Lercanidipine

Pharmacological properties

Mechanism of action. lercanidipine is a calcium antagonist of the dihydropyridine group, which suppresses the transmembrane influx of calcium into the cells of the heart and smooth muscles. the mechanism of its antihypertensive effect is due to the direct relaxing effect on the smooth muscles of blood vessels, resulting in reduced opss.

Pharmacodynamic effects. Despite the short T_½ lercanidipine, it has a prolonged hypotensive effect due to the high coefficient of membrane separation and is deprived of a negative inotropic effect due to its high vascular selectivity. Since 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. In addition to clinical studies to confirm therapeutic indications, another small, uncontrolled, but randomized study was conducted in patients with severe hypertension (mean ± SD of the diastolic blood pressure was 114.5 ± 3.7 mmHg) .). During this study, blood pressure returned to normal in 40% of 25 patients with a dose of lercanidipine hydrochloride 20 mg once daily and in 56% of 25 patients with a 10 mg lercanidipine hydrochloride twice daily. In a double-blind, randomized, controlled study in patients with systolic hypertension of lercanidipine, hydrochloride effectively reduced systolic blood pressure from an average of 172.6 ± 5.6 mmHg. Art. to a value of 140.2 ± 8.7 mm RT. Art.

Pharmacokinetics Absorption. Lercanidipine hydrochloride is completely absorbed after oral administration of 10–20 mg, and C_max in blood plasma is 3.30 ng / ml ± 2.09 standard deviations and 7.66 ng / ml ± 5.90 standard deviations, respectively, is achieved 1.5-3 hours after administration.

The two enantiomers of lercanidipine show a similar plasma concentration profile: time to reach C_max the same in plasma, C_max in plasma and AUC are on average 1.2 times higher in the (S) -enantiomer, and T_½ the two enantiomers are basically the same. Interconversion of enantiomers in in vivo studies was not observed.

Due to the high metabolism at the first passage, the bioavailability of lercanidipine hydrochloride taken by the patient after eating is about 10%, while it decreased to ¹/₃ of this value, if the drug was used by healthy volunteers on an empty stomach.

The bioavailability of lercanidipine hydrochloride after administration increases by 4 times if it is taken no later than 2 hours after eating very fatty foods, so lercanidipine hydrochloride 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 plasma proteins exceeds 98%. Since the plasma protein content in patients with severe renal or hepatic impairment is reduced, the free fraction of the drug can be increased.

Metabolism. Lercanidipine hydrochloride is actively metabolized by the enzyme CYP 3A4; unchanged drug in urine and feces is not determined. It turns mainly into inactive metabolites, and about 50% of the dose taken is excreted in the urine.

In vitro experiments with human liver microsomes have shown that lercanidipine somewhat inhibits CYP 3A4 and CYP 2D6 at concentrations of 160 and 40 times respectively higher than its C_max in blood plasma, which are achieved after applying a dose of 20 mg. In addition, studies of human interactions have shown that lercanidipine does not modify the level of midazolam, a typical CYP 3A4 substrate, in plasma or metoprolol, a typical CYP 2D6 substrate; Thus, when lercanidipine hydrochloride is used in therapeutic doses, biotransformation of drugs metabolized by CYP 3A4 or CYP 2D6 should not be expected.

Excretion occurs mainly through biotransformation.

The average terminal elimination time, according to calculations, is 8–10 hours; through high affinity for lipid membranes, therapeutic activity lasts 24 hours. After repeated use, cumulation was not detected.

Linearity / nonlinearity. With oral administration of lercanidipine hydrochloride, its concentration in blood plasma is not directly proportional to the dose (nonlinear kinetics). After taking 10, 20 and 40 mg C_max in the blood plasma had a ratio of 1: 3: 8, and AUC - 1: 4: 18, which indicates a gradual saturation of the metabolism during the first passage. Thus, the bioavailability of lercanidipine increases with increasing dose.

Additional information in It has been shown that the pharmacokinetics of lercanidipine in elderly patients and in patients with reduced renal or hepatic function of mild or moderate severity is similar to that observed in the general population. In patients with severe renal impairment or in patients undergoing hemodialysis, the concentration of drugs was higher (about 70%). In patients with moderate or severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to increase, since it is usually extensively metabolized in the liver.

The data obtained in the course of preclinical standard pharmacological safety studies, studies on multiple dose toxicity, genotoxicity, carcinogenic potential, as well as reproductive toxicity, indicate the absence of a particular danger of the drug to humans.

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

Significant effects that were observed in long-term studies in rats and dogs were directly or indirectly associated with the known effect of high doses of calcium antagonists, that is, were the result of excessively high pharmacodynamic activity.

Lercanidipine is not genotoxic and does not cause carcinogenic danger.

Lercanidipine did not affect fertility and general reproductive ability in rats.

Treatment with lercanidipine did not affect teratogenicity in rats and rabbits, however, the introduction of high doses led to the death of the offspring in the pre- and post-implantation periods, as well as to a slowdown in fetal development. The use of high doses of lercanidipine hydrochloride (12 mg / kg / day) during childbirth can lead to dystocia. The distribution of lercanidipine and / or its metabolites in the body of pregnant animals and their penetration into milk has not been studied.

