Lercanidipine-SZ 10 mg, 30 film-coated tablets

The group of calcium channel blockers (CCBs) is quite heterogeneous. It includes phenylalkylamines (verapamil), benzidiazepines (diltiazem) and dihydropyridine drugs. Verapamil was first approved for clinical use in 1963 and was used as an antianginal agent for patients with coronary heart disease. CCBs of various groups have become more widely used in the treatment of arterial hypertension (AH). In their effect on cardiovascular mortality, CCBs do not differ significantly from drugs of other groups. There is evidence of some preferential reduction in the risk of stroke when treated with drugs of this group [1]. In addition, additional indications for the use of CCBs include isolated hypertension and elderly patients [2].

A feature of dihydropyridine CCBs is their vasoselectivity, which determines the presence of hypotensive effects in drugs of this group. However, developing vasodilation provokes activation of the sympatheticoadrenal system and reflex tachycardia. The presence of this side effect is especially characteristic of the 1st generation of dihydropyridine CCBs, which are characterized by a rapid onset but short-lived effect. 2nd generation drugs have a longer half-life and fewer side effects. In general, the presence of specific side effects (tachycardia, pretibial edema) causes a rather low adherence of patients to treatment with dihydropyridine drugs.

Lercanidipine (Zanidip®-Recordati, RECORDATI IRELAND, Ltd., Ireland) is a 3rd generation dihydropyridine CCB. Its peculiarity is the high duration of binding to calcium channels, which is manifested in the duration of its pharmacological action and the gradual onset of the effect. These properties greatly help solve the problem of treatment adherence.

Features of pharmacodynamics and pharmacokinetics of lercanidipine

Like other dihydropyridine CCBs, the mechanism of action of lercanidipine is associated with the blockade of transmembrane calcium current across cell membranes via L-type calcium channels (slow calcium channels). This leads to relaxation of the smooth muscle muscles of the vascular wall and a decrease in blood pressure (BP). Dihydropyridone drugs are more selective for CaV1.3 channels expressed in vascular smooth muscle cells, and their effect on CaV1.2 channels expressed in cardiac muscle and sinus node cells is less pronounced. Lercanidipine has a high degree of vasoselectivity. It has been shown that its vasoselectivity index is 730: 1 (lacidipine - 193: 1, amlodipine - 95: 1, felodipine - 6: 1, nitrendipine - 3: 1). In addition, unlike other CCBs, lercanidipine has very little negative inotropic effect.

Lercanidipine is absorbed quite well from the gastrointestinal tract. It has been shown that when taking the drug after eating a meal (a standard low-calorie low-fat breakfast), the plasma level of the S-isomer of lercanidipine increases significantly. When taking the drug after eating fatty foods, there is a very rapid and significant increase in its concentration. When taking the drug on an empty stomach, the rate of absorption is more predictable and provides a slow increase in drug concentration. This dosage regimen is preferred to minimize the risk of side effects [3].

The absolute bioavailability of the drug is low (about 10%), which may be due to the first pass effect through the liver. Metabolic transformations of lercanidipine in the liver occur with the participation of cytochrome 3A4 of the P450 system. No clinically significant interactions of the drug were found either with inhibitors of this cytochrome or with its substrates. It is known that the pharmacokinetics of lercanidipine does not change significantly for elderly patients, as well as for patients with liver and kidney diseases, therefore, no dose adjustment of lercanidipine is required when treating these patients [4].

Peak plasma concentrations of lercanidipine develop 1.5–3.0 hours after administration, and the half-life after taking the first dose of the drug is 2–5 hours. With chronic treatment, the half-life of the drug increases to 10 hours [5].

With a relatively short half-life, the drug provides long-term blockade of calcium channels due to its high lyophilicity and good ability to penetrate cell membranes [6]. Two ether aminolkyl groups contained in the chemical structure of the drug improve lyophilicity and create additional stabilization of the effect of the drug. Lercanidipine slowly penetrates the lipid bilayer of cell membranes, where it accumulates in high concentrations, interacting with calcium channels. This explains the gradual onset of its hypotensive effect. The content of lercanidipine in cell membranes is 10–15 times higher than that of amlodipine. Lercanidipine is slowly washed out of the lipid bilayer, which determines its long-lasting effect. It has been shown that it is able to reach the smooth muscle layer of the vascular wall even in arteries severely affected by atherosclerosis, penetrating the area around cholesterol-rich plaques.

