Instructions for Vanlerk tablets 10 mg No. 30
Composition
active ingredient: lercanidipine;
1 tablet contains lercanidipine hydrochloride 10 mg or 20 mg, equivalent to lercanidipine 9.4 mg or 18.8 mg;
Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; magnesium stearate;
shell (for 10 mg tablets): Opadry II Yellow film-coating mixture: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); triacetin; iron oxide yellow (E 172);
shell (for 20 mg tablets): Opadry II Pink film-coating mixture: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; titanium dioxide (E 171); triacetin; iron oxide red (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
for 10 mg tablets: round tablets with a biconvex surface, with a score on one side, coated with a yellow film coating;
for 20 mg tablets: round tablets with a biconvex surface, with a score on one side, coated with a pink film coating.
Pharmacotherapeutic group
Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. ATC code C08C A13.
Pharmacological properties
Pharmacodynamics
Lercanidipine is a dihydropyridine calcium antagonist. It inhibits the transmembrane influx of calcium into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of lercanidipine is due to a direct relaxing effect on vascular smooth muscle, which reduces total peripheral vascular resistance. Despite its short plasma half-life, lercanidipine has a prolonged antihypertensive effect due to its high membrane distribution coefficient. Due to its high vascular selectivity, the drug does not have a negative inotropic effect. Acute arterial hypotension with reflex tachycardia occurs rarely due to the gradual development of vasodilation when taking lercanidipine.
As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its S-enantiomer.
The clinical efficacy and safety of lercanidipine at a dose of 10–20 mg once daily have been studied in clinical trials in patients with hypertension.
Most studies involved patients with mild to moderate essential hypertension (including elderly patients and diabetics) 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 study in patients with severe arterial hypertension (mean ± standard deviation (SD) diastolic blood pressure 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 daily and in 56% of 25 patients when taking 10 mg twice daily. It is reported that in a clinical study, when compared with placebo, in patients with systolic hypertension, lercanidipine effectively reduced blood pressure from a mean baseline value of 172.6 ± 5.6 mm Hg to a value of 140.2 ± 8.7 mm Hg.
Clinical studies in the pediatric population have not been conducted.
Pharmacokinetics
Absorption: Lercanidipine is completely absorbed after oral administration of 10–20 mg, with peak plasma concentrations (Cmax) of 3.30 ng/ml ± 2.09 s. v. and 7.66 ng/ml ± 5.90 s. v. respectively occurring approximately 1.5–3 hours later.
The two enantiomers of lercanidipine show a similar plasma level profile: the time to reach maximum plasma concentration (tmax) is the same, Cmax and area under the pharmacokinetic concentration-time curve (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 vivo.
Due to high first-pass metabolism, the absolute bioavailability of lercanidipine taken orally by a patient after a meal is approximately 10%, although it decreases to 1/3 of this value if the drug is administered on an empty stomach. If the drug is taken no later than 2 hours after a high-fat meal, its bioavailability increases 4-fold. Therefore, lercanidipine 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 plasma protein levels are reduced in patients with severe renal and hepatic impairment, the free fraction of the drug may increase.
In vitro experiments with human liver microsomes indicate that lercanidipine slightly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its maximum plasma concentrations achieved after a 20 mg dose. In addition, drug interaction studies in humans have shown that lercanidipine does not alter the plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate; thus, no biotransformation of drugs metabolised by CYP3A4 or CYP2D6 is expected when lercanidipine is used at therapeutic doses.
Elimination: Elimination is mainly by biotransformation. The mean terminal 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/non-linearity. When lercanidipine is administered orally, its plasma concentration is not directly proportional to the dose taken (non-linear kinetics). After administration of 10 mg, 20 mg and 40 mg, the maximum plasma concentrations observed had a ratio of 1:3:8 and the AUC 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 regarding specific patient groups
The pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction have been shown to be similar to that observed in the general population. In patients with severe renal dysfunction or in dialysis-dependent patients, 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.
Indication
Mild or moderate essential hypertension.
Contraindication
Hypersensitivity to lercanidipine or to any component of the drug;
obstruction of the outflow tract of the left ventricle;
untreated congestive heart failure;
unstable angina or recent (within 1 month) myocardial infarction;
severe liver failure;
severe renal failure (creatinine clearance <30 ml/min), including patients on hemodialysis;
simultaneous use with potent CYP3A4 inhibitors, cyclosporine, grapefruit or grapefruit juice.
Interaction with other medicinal products and other types of interactions
Concomitant use is contraindicated.
CYP3A4 inhibitors. Lercanidipine is metabolized by the enzyme CYP3A4, therefore inhibitors and inducers of this enzyme, taken concomitantly with lercanidipine, may affect the metabolism and elimination of lercanidipine. Interaction studies of lercanidipine with the potent CYP3A4 inhibitor ketoconazole have shown a significant increase in lercanidipine plasma levels (15-fold increase in AUC and 8-fold increase in maximum concentration of the S-lercanidipine eutomer).
