels or serum lipid levels.

In placebo-controlled clinical trials, peripheral edema occurred in 0.9% of patients receiving lercanidipine at doses of 10–20 mg and in 0.83% of those receiving placebo. This incidence reached 2% in the overall study population, including long-term clinical trials.

The use of some dihydropyridines may occasionally cause precordial pain or angina; in rare cases, in patients with angina, the frequency, duration, or severity of attacks may increase, and isolated cases of myocardial infarction have been reported.

Shelf life. 2 years.

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

Storage conditions. No special storage conditions required. Store in the original packaging. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

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

74, Kyrylivska Street, Kyiv, 04080, Ukraine.