The main indication for the use of lercanidipine is the treatment of hypertension. The recommended doses of the drug are 10–20 mg/day. The drug has a convenient regimen for the patient - once a day. At the same time, lercanidipine has a good ratio of peak and residual effects - about 0.8 for a dose of 10 mg/day in middle-aged patients and about 0.77 for elderly patients. Thus, the drug provides sufficient control of blood pressure throughout the day.

Use during pregnancy and breastfeeding

In animal studies, lercanidipine was not teratogenic, but teratogenic effects have been reported with other dihydropyridine derivatives. Therefore, the use of Lercanidipine-SZ during pregnancy and in women of childbearing age who do not use reliable contraception is contraindicated.

Due to the high lipophilicity of lercanidipine, it can be assumed that it passes into breast milk, therefore the use of the drug Lercanidipine-SZ during breastfeeding is contraindicated.

Hypotensive effect

The hypotensive effect of lercanidipine has been well studied. In order to lower blood pressure, the drug was tested in doses from 2.5 to 40 mg/day. When comparing the effectiveness of different doses of lercanidipine in a group of 243 patients with hypertension of the 1st and 2nd degrees of severity, it turned out that a dose of 2.5 mg/day did not cause significant changes in blood pressure. When taking lercanidipine at a dose of 5 mg/day, a significant decrease in only diastolic blood pressure was noted. Lercanidipine at a dose of 10 mg/day had a sufficient hypotensive effect, which was confirmed by data from 24-hour blood pressure monitoring [7]. Lercanidipine at a dose of 10 mg/day allows normalizing blood pressure in 54% of patients with hypertension of the 1st and 2nd degrees, 20 mg/day – in 63% of patients [8].

The drug creates a sufficient antihypertensive effect for patients with more severe hypertension. In an open, non-comparative study, the effectiveness of lercanidipine for patients with hypertension was analyzed depending on the degree of risk of cardiovascular complications. Lercanidipine was prescribed at a dose of 10 mg/day with further titration to 20 mg/day. The treatment lasted 6 months. A total of 3175 patients were treated (mean age: 63 ± 10 years). The risk of cardiovascular complications was low in 237 patients, moderate in 1396, high in 722, and very high in 820 patients. When patients with a higher risk were included, the initial blood pressure level was higher. The reduction in blood pressure in high-risk groups also turned out to be more significant. In the low-risk group, blood pressure decreased by -18.5/-13.8 mmHg. Art., medium risk – by -23/-15.2, high risk – by -24.4/- 16.1 and in the very high risk group – by -27.4/-17.4 mm Hg. Art. The drug was well tolerated. The most common side effects included edema (5.1%), headache (3.3%), dizziness (2.5%) and weakness (1%) [9].

In total, more than 20 thousand patients with hypertension of the 1st and 2nd severity were included in controlled studies of lercanidipine. The average reduction in blood pressure was 19–26 mm Hg for systolic. Art. and for diastolic – 13–15.

The effectiveness of lercanidipine is comparable to that of other CCBs. The LEAD study compared the effectiveness of three dihydropyridine CCB drugs - lercanidipine, felodipine and nifedipine GITS. The hypotensive effect, heart rate (HR) at rest and during exercise were studied. Data from mental tests before and after treatment were also assessed. The study involved 325 patients with a diastolic blood pressure level of 95–110 mmHg. Art. They were randomized to treatment with lercanidipine 10–20 mg/day, felodipine 10–20 or nifedipine 30–60 mg/day. After 4 and 8 weeks of treatment, all three groups showed a comparable decrease in blood pressure. The proportion of patients who responded well to therapy with these drugs was also comparable (about 75% in each group). There was no significant increase in heart rate both at rest and during exercise in any of the groups. The incidence of side effects such as weakness, swelling, and dizziness was lower in the lercanidipine group. Thus, edema developed in only 5.5% of patients taking lercanidipine, and in 14% of those taking other CCBs. The number of patients who discontinued treatment due to side effects was also the smallest in the lercanidipine group [10].

Lercanidipine is not inferior in its antihypertensive effectiveness to drugs from other main groups used in the treatment of hypertension. In patients with stage 1 and 2 hypertension, the effectiveness of lercanidipine and losartan was compared. Lercanidipine was prescribed at a dose of 10–20 mg/day, losartan at a dose of 50–100 mg/day. Normalization of diastolic blood pressure was recorded in 71% of patients in the lercanidipine group and in 65% in the losartan group. In the losartan group there was a significantly larger proportion of patients who required an increase in the dose of the drug. Drug tolerance did not differ significantly [11]. In elderly patients (age 60–85 years) with isolated systolic hypertension, a double-blind, placebo-controlled study with a crossover design examined the antihypertensive efficacy of enalapril at a dose of 20 mg/day, lercanidipine at a dose of 10 mg/day, and their combination. The duration of each treatment option was 4 weeks. The effectiveness of treatment was monitored according to medical monitoring and 24-hour blood pressure monitoring. Combination treatment turned out to be the most effective. It was also well tolerated [12].

