Lercamen 10 film-coated tablets 10 mg No. 60

Instructions for Lercamen 10 film-coated tablets 10 mg No. 60

Composition

active ingredient: lercanidipine;

1 film-coated tablet contains 10 mg of lercanidipine hydrochloride, equivalent to 9.4 mg of lercanidipine;

excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate, Opadry OY-SR-6497 shell, which includes: hypromellose, talc, titanium dioxide (E 171), polyethylene glycol, iron oxide (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets with a score line on one side. The score line is intended only for breaking to facilitate swallowing of the tablet, it is not intended for dividing the tablet into equal doses.

Pharmacotherapeutic group

Selective calcium antagonists with a primary vascular effect. Dihydropyridine derivatives. ATC code C08C A13.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle cells. The mechanism of its antihypertensive action is due to a direct relaxing effect on vascular smooth muscle, resulting in a decrease in total 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 is rarely observed in patients with arterial hypertension.

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 were evaluated in double-blind, placebo-controlled clinical trials (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo) and in long-term, uncontrolled, active comparator clinical trials in 3676 patients with 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 as monotherapy or in combination with ACE inhibitors, diuretics or beta-blockers.

In addition to the clinical studies conducted to confirm the therapeutic indications, another small uncontrolled but randomized study was conducted in patients with severe hypertension (mean ± standard deviation of diastolic blood pressure was 114.5 ± 3.7 mm Hg). In this study, blood pressure normalized in 40% of 25 patients with 20 mg lercanidipine hydrochloride once daily and in 56% of 25 patients with 10 mg lercanidipine hydrochloride twice daily. In a double-blind randomized controlled study in patients with systolic hypertension, lercanidipine hydrochloride effectively reduced systolic blood pressure from a mean of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.

Clinical studies involving children have not been conducted.

Pharmacokinetics.

Absorption

Lercanidipine hydrochloride is completely absorbed after oral administration of 10-20 mg, and maximum plasma concentrations of 3.30 ng/ml ± 2.09 standard deviation and 7.66 ng/ml ± 5.90 standard deviation, 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 taken by the patient after a meal is approximately 10%, while it is reduced to 1/3 of this value when the drug is administered to healthy volunteers on an empty stomach.

The bioavailability of lercanidipine hydrochloride after oral administration increases 4-fold if taken no later than 2 hours after a high-fat meal, therefore lercanidipine hydrochloride should be taken before meals.

Distribution

Distribution from 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, inhibition of the biotransformation of drugs metabolised by CYP3A4 or CYP2D6 is not expected when lercanidipine hydrochloride is used at therapeutic doses.

Elimination

Elimination occurs mainly through biotransformation.

The mean terminal elimination time is estimated to be 8-10 hours; due to the high affinity for lipid membranes, therapeutic activity lasts for 24 hours. No accumulation was observed after 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 and 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.

Additional information in 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 usually extensively metabolised in the liver.

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.

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.

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 teratogenic effects in rats and rabbits, however, administration of high doses to rats 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

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

Contraindications to simultaneous use

CYP3A4 inhibitors

It is known that lercanidipine is metabolized by the CYP3A4 enzyme, and therefore CYP3A4 inhibitors used together 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 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (see section "Contraindications").

Both lercanidipine and cyclosporine have been shown to increase their plasma concentrations following concomitant administration. 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 with cyclosporine resulted in a three-fold increase in the plasma concentration 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.

Inductors CYPZA4

The concomitant use of lercanidipine with CYP3A4 inducers such as anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution, as the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual (see section "Special warnings and precautions for use").

Alcohol

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

Precautions, including dose adjustments

CYP3A4 substrates

Caution should be exercised when using lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and 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 approximately 40% increase in the absorption of lercanidipine and a decrease in its absorption rate (3 hours instead of 1.75 hours to reach maximum concentration). Midazolam concentrations were not affected.

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 β-methyldigoxin did not reveal any pharmacokinetic interaction. However, an increase in Cmax of digoxin by an average of 33% was observed, while AUC and renal clearance were not significantly changed. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for possible signs of digoxin intoxication.

Concomitant use with other medicines

Fluoxetine

An interaction study with fluoxetine, an inhibitor of CYP2D6 and CYP3A4, conducted in healthy volunteers aged 65 ± 7 years (mean ± standard deviation), did not reveal any clinically significant modification of the pharmacokinetics of lercanidipine.

Cimetidine

Concomitant use of cimetidine at a daily dose of 800 mg 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 hydrochloride 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 the active metabolite 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 indicated 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 with other drugs that affect blood pressure, such as alpha-blockers for urinary tract symptoms, tricyclic antidepressants, neuroleptics. On the other hand, a weakening of the hypotensive effect may be observed when used with corticosteroids.

