Lercamen 20 film-coated tablets 20 mg blister No. 60

Instructions Lerkamen 20 film-coated tablets 20 mg blister No. 60

Composition

active ingredient: lercanidipine;

1 film-coated tablet contains 20 mg of lercanidipine hydrochloride, corresponding to 18.8 mg of lercanidipine;

excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K 30, magnesium stearate;

shell: Opadry 02F25077 (hypromellose, talc, titanium dioxide (E 171), macrogol 6000, iron oxide (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: pink, round, biconvex, film-coated tablets with a breakline on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group

Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. ATC code C08C A13.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Lercanidipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium into cardiac and smooth muscle cells. The mechanism of antihypertensive action of lercanidipine is due to a direct relaxing effect on vascular smooth muscle, resulting in a decrease in total vascular peripheral resistance.

Pharmacodynamic effects

Despite the short half-life of lercanidipine, it has a prolonged antihypertensive effect due to its high membrane distribution coefficient and is devoid of negative inotropic effects due to its high vascular selectivity. Since the vasodilation caused by lercanidipine hydrochloride occurs gradually, acute hypotension with reflex tachycardia in patients with hypertension is rare.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive effect of lercanidipine is mainly due to its (S)-enantiomer.

Clinical efficacy and safety

The clinical efficacy and safety of lercanidipine at a dose of 10 to 20 mg once daily was evaluated in a double-blind, placebo-controlled clinical trial (involving 1200 patients taking lercanidipine and 603 patients taking placebo), as well as in active-controlled and long-term uncontrolled clinical trials involving 3676 patients suffering from arterial hypertension.

Most clinical studies have been conducted in patients with mild to moderate essential hypertension (including elderly patients and patients with diabetes mellitus) who received lercanidipine alone or in combination with angiotensin-converting enzyme (ACE) inhibitors, diuretics or beta-blockers.

In addition to clinical trials conducted to confirm the therapeutic indications, another small uncontrolled but randomized study in patients with severe arterial hypertension (mean ± standard deviation of diastolic blood pressure is 114.5 ± 3.7 mm Hg) showed that blood pressure normalized in 40% of 25 patients when taking lercanidipine hydrochloride at a dose of 20 mg once a day, and in 56% of 25 patients when taking 10 mg twice a day.

In a double-blind, randomized, controlled trial compared with placebo in patients with isolated systolic hypertension, lercanidipine hydrochloride effectively reduced systolic blood pressure from a mean baseline value of 172.6 ± 5.6 mmHg to a value of 140.2 ± 8.7 mmHg.

No clinical trials have been conducted in children.

Pharmacokinetics

Absorption

Lercanidipine hydrochloride is completely absorbed after oral administration of 10–20 mg, and maximum plasma concentrations, which are 3.30 ± 2.09 ng/ml and 7.66 ± 5.90 ng/ml, respectively, are reached 1.5–3 hours after administration.

The two enantiomers of lercanidipine show a similar plasma concentration profile: the time to reach maximum plasma concentration is the same, the maximum plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer, and the half-lives of the two enantiomers are essentially the same. No interconversion of the enantiomers has been observed in in vivo studies.

Due to high first-pass metabolism, the absolute bioavailability of lercanidipine hydrochloride administered to a patient after a meal is approximately 10%, decreasing to ⅓ of this value when administered to healthy volunteers on an empty stomach.

The bioavailability of lercanidipine hydrochloride after oral administration increases 4-fold if it is taken no earlier than 2 hours after a high-fat meal, so the drug should be taken before meals.

Distribution

Distribution from blood plasma to tissues and organs is rapid and extensive.

The degree of binding of lercanidipine to serum proteins exceeds 98%. Since the plasma protein content in patients with severe renal or hepatic impairment is reduced, the free fraction of the drug may be increased.

Lercanidipine hydrochloride is extensively metabolized by the CYP3A4 enzyme; unchanged drug is not detected in urine or feces. It is mainly converted to inactive metabolites, and about 50% of the administered dose is excreted in the urine.

In vitro experiments with human liver microsomes have shown that lercanidipine slightly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its peak plasma concentrations achieved after a 20 mg dose. In addition, an interaction study in humans has shown that lercanidipine does not modify the plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate. Therefore, when lercanidipine hydrochloride is used at therapeutic doses, biotransformation of drugs metabolised by CYP3A4 or CYP2D6 is not to be expected.

Elimination

Elimination occurs mainly through biotransformation.

The average half-life is 8-10 hours, and the therapeutic effect lasts for 24 hours due to the high degree of binding of lercanidipine to cell membrane lipids. No accumulation was observed with repeated administration.