The concomitant use of lercanidipine with CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided.
Cyclosporine. When lercanidipine and cyclosporine are used together, the plasma levels of both substances increase. Studies have shown that the use of cyclosporine 3 hours after taking lercanidipine did not change the plasma levels of lercanidipine, while the AUC of cyclosporine increased by 27%. However, the simultaneous use of lercanidipine and cyclosporine leads to a 3-fold increase in the plasma levels of lercanidipine and an increase in the AUC of cyclosporine by 21%.
Cyclosporine and lercanidipine should not be used together.
Grapefruit or grapefruit juice. As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit juice, with subsequent increase in the systemic availability of lercanidipine and potentiation of the hypotensive effect. Lercanidipine and grapefruit or grapefruit juice should not be taken simultaneously.
Concomitant use is not recommended.
CYP3A4 inducers: Lercanidipine should be used with caution when used concomitantly with CYP3A4 inducers such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin due to possible reduction of the antihypertensive effect of lercanidipine. In these cases, more frequent monitoring of blood pressure is recommended.
Alcohol: Alcohol consumption should be avoided due to possible potentiation of the vasodilatory effect of antihypertensive drugs.
Interactions requiring dose adjustment
CYP3A4 substrates: Caution should be exercised when lercanidipine is used concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics such as amiodarone, quinidine, sotalol.
Metoprolol. Concomitant use of lercanidipine with metoprolol, a β-blocker that is mainly eliminated by the liver, does not alter the bioavailability of metoprolol, but results in a 50% reduction in the bioavailability of lercanidipine. This effect is possible due to the reduction in hepatic blood flow caused by β-blockers and may therefore occur with other drugs of this group. Therefore, lercanidipine can be used with β-blockers, but a dose adjustment may be necessary.
Digoxin. When lercanidipine 20 mg was co-administered to patients receiving continuous b-methyldigoxin, no evidence of a pharmacokinetic interaction was found. However, an increase in digoxin Cmax by an average of 33% was observed, while AUC and renal clearance were not significantly changed. Patients receiving digoxin concomitantly should be carefully monitored for signs of digoxin intoxication.
Concomitant use with other medicines
Fluoxetine: An interaction study with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) in patients aged 65 ± 7 years (mean ± s.e.) did not reveal any clinically significant change in the pharmacokinetics of lercanidipine.
Cimetidine: Concomitant administration of cimetidine at a dose of 800 mg per day does not cause significant changes in the plasma concentration of lercanidipine, but caution should be exercised when using higher doses due to the possibility of increasing the bioavailability and antihypertensive effect of lercanidipine.
Simvastatin. When lercanidipine 20 mg was co-administered with simvastatin 40 mg, the AUC of lercanidipine was not significantly changed, while the AUC of simvastatin increased by 56% and that of its active metabolite, the b-hydroxyacid, by 28%. These changes are unlikely to be of clinical significance. No interaction between these drugs is expected if lercanidipine is administered in the morning and simvastatin in the evening, as indicated for this drug.
Diuretics and angiotensin-converting enzyme (ACE) inhibitors: Lercanidipine can be used concomitantly with diuretics and ACE inhibitors.
Other medicinal products that affect blood pressure. As with all antihypertensive medicinal products, an increase in the hypotensive effect is possible when lercanidipine is used concomitantly with other medicinal products that affect blood pressure, such as α-blockers for the symptomatic treatment of bladder diseases, tricyclic antidepressants, neuroleptics.
On the contrary, a decrease in the hypotensive effect may be observed when used simultaneously with corticosteroids.
Application features
Sick sinus syndrome: Lercanidipine should be used with caution in patients with sick sinus syndrome (without an implanted pacemaker).
Left ventricular dysfunction: Although hemodynamically controlled studies have not revealed impaired ventricular function, caution should be exercised when prescribing the drug in left ventricular dysfunction.
Coronary heart disease. It is assumed that the use of some short-acting dihydropyridines increases the risk of cardiovascular complications in patients with coronary heart disease, therefore the use of lercanidipine in such patients requires caution, although lercanidipine has a prolonged effect. Some dihydropyridines can rarely lead to precordial pain or angina. Very rarely, in patients with pre-existing angina, an increase in the frequency, duration or severity of these attacks is possible. Isolated cases of myocardial infarction may be noted.
Peritoneal dialysis. The use of lercanidipine has been associated with the development of opacification of the peritoneal exudate in patients undergoing peritoneal dialysis. The opacification is due to an increased concentration of triglycerides in the peritoneal exudate. Although the mechanism is unknown, this effect tends to disappear shortly after discontinuation of lercanidipine. This relationship should be taken into account in order to avoid cases where opacification of the peritoneal exudate may be mistaken for infectious peritonitis, leading to unnecessary hospitalization and empirical administration of antibiotics.
