Vanlerk

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VANLERK (VANLERK)

Composition:

Active substance: lercanidipine;

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

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

coating (for 10 mg tablets): Opadry II Yellow film-coating system: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); triacetin; yellow iron oxide (E 172);

coating (for 20 mg tablets): Opadry II Pink film-coating system: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); triacetin; red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 10 mg tablets: yellow, round, biconvex tablets with a score line on one side, film-coated;

for 20 mg tablets: pink, round, biconvex tablets with a score line on one side, film-coated.

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 transmembrane calcium influx into cardiomyocytes and vascular smooth muscle cells. The antihypertensive mechanism of action of lercanidipine is due to its direct vasorelaxant effect on vascular smooth muscle, thereby reducing total peripheral vascular resistance. Despite its 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 because of 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 clinical trials involving patients with hypertension.

Most studies included patients with mild to moderate essential hypertension (including elderly patients and those with diabetes mellitus), receiving lercanidipine either as monotherapy or in combination with ACE inhibitors, diuretics, or beta-blockers.

In addition to the clinical trials conducted to confirm therapeutic indications, another study in patients with severe arterial hypertension (mean ± standard deviation (SD) diastolic blood pressure of 114.5 ± 3.7 mmHg) 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. There is also information from a clinical trial comparing with placebo in patients with systolic hypertension, demonstrating that lercanidipine effectively reduced 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 (Cmax) 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 a similar plasma concentration profile: the time to reach maximum plasma concentration (tmax) is identical; Cmax and the area under the plasma concentration-time curve (AUC) are on average 1.2 times higher for the S-enantiomer; and the elimination half-life of both enantiomers is essentially the same. No in vivo interconversion of enantiomers has been observed.

Due to extensive first-pass hepatic metabolism, the absolute bioavailability of orally administered lercanidipine is approximately 10% when taken after food, although it decreases to one-third of this value when administered in the fasting state. 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 food.

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.

Biological transformation. Lercanidipine is extensively metabolized by the CYP3A4 isoenzyme; unchanged drug is not detected in urine or feces. It is converted predominantly 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 concentrations 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, clinically significant interactions due to inhibition of CYP3A4- or CYP2D6-mediated metabolism of other drugs are 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 dosing.

Linearity/non-linearity. After oral administration, lercanidipine plasma concentrations are not directly proportional to the administered dose (non-linear kinetics). Following administration of 10 mg, 20 mg, and 40 mg, the observed maximum plasma concentrations showed ratios of 1:3:8, and AUC ratios of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, the bioavailability of lercanidipine increases with increasing dose.

Additional information on specific patient groups

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction are similar to those observed in the general patient population. In patients with severe renal impairment or those dependent on dialysis, drug concentrations were higher (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as it is primarily 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 obstruction;
• Uncompensated heart failure;
• Unstable angina or recent (within 1 month) myocardial infarction;
• 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, concomitant administration of inhibitors and inducers of this enzyme may affect the metabolism and elimination of lercanidipine. Interaction studies between lercanidipine and the potent CYP3A4 inhibitor ketoconazole demonstrated a significant increase in plasma levels of lercanidipine (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. Concomitant administration of lercanidipine and cyclosporine increases plasma levels of both substances. Studies have shown that administration of cyclosporine 3 hours after lercanidipine intake did not alter lercanidipine plasma levels, while the AUC of cyclosporine increased by 27%. However, simultaneous 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, the metabolism of lercanidipine is slowed by grapefruit juice, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect. Concomitant intake of lercanidipine with grapefruit or grapefruit juice should be avoided.

Concomitant use is not recommended

Inducers of CYP3A4. Lercanidipine should be used with caution when administered concomitantly with CYP3A4 inducers such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, due to the potential reduction in antihypertensive efficacy 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 is required when administering lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and Class III antiarrhythmics such as amiodarone, quinidine, and sotalol.

Midazolam. In elderly volunteers, concomitant administration of 20 mg lercanidipine and midazolam increased lercanidipine absorption (by approximately 40%) and decreased the rate of absorption (tmax prolonged from 1.75 to 3 hours). Midazolam concentration was 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 result from 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 necessary.