In general, various comparative studies have shown that lercanidipine at a dose of 10 mg/day corresponds in its hypotensive effect to 50 mg captopril per day, 20 mg enalapril per day, 50 mg atenolol per day or 16 mg candesartan [13].

special instructions

Caution should be exercised when prescribing to patients with impaired renal function, coronary artery disease (there is a risk of increased frequency of angina attacks); regarding CHF: it is necessary to compensate for it before starting to use the drug.

The drug should be used with extreme caution in patients with sick sinus syndrome (without a pacemaker).

Although controlled hemodynamic studies have not revealed abnormalities in left ventricular function, treatment of patients with signs of left ventricular dysfunction with CCBs should be carried out with extreme caution. There is also an opinion that patients with coronary artery disease receiving short-acting dihydropyridines represent a high-risk group for cardiovascular diseases.

Particular caution should be observed in the initial stages of treatment in patients with mild to moderate liver dysfunction.

Influence on the ability to drive vehicles and machinery.

During the treatment period, caution should be exercised when performing work that requires increased attention, driving, especially at the beginning of treatment and when increasing the dose of the drug (risk of drowsiness, headache and dizziness).

Efficacy of lercanidipine in elderly patients

An additional indication for the choice of CCBs as antihypertensive drugs is the elderly age of patients. Lercanidipine demonstrated good efficacy for patients with hypertension of different age groups. One study compared its effectiveness in different age groups. 375 patients under the age of 65 years and 315 patients over 65 years of age were included. Lercanidipine was prescribed at a dose of 10–20 mg/day. The effectiveness of lercanidipine, its dose at the end of treatment, and the need for combination therapy did not differ significantly in different age groups. The incidence of edema was small (3%) and did not differ between the two groups [14].

In a placebo-controlled, randomized trial, 144 elderly (60–85 years) patients were prescribed lercanidipine at a dose of 10 mg/day. Patients receiving lercanidipine had a significantly more pronounced decrease in systolic (15 and 7 mm Hg, respectively) and diastolic (10 and 6 mm Hg) blood pressure compared to the placebo group. The proportion of patients with normalization of blood pressure also turned out to be significantly higher: 59% in the lercanidipine group and 38% in the placebo group [15].

Lercanidipine is not inferior in effectiveness to other dihydropyridine CCBs in elderly patients. In elderly patients with isolated systolic hypertension, lercanidipine at a dose of 10–20 mg/day showed comparable antihypertensive efficacy to lacidipine at a dose of 2–4 mg/day [16]. In a similar comparison with nifedipine GITS at a dose of 30-60 mg, the antihypertensive effectiveness was similar, and the incidence of side effects in treatment with lercanidipine was significantly lower (19.4%) compared with treatment with nifedipine (28.4%). Edema developed significantly less frequently: 2.8% in the lercanidipine group and 10.1% in the nifedipine group [17].

Therapy with lercanidipine can lead to an improvement in mnestic-intellectual functions, which is especially important for patients in older age groups. This was shown in an open-label study where 467 patients over 40 years of age with grade 1 and 2 hypertension received lercanidipine for 6 months. Lercanidipine was prescribed at a dose of 10 mg/day. At the end of treatment, 98% of patients continued taking lercanidipine. Adequate blood pressure control was achieved in 68% of patients. Blood pressure decreased from 154.4/95.3 to 134.8/80.7 mm Hg. Art. According to testing data, by the end of treatment there was a significant improvement in mental functions, more significant for those patients for whom lercanidipine provided sufficient blood pressure control [18].

