Lercanidipine-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERCANIDIPINE-TEVA (Lercanidipine-Teva)

Composition:

Active substance: lercanidipine hydrochloride equivalent to lercanidipine;

One film-coated tablet contains lercanidipine hydrochloride 10 mg (equivalent to lercanidipine 9.4 mg) or lercanidipine hydrochloride 20 mg (equivalent to lercanidipine 18.8 mg);

Excipients:

Tablets 10 mg: povidone; sodium starch glycolate (type A); lactose monohydrate; microcrystalline cellulose; magnesium stearate; polyvinyl alcohol, partially hydrolyzed*; titanium dioxide (E 171)*; macrogol*; talc*; yellow iron oxide (E 172)*;

*contained in Opadry II Yellow 85F32553.

Tablets 20 mg: povidone; sodium starch glycolate (type A); lactose monohydrate; microcrystalline cellulose; magnesium stearate; polyvinyl alcohol, partially hydrolyzed*; titanium dioxide (E 171)*; macrogol*; talc*; yellow iron oxide (E 172)*; red iron oxide (E 172)*.

*contained in Opadry II Pink 85F34564.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex yellow or pink tablets, coated, with a diameter of 6.5 ± 0.3 mm or 8.5 ± 0.4 mm, with a score line on one side and the imprint "L" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

Lercanidipine is a dihydropyridine group calcium antagonist. It inhibits transmembrane calcium influx into cardiomyocytes and vascular smooth muscle cells. The antihypertensive mechanism 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, 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 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), as well as 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 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 trial 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 and 7.66 ng/mL ± 5.90 SD, respectively, reached approximately 1.5–3 hours post-administration.

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 elimination half-lives of both enantiomers are essentially the same. In vivo interconversion of enantiomers has not been observed.

Due to extensive first-pass hepatic metabolism, the absolute oral bioavailability of lercanidipine administered after food is approximately 10%. However, bioavailability 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 plasma 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 weakly 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, clinically significant 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

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

Additional information in specific patient populations

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 on dialysis, drug concentrations were approximately 70% higher. 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.
• Obstruction of the left ventricular outflow tract.
• Uncompensated congestive heart failure.
• Unstable angina or recent myocardial infarction (within the past 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 contraindicated

CY3A4 inhibitors

Lercanidipine is metabolized by the CYP3A4 enzyme; therefore, concomitant use of CYP3A4 inhibitors or inducers may affect the metabolism and elimination of lercanidipine. 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 (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided.

Cyclosporine

Concomitant use 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 intake did not alter lercanidipine plasma levels, while the AUC of cyclosporine increased by 27%. However, concomitant administration of lercanidipine and cyclosporine leads to a threefold increase in lercanidipine plasma levels and a 21% increase in cyclosporine AUC.

Lercanidipine and cyclosporine should not be used concomitantly.

Grapefruit or grapefruit juice

As with other dihydropyridines, grapefruit juice slows the metabolism of lercanidipine, resulting in increased systemic availability and enhanced antihypertensive effect. Concomitant intake of lercanidipine with grapefruit or grapefruit juice should be avoided.

Concomitant use not recommended

CY3A4 inducers

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 blood pressure monitoring is recommended.

Alcohol

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

Interactions requiring dose adjustment

CY3A4 substrates

Caution is advised when lercanidipine is used 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 resulted in increased absorption of lercanidipine (by approximately 40%) and reduced absorption rate (tmax prolonged from 1.75 to 3 hours). Midazolam concentration was not altered.

Metoprolol

Concomitant administration of lercanidipine and 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 also occur when lercanidipine is used with other agents in this class. Therefore, 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 with lercanidipine should be closely monitored for signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

A drug interaction study in volunteers aged 65 ± 7 years (mean ± SD) receiving fluoxetine (an inhibitor of CYP2D6 and CYP3A4) showed no clinically significant change in the pharmacokinetics of lercanidipine.

Cimetidine

Concomitant administration of cimetidine 800 mg daily does not cause significant changes in lercanidipine plasma concentration. However, caution is advised when higher doses of cimetidine are used, 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 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 drugs 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 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 worsening of ventricular function, caution should be exercised when prescribing in patients with left ventricular dysfunction.

Ischemic heart disease

It has been suggested that some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischemic heart disease. Although Lercanidipine-Teva is a long-acting formulation, the drug should still 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

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 association 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

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.

Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per 1 tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

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.

It is not definitively known whether lercanidipine or its metabolites are excreted in human breast milk. Therefore, a 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 observed in patients treated with calcium channel blockers, which may affect fertilizing capacity. 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 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.

Method of Administration and Dosage.

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 maximum antihypertensive effect develops within 2 weeks of treatment.

For patients whose blood pressure is not adequately controlled with monotherapy using antihypertensive agents, the addition of the medicinal product Lercanidipine-Teva to treatment regimens containing β-adrenoblockers (atenolol), diuretics (hydrochlorothiazide), or ACE inhibitors (captopril or enalapril) may be considered.

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, 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 lercanidipine in patients with mild to moderate renal or hepatic impairment should be initiated under medical supervision. The usual recommended dose of 10 mg is generally well tolerated in these patient subgroups; however, 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.

Method of Administration.

Prior to administration, the following should be considered:

• 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.

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

Overdose.

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

Symptoms. By analogy with other dihydropyridines, overdose with lercanidipine may result in 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 should be implemented, including continuous 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 action of lercanidipine, cardiovascular monitoring of such patients is required for at least 24 hours following overdose. Because of the high protein binding of lercanidipine, dialysis may be ineffective. Patients with expected moderate or severe intoxication should be monitored in intensive care conditions.

Adverse Reactions

According to data from clinical studies and post-marketing use, the most frequently 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 according to MedDRA classification and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each group, reactions are listed in order of decreasing severity according to frequency.

1Adverse reactions from spontaneous reports 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 doses of 10–20 mg and in 0.83% of patients 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 have been reported.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

14 tablets per blister pack; 2 or 4 blister packs per carton.

Prescription status.

Prescription only.

Manufacturer.

Balkanpharma-Dupnitsa AD.

Manufacturer's address and location of its business operations.

3 Samokovsko Shose Str., Dupnitsa, 2600, Bulgaria.