Linearity/nonlinearity

When lercanidipine hydrochloride is administered orally, its plasma concentration is not directly proportional to the dose taken (non-linear kinetics). After administration of 10, 20 or 40 mg, the maximum plasma concentrations observed had a ratio of 1:3:8 and the areas under the plasma concentration-time curves had a ratio of 1:4:18, indicating a gradual saturation of the first-pass metabolism. Thus, the bioavailability of lercanidipine increases with increasing dose.

Special patient groups

The pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic impairment have been shown to be similar to that observed in the general population. In patients with severe renal dysfunction or in patients undergoing haemodialysis, drug concentrations were higher (approximately 70%). In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased, as it is metabolised mainly in the liver.

Safety pharmacology studies conducted in animals have shown no effects on the autonomic nervous system, the central nervous system, or gastrointestinal function at antihypertensive doses.

Data obtained during non-clinical standard pharmacological safety studies, studies on repeated dose toxicity, genotoxicity, carcinogenic potential, as well as reproductive toxicity indicate the absence of a special hazard of the medicinal product for humans.

The significant effects observed in long-term studies in rats and dogs were directly or indirectly related to the known effects of high doses of calcium antagonists, i.e. were a consequence of excessively high pharmacodynamic activity.

Lercanidipine is not genotoxic and does not exhibit carcinogenic risk.

Lercanidipine had no effect on fertility and general reproductive performance in rats.

Lercanidipine treatment had no effect on teratogenicity in rats and rabbits, however, in rats, administration of high doses resulted in pre- and post-implantation loss of offspring, as well as a slowdown in intrauterine development.

The use of high doses of lercanidipine hydrochloride (12 mg/kg/day) during labor may lead to dystocia. The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in milk have not been studied.

Metabolites were not separately evaluated in toxicological studies.

Indication

Mild or moderate essential hypertension.

Contraindication

- Hypersensitivity to the active substance or to other dihydropyridines or to any of the excipients of the medicinal product (see section "Composition").

- Obstruction of the vessels leaving the left ventricle.

- Untreated congestive heart failure.

- Unstable angina or recent (within 1 month) myocardial infarction.

- Severe liver failure.

- Severe renal insufficiency (GFR < 30 ml/min), including patients undergoing dialysis.

- Concomitant use with strong CYP3A4 inhibitors, cyclosporine, grapefruit or grapefruit juice (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Concomitant use is contraindicated

CYP3A4 inhibitors

Lercanidipine is known to be metabolized by the CYP3A4 enzyme, and therefore CYP3A4 inhibitors used with lercanidipine may affect its metabolism and elimination.

An interaction study with the strong CYP3A4 inhibitor, ketoconazole, showed a significant increase in plasma lercanidipine concentrations (15-fold increase in AUC (area under the curve) and 8-fold increase in Cmax of the S-lercanidipine eutomer).

The concomitant use of lercanidipine with CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin should be avoided (see section "Contraindications").

Increased plasma concentrations of both lercanidipine and cyclosporine have been observed when co-administered. A study in young healthy volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, the plasma concentration of lercanidipine did not change, while the AUC of cyclosporine increased by 27%. However, concomitant administration of lercanidipine and cyclosporine resulted in a 3-fold increase in plasma concentrations of lercanidipine and a 21% increase in the AUC of cyclosporine.

Cyclosporine and lercanidipine should not be used together (see section "Contraindications").

Grapefruit or grapefruit juice

As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit or grapefruit juice, with a subsequent increase in the systemic availability of lercanidipine and an increase in the hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section "Contraindications").

Concomitant use is not recommended.

CYP3A4 inducers

Lercanidipine should be used with caution with CYP3A4 inducers such as anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine) and rifampicin, as the antihypertensive effect may be reduced. Blood pressure should also be monitored more frequently than usual (see section 4.4).

Alcohol

Alcohol should be avoided as it may enhance the effect of vasodilating antihypertensive drugs (see section "Special warnings and precautions for use").

Precautions including dose adjustments

CYP3A4 substrates

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

Midazolam

Concomitant administration of midazolam and lercanidipine at a dose of 20 mg in elderly volunteers resulted in an increase in the absorption of lercanidipine (by approximately 40%) and a decrease in its absorption rate (Tmax 3 hours instead of 1.75 hours), while the concentration of midazolam did not change.

Metoprolol

Concomitant administration of lercanidipine and metoprolol (a β-blocker that is mainly eliminated by the liver) did not alter the bioavailability of metoprolol, while the bioavailability of lercanidipine was reduced by 50%. This effect may be due to the reduction in hepatic blood flow caused by β-blockers and may occur with other drugs of this class. Therefore, lercanidipine can be safely used with β-blockers, although dose adjustment may be necessary.

Digoxin

Concomitant administration of lercanidipine at a dose of 20 mg to patients receiving continuous β-methyldigoxin did not reveal any pharmacokinetic interaction. However, a 33% increase in Cmax of digoxin was observed, while there were no significant changes in AUC or renal clearance. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for possible signs of digoxin intoxication.

Other interactions

Fluoxetine

Interaction studies with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) conducted in volunteers aged 65 ± 7 years (mean ± standard deviation) showed no clinically significant changes in the pharmacokinetics of lercanidipine.

Cimetidine

Concomitant use of cimetidine at a daily dose of 800 mg per day does not cause significant changes in the concentration of lercanidipine in the blood, but caution should be exercised with higher doses, as the bioavailability and antihypertensive effect of lercanidipine may increase.

Simvastatin

When lercanidipine 20 mg was repeatedly co-administered with simvastatin 40 mg, the AUC of lercanidipine was slightly changed, while the AUC of simvastatin increased by 56% and the AUC of its active metabolite, the b-hydroxyacid, by 28%. These changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as recommended for this medicinal product.

Diuretics and ACE inhibitors

Lercanidipine can be safely used with diuretics and ACE inhibitors.

Other medicines that affect blood pressure

As with other antihypertensive drugs, an increase in the hypotensive effect may be observed when lercanidipine is used concomitantly with other drugs that affect blood pressure, such as alpha-blockers used to treat urinary tract symptoms, tricyclic antidepressants, neuroleptics. On the other hand, a decrease in the hypotensive effect may be observed when used concomitantly with corticosteroids.

Application features

Sick sinus syndrome

Particular caution should be exercised when administering lercanidipine to patients with sick sinus syndrome who do not have an implanted pacemaker.

Left ventricular dysfunction

Use with caution in left ventricular dysfunction, despite the fact that hemodynamically controlled studies have not revealed any abnormalities in ventricular function.

Some short-acting dihydropyridines are thought to be associated with an increased cardiovascular risk in patients with coronary heart disease. Although lercanidipine is a long-acting drug, it should be used with caution in such patients.

Some dihydropyridines may in isolated cases cause pain in the heart area or angina pectoris. Very rarely, patients with pre-existing angina pectoris may experience an increase in the frequency, duration and severity of its attacks. In isolated cases, myocardial infarction may occur (see section "Adverse reactions").

Patients with renal or hepatic insufficiency

Special caution should be exercised in treating patients with mild to moderate renal dysfunction. Although the usual recommended dose of 10 mg/day may be well tolerated in this patient group, increasing the dose to 20 mg/day should be approached with caution. The hypotensive effect of the drug may be enhanced in patients with moderate hepatic dysfunction; therefore, dose adjustment may be necessary in such cases.

Lercanidipine is contraindicated in patients with severe hepatic or severe renal impairment (GFR < 30 ml/min), including patients undergoing dialysis (see sections 4.2 and 4.3).

Peritoneal dialysis

Lercanidipine has been associated with dialysate turbidity in patients undergoing peritoneal dialysis. The turbidity is due to increased triglyceride concentrations in the dialysate being drained. Although the mechanism of this phenomenon is not clear, the turbidity resolves shortly after lercanidipine is discontinued. This should be taken into account as dialysate turbidity may be mistaken for infectious peritonitis, which may lead to unnecessary hospitalization and the use of empirical antibiotic therapy.

CYP3A4 inducers

CYP3A4 inducers, such as anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin, may reduce the plasma concentration of lercanidipine and therefore the efficacy of lercanidipine may be lower than expected (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol

Concomitant alcohol consumption should be avoided as it may lead to an increase in the vasodilatory antihypertensive effect of the medicinal products (see section “Interaction with other medicinal products and other types of interactions”).

Lactose

This medicinal product contains lactose and should not be taken by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy: There are no data on the use of lercanidipine in pregnant women. Animal studies have not shown a teratogenic effect (see “Special patient groups” in the “Pharmacokinetics” section), but other dihydropyridines have shown a teratogenic effect in animal studies. Lercanidipine is not recommended for use during pregnancy or in women of childbearing potential if they wish to become pregnant and are not using contraception.

Breastfeeding. It is not known whether lercanidipine or its metabolites are excreted in human milk. A risk to the newborn or infant cannot be excluded. Lercanidipine should not be taken during breast-feeding.

Fertility: There are no clinical data on lercanidipine. In some patients, channel blockers have been reported to cause reversible biochemical changes in the sperm head, which may adversely affect the fertilization process. In the event of repeated unsuccessful attempts at in vitro fertilization in the absence of other explanations, the possibility of calcium channel blockers being the cause should be considered.