Digoxin. When 20 mg lercanidipine was administered concomitantly to patients on chronic β-methyldigoxin therapy, 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 patients aged 65 ± 7 years (mean ± SD) showed no 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 is advised with 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 clinically significant. No interaction between these agents is expected if lercanidipine is administered in the morning and simvastatin in the evening, as recommended for simvastatin.

Diuretics and angiotensin-converting enzyme (ACE) inhibitors. Lercanidipine may be used concomitantly with diuretics and 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 for symptomatic treatment of bladder disorders, tricyclic antidepressants, and neuroleptics.

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

Special precautions for use.

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

Left ventricular dysfunction. Although hemodynamically controlled studies have not revealed impairment of ventricular function, the drug should be prescribed with caution in patients with left ventricular dysfunction.

Ischemic heart disease. It is believed that the use of certain short-acting dihydropyridines may increase the risk of cardiovascular complications in patients with ischemic heart disease; therefore, the use of lercanidipine in such patients requires caution, despite lercanidipine's prolonged action. Some dihydropyridines may rarely cause precordial pain or angina. Very rarely, in patients with pre-existing angina, 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. The turbidity is due to elevated triglyceride concentrations in the peritoneal exudate. Although the mechanism is unknown, this effect tends to resolve shortly after discontinuation of lercanidipine. This association should be taken into account to avoid situations where turbidity of the peritoneal exudate might be mistakenly interpreted as infectious peritonitis, leading to unnecessary hospitalization and empirical antibiotic therapy.

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.

Use during pregnancy or breastfeeding.

Pregnancy. There is no clinical experience with the use of lercanidipine during pregnancy. Animal studies have not shown 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.

Breastfeeding period. It is not definitively known whether lercanidipine or its metabolites are excreted in human milk. Therefore, the 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, calcium channel blockers should be considered as a possible contributing factor.

Ability to influence 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.

Method of Administration and Dosage

Method of Administration

Before using the medication, it is important to consider the following:

• 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.

The recommended dose is 10 mg orally once daily, taken no sooner than 15 minutes before food intake. Depending on the individual patient's response to treatment, the dose may be increased to 20 mg.

Dosage should be titrated gradually, as maximum antihypertensive effect develops within 2 weeks of treatment.

For patients whose blood pressure is not adequately controlled on monotherapy with antihypertensive agents, Vanlerk may be added to treatment regimens containing β-blockers (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, lercanidipine can be used in 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 Vanlerk in patients with mild to moderate renal or hepatic impairment should be initiated under medical supervision. The usual recommended dose of 0 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 liver dysfunction or severe renal impairment (creatinine clearance < 30 mL/min), including patients on hemodialysis.

Children

Safety and efficacy of the medicinal product in children under 18 years of age have not been studied; data on use in pediatric patients are lacking.

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, profound 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 continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated lower limbs, control of circulating fluid volume and diuresis. Due to the prolonged pharmacological action of lercanidipine, monitoring of cardiovascular status in cases of 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 intensive care settings.

Adverse reactions.

The most commonly observed adverse reactions associated with the use of lercanidipine are: peripheral edema, headache, flushing, tachycardia, palpitations.

Immune system disorders: hypersensitivity.

Nervous system disorders: headache, dizziness, somnolence, syncope.

Cardiac disorders: tachycardia, palpitations, angina pectoris.

Vascular disorders: flushing, hypotension.

Gastrointestinal disorders: dyspepsia, nausea, upper abdominal pain, vomiting, diarrhea, gingival hyperplasia\1, turbidity of peritoneal exudate\1.

Liver and biliary disorders: increased serum transaminase levels\1.

Skin and subcutaneous tissue disorders: rash, pruritus, skin eruptions, swelling\1.

Musculoskeletal and connective tissue disorders: myalgia.

Renal and urinary disorders: polyuria, pollakiuria.

General disorders and administration site conditions: peripheral edema, asthenia, increased fatigue, chest pain.

\1Adverse reactions reported spontaneously during post-marketing use worldwide.

Lercanidipine does not negatively affect blood glucose levels or serum lipid levels. The use of some dihydropyridines may occasionally cause precordial pain or angina pectoris; in rare cases, the frequency, duration, or severity of angina attacks may increase in patients with angina, and isolated cases of myocardial infarction may occur. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report all suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua