Lernicor, 10 mg 28 pcs.

Lercanidipine is a selective slow calcium channel blocker, a 1,4-dihydropyridine derivative, inhibits transmembrane flow of calcium ions into vascular smooth muscle cells.

Lercanidipine is a racemic mixture of (+)-R- and (-)S- enantiomers. The antihypertensive effect of lercanidipine is primarily due to the S enantiomer.

The mechanism of antihypertensive action of lercanidipine is due to a direct relaxant effect on vascular smooth muscle cells, resulting in a decrease of total peripheral resistance. Despite relatively short plasma elimination half-life, lercanidipine has prolonged antihypertensive effect due to high membrane distribution coefficient.

Owing to high vascular selectivity, it has no negative inotropic effect. Acute arterial hypotension with reflex tachycardia is rare due to the gradual development of vasodilation when taking lercanidipine.

Lercanidipine is metabolically neutral and has no significant effect on serum lipoprotein and apolipoprotein content and does not alter lipid profile in patients with arterial hypertension.

Indications

Active ingredient

Composition

Yellow film-coated, round, biconvex tablets.

Associates:

microcrystalline cellulose – 39 mg,

lactose monohydrate – 30 mg,

sodium carboxymethyl starch (sodium starch glycolate) – 15.5 mg,

povidone K30 – 4.5 mg,

magnesium stearate – 1 mg.

Shell contents:

Opadray II 85F38107 yellow (polyvinyl alcohol – 1.2 mg, titanium dioxide – 0.6684 mg, macrogol (polyethylene glycol) – 0.606 mg, talc – 0.444 mg, quinoline yellow dye aluminum varnish – 0.0807 mg, iron oxide red – 0.0009 mg).

Interaction

Lercanidipine may be used concomitantly with beta-adrenoblockers, diuretics, angiotensin-converting enzyme inhibitors (ACEIs).

In concomitant use with metoprolol, the bioavailability of lercanidipine decreases by 50%. This effect may also occur with concomitant use with other beta-adrenoblockers; therefore, adjustment of the dose of lercanidipine may be required to achieve the therapeutic effect with this combination. Lercanidipine is metabolized with the participation of CYP3A4 isoenzyme, so inhibitors and inducers of this isoenzyme, when used simultaneously, may affect the metabolism and excretion of lercanidipine. Concomitant use of lercanidipine with potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) is not recommended.

The concomitant use of cyclosporine and lercanidipine is not recommended because an increase in plasma concentrations of both substances is observed.

Precautions should be taken when using lercanidipine concomitantly with other CYP3A4 substrates (terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine).

The bioavailability of lercanidipine at a dose of 20 mg with midazolam may increase by approximately 40% in elderly patients.

Lercanidipine should be used with caution in conjunction with CYP3A4 inducers, such as anticonvulsants (phenytoin, carbamazepine) and rifampicin, because the antihypertensive effect may decrease. Regular monitoring of blood pressure (BP) is necessary.

No pharmacokinetic interaction was noted with concomitant administration of 20 mg lercanidipine in patients continuously taking beta-methyldigoxin, whereas an increase in Cmax was noted in healthy volunteers treated with digoxin.sub>max for digoxin by an average of 33% after fasting administration of 20 mg of lercanidipine, with little change in AUC (area under the concentration-time curve) and renal clearance. It is necessary to monitor for signs of digoxin intoxication in patients taking digoxin and lercanidipine concomitantly.

The concomitant use of lercanidipine with cimetidine (up to 800 mg) does not cause significant changes in plasma concentrations of lercanidipine. The bioavailability and antihypertensive effect of lercanidipine may be increased with high doses of cimetidine.

When using lercanidipine (20 mg) and simvastatin (40 mg) concomitantly, the AUC value for simvastatin increased by 56%, and the same value for its active metabolite – beta-hydroxy acid – by 28%. When taking the drugs at different times of the day (lercanidipine in the morning, simvastatin in the evening) unwanted interaction can be avoided.

There were no changes in warfarin pharmacokinetics in healthy volunteers when concomitant use of 20 mg of lercanidipine and warfarin.

Concomitant use with fluoxetine (CYP2D6 and CYP3A4 inhibitor) in elderly patients showed no clinically significant changes in the pharmacokinetics of lercanidipine.

The antihypertensive effect may be enhanced with concomitant administration of grapefruit juice and lercanidipine.

Ethanol may potentiate the antihypertensive effect of lercanidipine.

Directions for use

Overly, at least 15 minutes before a meal, preferably in the morning, without chewing, with plenty of water.

The recommended dose of the drug is 10 mg once daily. Depending on individual tolerance of the drug by the patient, the dose can be increased up to 20 mg. If necessary, increase daily dose up to 20 mg in 2 weeks after the beginning of the drug administration.

The therapeutic dose is adjusted gradually, because the maximum antihypertensive effect occurs approximately 2 weeks after starting the drug.

It is unlikely that the potency of the drug will increase with a dose higher than 20 mg/day, while at the same time there is an increased risk of side effects.

The pharmacokinetic profile and data from clinical studies indicate that no dose adjustment of lercanidipine is necessary in elderly patients. However, caution should be exercised during initial treatment in this group of patients.

In the presence of renal insufficiency (CKG more than 30 ml/min) or mild to moderate hepatic insufficiency, the initial dose is 10 mg, then the dose is cautiously increased to 20 mg/day. Antihypertensive effect may increase in patients with mild to moderate hepatic insufficiency and dose adjustment (reduction) may be required.