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increase in blood pressure and reduce the effectiveness of selected antihypertensive therapy in patients with hypertension. Taking NSAIDs, often uncontrolled, is one of the reasons for hypertension resistance to therapy. This is especially significant for elderly patients, who have a high incidence of concomitant diseases of the musculoskeletal system. It is known that taking NSAIDs has the greatest effect on the effectiveness of angiotensin-converting enzyme inhibitors (ACEIs). For lercanidipine, a special study examined the effectiveness of the drug in patients with hypertension over 60 years of age taking NSAIDs. A total of 334 patients were included in the study, 280 completed the study. Blood pressure control was carried out according to 24-hour blood pressure monitoring data. First, patients received therapy with lercanidipine at a dose of 10 mg/day for 8 weeks. At the same time, a significant decrease in blood pressure was noted, which reached a level of 139/82 mm Hg. Art. Blood pressure control was achieved in 156 (55.7%) patients. Then a course of NSAID therapy (mainly diclofenac and naproxen) was started. Good blood pressure control was maintained in 128 patients. The blood pressure level of 28 patients slightly exceeded 140/90 mmHg. Art. There were no significant changes in blood pressure in the group as a whole. Thus, taking NSAIDs has little effect on the effectiveness of lercanidipine therapy [19].

Compound

Nephroprotective effect of lercanidipine

It is believed that dihydropyridine CCBs do not have nephroprotective properties, which is associated with their predominant effect on the afferent arteriole of the renal glomeruli. This creates conditions for increased intraglomerular pressure and progression of nephroangiosclerosis. The ability of lercanidipine to penetrate tissue creates the possibility of affecting both the afferent and efferent arterioles. Thus, the use of lercani dipina may help reduce intraglomerular pressure.

Nephroprotective effects have also been shown clinically. The most interesting are the results of the DIAL (Diabete, ipertensione, albuminuria, lercanidipina) study, which compared the effects of ramipril and lercanidipine on the condition of the kidneys of patients with hypertension and diabetes mellitus. The study included 277 patients with type 2 diabetes mellitus, hypertension of 1st and 2nd degrees of severity and microalbuminuria. Patients received therapy with lercanidipine at a dose of 10–20 mg/day or ramipril at a dose of 5–10 mg/day for 12 months. The dynamics of blood pressure and the level of albumin excretion in urine were monitored. By the end of treatment, the reduction in blood pressure was significant with both drugs and did not differ significantly between the groups. The decrease in albumin excretion rate was -17.4 ± 65 μg/min in the lercanidipine group (p < 0.05) and -19.7 ± 52.5 μg/min in the ramipril group (p < 0.05). The differences in the dynamics of albuminuria between the groups were not significant. Thus, the nephroprotective properties of lercanidipine were shown, in which it was not inferior to ACE inhibitors [20].

Lercanidipine may be a component of combination antihypertensive therapy for patients with chronic kidney disease. In a group of 69 patients with hypertension and proteinuria (albumin excretion more than 50 mg/day), the effectiveness of adding lercanidipine to antihypertensive therapy was studied. At inclusion, patients received antihypertensive therapy with ACE inhibitors or sartans, but did not achieve target blood pressure levels (BP remained above 130/80 mmHg). Lercanidipine was added to therapy at a dose of 20 mg/day. The degree of proteinuria was assessed after 1, 3 and 6 months of treatment, as well as creatinine clearance based on measurements of daily diuresis. During therapy, there was a significant decrease in systolic blood pressure. At the same time, in 42.5% of cases, the target blood pressure level was achieved, and of the remaining cases, in 58.8%, a decrease in blood pressure below 140/90 mm Hg was noted. Art. Blood creatinine levels and creatinine clearance did not change significantly during therapy. There was a significant decrease in the level of total cholesterol and triglycerides, as well as a significant decrease in proteinuria: by 23% after a month, by 37% after 3 and by 33% after 6 months of treatment. Thus, the addition of lercanidipine to therapy created additional hypotensive and nephroprotective effects [21].

In the ZAFRA study (Zanidip en Función Renal Alterada), the renoprotective properties of lercanidipine were studied in patients with hypertension and chronic renal failure (blood creatinine above 1.4 mg/dL and creatinine clearance below 70 ml/min). Of the 203 patients included in the study, 20% had diabetes. Lercanidipine was prescribed for 6 months to assess its effect on blood pressure and renal function. All patients at the beginning of the study received therapy with ACE inhibitors (63.4%) and angiotensin receptor blockers (36.6%), but patients with nephropathy did not achieve the target blood pressure level. After adding lercanidipine to therapy, 58.1% of patients achieved blood pressure of 130/85 mmHg. Art. Systolic blood pressure decreased from 162 ± 16.6 to 131.6 ± 11.6 mmHg. Art., diastolic – from 93.2 ± 8.3 to 78.2 ± 6.4 mm Hg. Art. At the same time, the creatinine level did not change significantly during therapy, and creatinine clearance increased from 41.8 ± 16.0 ml/min at the beginning of the study to 45.8 ± 18.0 ml/min at the end (p = 0.019). Patients showed a significant decrease in daily proteinuria - from 3.5 ± 3.2 to 2.8 ± 2.8 g/day - and a decrease in total cholesterol levels [22].