Indications

Essential ag to mild or moderate degree.

Application

The drug should be used mainly in the morning, at least 15 minutes before breakfast. take Lercamen tablets orally 1 time per day, at least 15 minutes before meals. this medicine should not be taken with grapefruit juice. the recommended dose is 10 mg, but it can be increased to 20 mg, depending on the individual sensitivity of the patient. dose selection should be gradual, since the maximum antihypertensive effect may occur 2 weeks after the start of treatment.

For some individuals who cannot adequately control blood pressure with a single antihypertensive drug, treatment with lercanidipine hydrochloride simultaneously with a β-adrenergic blocker (atenolol), diuretic (hydrochlorothiazide) or an ACE inhibitor (captopril or enalapril) may be appropriate.

Since the dose-response curve is steep and plateau at doses of 20-30 mg, it is unlikely that efficacy will be higher with higher doses, while the incidence of side effects may increase.

Elderly patients.Although pharmacokinetic data and clinical experience indicate that daily dose adjustment is not required, particular care and caution should be exercised when starting treatment of elderly patients.

Patients with renal or hepatic impairment. You should be especially careful at the beginning of treatment of patients with impaired renal or hepatic function of mild to moderate severity. Despite the fact that, as a rule, these patients tolerate the drug normally, an increase in the daily dose to 20 mg should be carried out with caution. The antihypertensive effect can be enhanced in patients with impaired liver function, so that in such cases a dose adjustment is necessary.

Lercamen is not recommended for use in patients with severe hepatic or severe renal failure (GFR 30 ml / min).

Contraindications

Hypersensitivity to the active substance or any excipient of the drug (see composition).

The period of pregnancy and lactation (see. Use during pregnancy and lactation).

It is contraindicated in women of reproductive age if they do not use effective contraception.

Obstruction of vessels leaving the left ventricle.

Untreated congestive heart failure.

Unstable angina pectoris.

Severe hepatic and renal failure.

It is contraindicated to use within 1 month after myocardial infarction.

Concomitant use with strong CYP 3A4 inhibitors, cyclosporine, grapefruit and grapefruit juice (see INTERACTIONS).

Side effects

Approximately 1.8% of patients experienced adverse reactions.

The table below shows the incidence of adverse reactions that may have occurred as a result of the use of this drug. They are distributed by organs and organ systems according to MedDRA and by frequency: very often (≥1 / 10), often (≥ 1/100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (≥1 / 10,000 to 1/1000), very rarely (1/10 000), unknown (evaluation based on available data is impossible). In each group, the frequency of adverse reactions that occur is indicated in order of severity.

As can be seen from the table, the most frequent adverse reactions during controlled clinical trials were headache, dizziness, peripheral edema, tachycardia, palpitations, hot flashes, each of them occurred in at least 1% of patients.

In the framework of post-marketing surveillance, according to spontaneous reports, such side effects were very rarely observed (1/10 000): gum hypertrophy, reversible increase in the number of liver transaminases in blood plasma, hypotension, increased urination and chest pain.

Some dihydropyridines rarely cause pain in the heart or angina pectoris. Very rarely, in patients with existing angina pectoris, an increase in the frequency, duration or severity of these attacks is possible. Isolated cases of myocardial infarction may be observed.

Lercanidipine does not have a side effect on blood glucose and serum lipids.

Reported suspected adverse reactions. Reporting suspected adverse reactions after drug registration is important.This allows continued monitoring of the benefit / risk ratio of the drug. Medical professionals are asked to report any adverse reactions.

special instructions

You should be especially careful at the beginning of treatment of elderly patients.

Sick sinus syndrome. Special care should be taken when using Lercamen in patients with sinus node weakness syndrome, for whom a pacemaker is not implanted.

Left ventricular dysfunction and ischemic heart disease. Use with caution in case of dysfunction of the left ventricle of the heart, despite the fact that hemodynamically controlled studies have not revealed impaired ventricular function. It is suggested that some short-acting dihydropyridines are associated with an increased cardiovascular risk in patients with coronary artery disease. Despite the fact that lercanidipine hydrochloride is a long-acting drug, in such patients the drug should be used with caution.

Some dihydropyridines can, in rare cases, cause pain in the heart or angina pectoris. Very rarely, patients with existing angina may notice an increase in the frequency, duration and severity of its attacks. In some cases, myocardial infarction may be observed (see ADVERSE EFFECTS).

Patients with renal or hepatic impairment. When treating patients with mild or moderate renal or hepatic dysfunction, special care should be taken. Although the usually recommended dosage regimen can be tolerated normally by this group of patients, caution should be exercised in increasing the dose to 20 mg / day. The antihypertensive effect of the drug may be enhanced in patients with liver dysfunction, therefore, in such cases, dose adjustment may be required.

Lercanidipine is not recommended for patients with severe liver or kidney dysfunction (GFR 30 ml / min) (see APPLICATION).

Inductors CYP 3A4.