Application features

Sick sinus syndrome

Lercanidipine should be used with caution in 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").

Use in renal or hepatic impairment

Special caution should be exercised when treating patients with mild to moderate renal impairment. Although the usual recommended dose of 10 mg per day may be well tolerated, increasing the dose to 20 mg per day should be approached with caution.

The hypotensive effect may be increased in patients with moderate hepatic impairment; therefore, dose adjustment may be necessary in such cases.

Lercanidipine is contraindicated in patients with severe hepatic or renal impairment (GFR < 30 ml/min), including patients on dialysis (see sections “Method of administration and dosage” and “Contraindications”).

Peritoneal dialysis

The use of lercanidipine has been associated with the development of peritoneal drainage turbidity in patients undergoing peritoneal dialysis. The turbidity is associated with increased triglyceride concentrations in the peritoneal drainage. Although the mechanism of development is unknown, the turbidity resolves shortly after discontinuation of lercanidipine. This association should be considered because turbidity of the peritoneal drainage may be mistaken for infectious peritonitis, which may lead to unnecessary hospitalization and empirical antibiotic treatment.

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

The simultaneous use of alcohol and Lerkamen® 10 should be avoided, as this may lead to an increase in the vasodilatory antihypertensive effect of the drugs (see section “Interaction with other medicinal products and other types of interactions”).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of lercanidipine in pregnant women. Animal studies have not shown teratogenic effects (see preclinical safety data), but these have been observed with other dihydropyridine derivatives. Lercanidipine is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding

It is not known whether lercanidipine/metabolites are excreted in human milk. A risk to the newborn/infants cannot be excluded. Lercanidipine should not be used during breast-feeding.

Fertility

There are no clinical data available for lercanidipine. Reversible biochemical changes in the sperm head, which may impair fertilization, have been reported in some patients treated with channel blockers. In cases of repeated failures in in vitro fertilization and in the absence of other explanations, the possibility that calcium channel blockers may be the cause of these failures 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

Method of application

Precautions to be taken when taking or handling the medicine: The medicine should be taken preferably in the morning, at least 15 minutes before breakfast.

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

The recommended dose is 10 mg orally once daily at least 15 minutes before meals; the dose may be increased to 20 mg depending on individual patient response. Dose titration should be gradual, as 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 impairment or severe renal impairment (GFR < 30 ml/min), including patients on dialysis (see sections “Interaction with other medicinal products and other forms of interaction” 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

From post-marketing experience with lercanidipine, several cases of overdose (dose range from 30-40 mg to 800 mg, including reports of suicide attempts) are known.

Symptoms

As with other dihydropyridines, overdose with lercanidipine leads to excessive peripheral vasodilation with marked hypotension and reflex tachycardia. However, when the drug is used in very high doses, loss of peripheral selectivity is possible, causing bradycardia and a negative inotropic effect. The most frequent adverse reactions caused by overdose were hypotension, dizziness, headache and palpitations.

Treatment

Patients with clinically significant hypotension require active cardiovascular support, including frequent monitoring of cardiac and respiratory function, horizontal position with raised lower extremities, monitoring of circulating fluid volume and diuresis. Given the prolonged pharmacological action of lercanidipine, it is important to monitor the patient's cardiovascular status for at least 24 hours. Since the drug is highly protein-bound, dialysis is unlikely to be effective. In cases of suspected moderate or severe poisoning, patients should be monitored in an intensive care unit.

Side effects

Overall safety profile

The safety of lercanidipine at doses of 10 to 20 mg once daily was evaluated in a double-blind, placebo-controlled clinical trial (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo) and in long-term, uncontrolled, active comparator clinical trials in 3676 hypertensive patients receiving lercanidipine.

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

Adverse reactions table

The following table presents adverse reactions reported during clinical trials and post-marketing surveillance worldwide and for which there is a reasonable causal relationship with the use of the drug; they are distributed by MedDRA system organ class and by 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 that occurred are presented in order of decreasing seriousness.

1 Adverse reactions obtained spontaneously during post-marketing surveillance worldwide.

Description of selected adverse reactions

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 has no adverse effects on blood sugar or serum lipids.

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 are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Do not use the drug after the expiration date indicated on the package!

Storage conditions

No special storage conditions are required. Store the medicine in its original packaging. Keep out of the reach of children!

Packaging

7, or 14, or 15 tablets in a blister; 1 blister of 7 tablets, or 1 or 2 blisters of 14 tablets, or 4 or 6 blisters of 15 tablets in a cardboard box.

Vacation category

According to the recipe.

Producer

BERLIN-CHEMI AG.

Address

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

Applicant

Menarini International Operations Luxembourg S.A., Luxembourg.

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