Ability to influence reaction speed when driving vehicles or other mechanisms

Lercanidipine has a minor influence on the ability to drive or use machines. However, caution should be exercised as dizziness, asthenia, fatigue, and in rare cases drowsiness may occur.

Method of administration and doses

Reservation

Lercanidipine should be taken in the morning at least 15 minutes before breakfast.

This medicine should not be taken with grapefruit juice (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).

Dosage. The recommended dose is 10 mg once daily, taken at least 15 minutes before meals. The dose may be increased to 20 mg, depending on the individual patient's response. Dose titration should be gradual, as the maximum antihypertensive effect may not be achieved until 2 weeks after initiation of treatment.

For some individuals whose blood pressure is not adequately controlled with a single antihypertensive drug, treatment with lercanidipine hydrochloride together with a β-adrenergic blocker (atenolol), a diuretic (hydrochlorothiazide) or an angiotensin-converting enzyme inhibitor (captopril or enalapril) may be appropriate.

Elderly patients: Although pharmacokinetic data and clinical experience suggest that no adjustment of the daily dose is necessary, special attention and caution should be exercised when initiating treatment in elderly patients.

Patients with renal or hepatic impairment: Particular caution should be exercised when initiating treatment in patients with mild to moderate renal or hepatic impairment. Although these patients generally tolerate the drug well, increasing the daily dose to 20 mg should be done with caution. The antihypertensive effect may be enhanced in patients with hepatic impairment, and dose adjustment is therefore necessary in such cases.

Lercanidipine hydrochloride is contraindicated in patients with severe hepatic or severe renal impairment (GFR < 30 ml/min), including patients undergoing dialysis (see sections "Contraindications" and "Special warnings and precautions for use").

Children. The use of lercanidipine in children under 18 years of age is not recommended due to lack of clinical experience.

Overdose

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

Symptoms

As with other dihydropyridines, overdose of lercanidipine will cause excessive peripheral vasodilation with marked hypotension and reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, resulting in bradycardia and a negative inotropic effect. The most common adverse reactions associated with overdose were hypotension, dizziness, headache and palpitations.

Treatment

Clinically significant hypotension caused by overdose requires active cardiovascular support, including the following measures: monitoring of cardiac and respiratory function, elevation of extremities, control of circulating fluid volume and diuresis.

Given the long-term pharmacological effect of lercanidipine, it is necessary to continue monitoring the patient's cardiovascular system for at least 24 hours. Given the high degree of protein binding of the drug, dialysis is assumed to be ineffective. If moderate or severe poisoning is suspected, the patient should be monitored in the intensive care unit.

Adverse reactions

The safety of lercanidipine at a dose of 10 to 20 mg once daily was evaluated in a double-blind, placebo-controlled clinical trial (involving 1200 patients taking lercanidipine and 603 patients taking placebo), as well as in active-controlled and uncontrolled long-term clinical trials with an active comparator in 3676 patients suffering from arterial hypertension and receiving lercanidipine.

The most common adverse reactions reported in clinical trials and post-marketing surveillance were: peripheral edema, headache, flushing, tachycardia, and palpitations.

The table below presents adverse reactions for which a causal relationship with the use of the drug has been established as a result of clinical trials and post-marketing surveillance in various countries around the world.

They are listed by MedDRA 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing incidence.

1 Adverse reactions identified in the post-marketing period, according to spontaneous reports from various countries around the world.

In placebo-controlled clinical trials, the incidence of peripheral oedema was 0.9% for lercanidipine 10 to 20 mg and 0.83% for placebo. In the overall study population, including long-term clinical trials, the incidence was 2%.

Lercanidipine is unlikely to have a negative effect on blood glucose levels and serum lipid levels.

Some dihydropyridines may rarely cause heart pain or angina pectoris. Very rarely, in patients with pre-existing angina pectoris, the frequency, duration or severity of these attacks may increase. Isolated cases of myocardial infarction may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is of great importance. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any adverse reactions.

Expiration date

3 years.

Storage conditions

No special storage conditions are required.

Store in original packaging out of the reach of children.

Packaging

1 blister of 7 film-coated tablets; 1 or 2 or 4 blisters of 14 film-coated tablets; 6 or 9 blisters of 10 film-coated tablets and instructions for medical use in a cardboard box.

Vacation category

According to the recipe.

Producer

BERLIN-CHEMI AG.

Location of the manufacturer and address of its place of business

Glienicker Weg 125, 12489 Berlin, Germany.

Applicant

Menarini International Operations Luxembourg S.A.

Applicant's location

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.