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 is no clinical experience with the use of lercanidipine during pregnancy. Animal studies have not shown a teratogenic effect, but it has been observed with other dihydropyridine compounds. Lercanidipine is not recommended for use in pregnant women and women of childbearing potential unless they use effective contraception.
Fertility: There are no clinical data on the effect of lercanidipine on fertility. There is evidence of reversible biochemical changes in the head of spermatozoa, which may affect the possibility of fertilization, in patients treated with calcium channel blockers. In the event of repeated in vitro fertilization failure and in the absence of other explanations, the use of calcium channel blockers should be considered as a possible cause.
Ability to influence reaction speed when driving vehicles or other mechanisms
The effect of lercanidipine on the ability to drive or use machines is negligible. However, the possibility of dizziness, weakness, increased fatigue, and rarely drowsiness should be taken into account.
Method of administration and doses
Method of application
Before using the drug, it is necessary to take into account that:
It is advisable to use the drug in the morning, at least 15 minutes before breakfast;
This medicine should not be taken with grapefruit juice.
The recommended dose is 10 mg orally once daily, taken no earlier than 15 minutes before a meal. Depending on the individual patient's response to treatment, the dose may be increased to 20 mg.
Dose titration should be gradual, as the maximum antihypertensive effect develops within 2 weeks of treatment.
Patients whose blood pressure is not adequately controlled with antihypertensive drugs alone may be offered the addition of Vanlerk to a regimen of beta-blockers (atenolol), diuretics (hydrochlorothiazide) or ACE inhibitors (captopril or enalapril).
Since the dose-response curve plateaus at doses of 20–30 mg, it is unlikely that the efficacy of the drug will increase with higher doses, while the risk of side effects may increase.
Elderly patients
According to pharmacokinetic and clinical studies, lercanidipine can be used in elderly patients without special dose adjustment, but treatment in elderly patients should be initiated under supervision.
Patients with renal or hepatic insufficiency
Patients with mild to moderate renal or hepatic impairment should be started on Vanlerk under close supervision. The usual recommended dose of 10 mg is generally well tolerated in these subgroups, but increasing the dose to 20 mg requires caution.
In patients with hepatic insufficiency, the antihypertensive effect of the drug may be increased, requiring dose adjustment.
The use of lercanidipine is contraindicated in patients with severe hepatic dysfunction or severe renal dysfunction (creatinine clearance < 30 ml/min), including patients on hemodialysis.
Children
The safety and efficacy of the drug in children under 18 years of age have not been studied, and there are no data on its use in children.
Overdose
During post-marketing use, some cases of overdose (from 30-40 mg to 800 mg, including a suicide attempt) have been reported.
Symptoms: As with other dihydropyridines, excessive peripheral vasodilation and marked hypotension and reflex tachycardia are to be expected in overdose with lercanidipine. However, at very high doses, peripheral selectivity may be lost, which may lead to bradycardia and a negative inotropic effect. The most common adverse reactions associated with overdose are hypotension, dizziness, headache and palpitations.
Treatment. In severe hypotension, active cardiovascular support measures should be taken, including frequent monitoring of cardiac and respiratory function, placing the patient in a horizontal position with the lower extremities elevated, monitoring of circulating fluid and urination. Given the prolonged pharmacological action of lercanidipine, in the event of overdose, it is necessary to monitor the cardiovascular system of such patients for at least 24 hours. Given the high protein binding of lercanidipine, dialysis may be ineffective. Patients with suspected moderate or severe intoxication should be monitored in an intensive care unit.
Side effects
The most frequently observed adverse reactions associated with the use of lercanidipine were: peripheral edema, headache, hot flashes, tachycardia, and palpitations.
On the part of the immune system: hypersensitivity.
From the nervous system: headache, dizziness, drowsiness, fainting.
Cardiac: tachycardia, palpitations, angina pectoris.
From the vascular system: hot flashes, hypotension.
Gastrointestinal: dyspepsia, nausea, upper abdominal pain, vomiting, diarrhea, gingival hypertrophy1, peritoneal exudate clouding1.
Hepatobiliary disorders: increased serum transaminase levels1.
Skin and Appendages: rash, itching, exanthema, edema1.
Musculoskeletal, connective tissue and bone disorders: myalgia.
From the kidneys and urinary tract: polyuria, pollakiuria.
General disorders and administration site conditions: peripheral edema, asthenia, fatigue, chest pain.
Lercanidipine does not adversely affect blood sugar levels and serum lipid levels. The use of some dihydropyridines may occasionally lead to precordial pain or angina pectoris, in exceptional cases in patients with angina pectoris the frequency, duration or severity of attacks may increase, isolated cases of myocardial infarction may be noted. Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after the approval of a medicinal product by the regulatory authorities is an important procedure. It allows monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report all suspected adverse reactions through the national pharmacovigilance system.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Address
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