Lercanidipine can also be used in patients with severely reduced renal function. In patients with end-stage chronic renal failure, the effectiveness of lercanidipine and carvedilol was compared. Therapy lasted 8 weeks. The levels of blood pressure, glucose, creatinine, protein, cholesterol, triglycerides and potassium were monitored. The hypotensive effect of both drugs did not differ significantly. There were no significant differences in the dynamics of the main biochemical parameters, except for the level of potassium, which at the end of treatment was significantly higher in the carvedilol group [23].

Contraindications

hypersensitivity to lercanidipine, other dihydropyridine derivatives or any component of the drug;

untreated heart failure;

unstable angina;

obstruction of the outflow tract of the left ventricle;

period within 1 month after myocardial infarction;

severe liver failure;

severe renal failure (creatinine Cl less than 30 ml/min);

use in women of childbearing age who do not use reliable contraception;

lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

simultaneous use with inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin) (see “Interaction”);

simultaneous use with cyclosporine (see “Interaction”);

simultaneous use with grapefruit juice (see “Interaction”);

pregnancy;

breastfeeding period;

age under 18 years (efficacy and safety have not been established).

Carefully:

renal failure (creatinine Cl more than 30 ml/min); mild to moderate liver dysfunction; elderly age; sick sinus syndrome (without pacemaker); dysfunction of the left ventricle of the heart and coronary heart disease; chronic heart failure; simultaneous use with substrates of the CYP3A4 isoenzyme (terfenadine, asmetol, class III antiarrhythmic drugs, including amiodarone, quinidine) (see “Interaction”); simultaneous use with inducers of the CYP3A4 isoenzyme, incl. anticonvulsants (phenytoin, carbamazepine) and rifampicin (see “Interactions”); simultaneous use with beta-blockers, digoxin (see “Interaction”).

Lercanidipine and the condition of the vascular wall

An essential component that determines the advantages of CCBs in influencing the prognosis of patients with hypertension over other classes of antihypertensive drugs is the ability to influence the condition of the vascular wall and influence central pressure. The significance of these effects was demonstrated in the CAFE (Conduit Artery Function Evaluation) study conducted as part of the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) project. The combination of amlodipine and perindopril has been shown to reduce central aortic pressure to a greater extent than treatment with atenolol and bendroflumethiazide. As is known, central blood pressure is closely related to the stiffness/elasticity of the vascular wall and pulse wave speed, which in turn can affect the occurrence of cardiovascular events, especially stroke. Lercanidipine has been shown to have angioprotective properties in several studies.

Treatment with lercanidipine may affect the state of endothelium-dependent vasodilation and endothelial NO production. This was shown in a study where the endothelial function of 15 healthy individuals and 15 patients with hypertension was assessed by the degree of vasodilation in response to bradykinin infusion. Therapy with lercanidipine at a dose of 10 mg/day for 3 months significantly increased the response of the brachial artery to bradykinin infusion. The blocking effect of NO inhibitors decreased, as well as plasma concentrations of malonaldehyde and isoprostanoids, and the antioxidant activity of blood plasma increased [24].

The effects of lercanidipine and hydrochlorothiazide on vascular health were compared in a study involving 26 previously untreated hypertensive patients. The effects of drugs on blood pressure, blood flow assessed by plethysmography, vascular resistance, and changes in blood flow in response to ischemia were assessed. Treatment continued for 12 months with assessment of blood flow parameters at 6 and 12 months. It turned out that lercanidipine causes a more significant decrease in vascular resistance in the arteries of the upper and lower extremities (-46.1 and -40.9% versus 22.5 and -19.9%, respectively; p < 0.01 in both cases). However, the state of blood flow did not reach the levels characteristic of healthy individuals [25].

In a relatively small study (59 patients over the age of 60 years with isolated systolic hypertension), the effect of drugs of different groups (perindopril, atenolol, lercanidipine and bendrofluthiazide) on central pressure, pulse wave velocity and augmentation index was studied. Therapy continued for 10 weeks. The levels of systolic and pulse blood pressure did not differ significantly either before or during treatment. Central pressure decreased during treatment with all drugs except atenolol. Lercanidipine was the only drug that reduced the augmentation index. No reliable dynamics of pulse wave propagation speed was achieved in any of the treatment groups [26].