Lerrex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERREX

Composition:

Active substance: lercanidipine;

1 tablet contains 10 mg or 20 mg of lercanidipine hydrochloride (as lercanidipine hydrochloride hemihydrate);

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate; Opadry II Yellow 85F520410 [partially hydrolyzed polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol (E 1521), talc (E 553b), yellow iron oxide (E 172), red iron oxide (E 172)] — for 10 mg tablets; Opadry II Pink 85F540460 [partially hydrolyzed polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol (E 1521), talc (E 553b), red iron oxide (E 172)] — for 20 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: yellow, film-coated, round-shaped, biconvex tablets, marked with «3» and «4» on both sides of the breakline on one side and «HL» on the other;

20 mg tablets: pink to peach-colored, film-coated, round-shaped, biconvex tablets, marked with «3» and «5» on both sides of the breakline on one side and «HL» on the other.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. 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 lercanidipine is due to direct vasorelaxant effects on vascular smooth muscle, resulting in reduced 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 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 received placebo) and in active-controlled and uncontrolled long-term clinical studies 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 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 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, with peak plasma concentrations of 3.30 ng/mL ± 2.09 SD (standard deviation) and 7.66 ng/mL ± 5.90 SD, respectively, reached approximately 1.5–3 hours after intake.

The two enantiomers of lercanidipine exhibit similar plasma concentration profiles: time to peak concentration is identical, peak concentration and AUC values are on average 1.2 times higher for the S-enantiomer, and the half-life of both enantiomers is essentially the same. No in vivo interconversion of enantiomers has been observed.

Due to extensive first-pass metabolism in the liver, the absolute bioavailability of orally administered lercanidipine taken after food is approximately 10%, although it decreases to 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 with 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 in plasma 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 metabolism 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 areas under the plasma concentration-time curves (AUC) showed a ratio of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, lercanidipine bioavailability increases with increasing dose.

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 impairment or those on dialysis, drug concentrations were higher (approximately 70%). In patients with moderate or severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as the drug 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 tract obstruction.
• Uncompensated 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, when administered concomitantly with lercanidipine, may affect its metabolism and elimination. Interaction studies between lercanidipine and the potent CYP3A4 inhibitor ketoconazole have 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

Concomitant administration of lercanidipine and cyclosporine increases plasma levels of both substances. A study in young healthy volunteers showed that administration of cyclosporine 3 hours after lercanidipine 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. Grapefruit or grapefruit juice should not be consumed simultaneously with lercanidipine.

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 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 is advised 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 be due to reduced hepatic blood flow caused by β-blockers and may therefore occur 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 on chronic β-methyldigoxin therapy, no evidence of pharmacokinetic interaction was observed. However, an increase in digoxin Cmax by an average of 33% was noted, 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 is advised with higher doses due to the potential for increased bioavailability and antihypertensive effect of lercanidipine.

Simvastatin

When 20 mg lercanidipine was administered concomitantly with 40 mg simvastatin, the AUC of lercanidipine did not change significantly, while the AUC of simvastatin increased by 56% and that of its active metabolite, β-hydroxy acid, 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 disorders, tricyclic antidepressants, and neuroleptics.

Conversely, a reduced hypotensive effect may be observed 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 haemodynamically controlled studies have not shown worsening of ventricular function, this medication should be prescribed with caution in patients with left ventricular dysfunction.

Ischaemic heart disease

It has been hypothesized that certain short-acting dihydropyridines may increase cardiovascular risk in patients with ischaemic heart disease. Although Lerrex is a long-acting formulation, it should be used with caution in such patients. 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 dialysate in patients undergoing peritoneal dialysis. This turbidity is due to increased triglyceride concentration in the peritoneal exudate. Although the mechanism is unknown, this effect tends to resolve shortly after discontinuation of lercanidipine. This effect should be taken into account to avoid misdiagnosing peritoneal dialysate turbidity as infectious peritonitis, which could lead to unnecessary hospitalization and empirical antibiotic therapy.

Lactose

Lerrex contains lactose. If a patient has known 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 shown teratogenic effects; however, such effects have been observed with other dihydropyridine compounds. Lercanidipine is not recommended for use in pregnant women or in women of childbearing potential who are not using effective contraception.

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

Fertility

There are no clinical data on the effect of lercanidipine on fertility. Available data indicate reversible biochemical changes in the sperm head observed in patients treated with calcium channel blockers, which may affect fertilizing capacity. In cases of repeated unsuccessful in vitro fertilization without other explanations, calcium channel blockers should be considered as a possible contributing factor.

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, one should take into account the possibility of dizziness, weakness, increased fatigue, and, rarely, somnolence.

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

For patients whose blood pressure is not adequately controlled on monotherapy with antihypertensive agents, LERREX 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 increase.

Elderly patients. According to pharmacokinetic and clinical data, LERREX 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. In patients with mild to moderate renal or hepatic impairment, treatment with LERREX should be initiated under medical supervision. The usual recommended dose of 10 mg is generally well tolerated in these patient 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 dysfunction (creatinine clearance < 30 mL/min), including patients on hemodialysis.

Administration

The following should be considered:

• LERREX 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 established; data on use in children are lacking.

Overdose

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

Symptoms. As with other dihydropyridines, overdose with lercanidipine is expected to result in excessive peripheral vasodilation and marked arterial hypotension with reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, potentially leading to bradycardia and negative inotropic effects. The most commonly reported 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, monitoring circulating fluid volume and urine output. Due to the prolonged pharmacological effect of lercanidipine, cardiovascular monitoring of such patients should continue for at least 24 hours following overdose. Because of the high protein binding of lercanidipine, dialysis may be ineffective. Patients with anticipated moderate or severe intoxication should be managed under intensive care conditions.

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's use has been considered reasonable. 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data). Within each frequency category, reactions are listed in order of decreasing severity.

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

Lercanidipine does not have a negative effect on blood glucose levels or serum lipid levels.

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

The use of certain dihydropyridines may occasionally lead to 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 may occur.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited, India / Hetero Labs Limited, India.

Manufacturer's address and location of its business operation

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.