Special Instructions

Special caution should be exercised when prescribing lercanidipine to patients with sinus node weakness syndrome (without a pacemaker).

While hemodynamically controlled studies have shown no worsening of ventricular function when taking lercanidipine, caution should be exercised when prescribing lercanidipine to patients with left ventricular dysfunction. It has been suggested that administration of some dihydropyridines may be associated with the risk of increased frequency of angina attacks in patients with coronary heart disease. Therefore, therapy with lercanidipine should be used with extreme caution in these patients.

Impact on driving and operating machinery

As dizziness, asthenia, increased fatigability and, in rare cases, somnolence may occur during the drug therapy, patients should be particularly careful when driving motor transport and engaging in other potentially dangerous activities requiring high psychomotor reactions.

Features

Introduction

Lercanidipine is completely absorbed after oral administration. Maximum plasma concentration (Cmax) is reached after 1.5-3 hours and is 3.3±2.09 ng/ml and 7.66±5.90 ng/ml after administration of 10 and 20 mg of lercanidipine, respectively.

The (+)-R- and (-)S- enantiomers of lercanidipine show a similar pharmacokinetic profile: Have the same time to reach maximum concentration (TCmax), the same half-life (T1/2); Cmax and area under the concentration-time curve (AUC) values are 1.2 times higher for the (-)S-enantiomer. No interconversion of enantiomers was observed in the in vivo experiments.

The absolute bioavailability of lercanidipine when taken orally after a meal is approximately 10%; when taken on an empty stomach the bioavailability decreases by 1/3. When lercanidipine is taken within 2 hours after a fatty meal its bioavailability increases 4-fold, therefore lercanidipine should not be taken after a meal. When lercanidipine is taken orally, its plasma concentration is not directly proportional to the dose taken (nonlinear kinetics). The saturation of presystemic metabolism, occurs gradually. Thus, bioavailability increases with increasing dose.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive. The binding to plasma proteins exceeds 98%.

Metabolism and excretion

Lercanidipine is metabolized with participation of CYP3A4 isoenzyme to form inactive metabolites.

About 50% of the dose taken is excreted by the kidneys (about 50% is excreted in the intestine). Elimination occurs mainly by biotransformation. The average T1/2 is 8-10 h. The duration of therapeutic action is 24 h.

Cumulation of lercanidipine in repeated oral administration is not observed.

Pharmacokinetics in special clinical cases

. The pharmacokinetics of lercanidipine in elderly patients, patients with renal impairment (creatinine clearance (CK) greater than 30 mL/min) and patients with mild to moderate hepatic impairment have been shown to be similar to those observed in the general patient population.

In patients with severe renal and/or hepatic impairment, due to decreased plasma protein concentrations, the free fraction of lercanidipine may increase.

In patients with renal insufficiency (CKR less than 30 ml/min) and in patients on hemodialysis, plasma concentrations of lercanidipine were higher (approximately 70%).

In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely increased because lercanidipine is metabolized primarily in the liver.

Contraindications

Side effects

Possible adverse reactions are listed below in descending frequency of occurrence: frequently (<1/10, >1/100), infrequently (<1/100, >1/1000), rarely (<1/1000, >1/10 000), very rarely (<1/10 000) including individual reports.

Nervous system disorders: infrequent – headache, dizziness; rarely – drowsiness.

The cardiovascular system: infrequent – palpitations, tachycardia, “rushes” of blood to the face; rare – angina pectoris, pain behind the chest; very rare – syncope, myocardial infarction, marked BP decrease, in patients with angina pectoris may increase the frequency, duration and severity of attacks.

Gastrointestinal tract: rare – nausea, dyspepsia, diarrhea, epigastric pain, vomiting; very rare – reversible increase in liver transaminase activity, gum hyperplasia.

Respiratory system, chest and mediastinal organs: very rarely – pain in the chest.

Skin and subcutaneous tissues: rarely – skin rash.

Musculoskeletal system: rarely – myalgia.

Perior renal and urinary tract: rare – polyuria; very rare – pollakiuria (increased frequency of urination).

The immune system: very rare – hypersensitivity reactions.

General disorders and disorders at the site of administration: infrequent – peripheral edema; rare – asthenia, increased fatigue.

Overdose

Symptoms: presumably in case of overdose of lercanidipine there will be symptoms similar to those of overdose of other dihydropyridine derivatives – peripheral vasodilation with marked BP reduction and reflex tachycardia.

The treatment: symptomatic. In case of marked BP decrease, loss of consciousness, cardiovascular therapy is indicated, in bradycardia – intravenous injection of atropine.

There are data on 3 cases of overdose when taking lercanidipine in doses of 150 mg, 280 mg and 800 mg with the purpose of suicide.

In the case of taking 150 mg of lercanidipine + alcohol (unspecified amount) drowsiness was observed. Treatment: gastric lavage, administration of activated charcoal.

In case of administration of 280 mg of lercanidipine + 5.6 mg of moxonidine the following symptoms were observed: cardiogenic shock, marked myocardial ischemia, mild renal failure. Treatment: cardiac glycosides, diuretics (furosemide), high doses of catecholamines, plasma substitutes.

In case of administration of 800 mg of lercanidipine, nausea and marked BP decrease were observed. Treatment: administration of activated charcoal and laxative, intravenous dopamine.

In all cases of overdose all patients survived. There is no information on dialysis efficacy for lercanidipine. It is most likely that due to the high binding of lercanidipine to plasma proteins, dialysis may not be effective.

Similarities