Instructions for Ezantal film-coated tablets 20 mg No. 30
Composition
active ingredient: lercanidipine;
1 tablet contains 10 mg or 20 mg of lercanidipine hydrochloride (as lercanidipine hydrochloride hemihydrate);
Excipients: lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; povidone; polysorbate; magnesium stearate; hypromellose; polyethylene glycol 6000 (macrogol 6000); titanium dioxide (E 171); talc; iron oxide yellow (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, yellow tablets, film-coated.
Pharmacotherapeutic group
Calcium channel blockers. Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. Lercanidipine. 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 were studied in a double-blind, placebo-controlled clinical trial (in which 1200 patients received lercanidipine, 603 patients received placebo) and in active-controlled and uncontrolled long-term clinical trials with a total of 3676 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 β-blockers.
In addition to the clinical trials conducted to confirm the therapeutic indications, a further small uncontrolled but randomized study of the drug in patients with severe arterial hypertension (mean ± standard deviation of diastolic blood pressure 114.5 ± 3.7 mm Hg) demonstrated normalization of blood pressure in 40% of 25 patients taking the drug at a dose of 20 mg once a day and in 56% of 25 patients taking lercanidipine at a dose of 10 mg twice a day. In a double-blind, randomized, placebo-controlled study in patients with isolated systolic hypertension, lercanidipine effectively reduced
systolic blood pressure from a mean initial value of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.
Children
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 recorded after approximately 1.5–3 hours.
The two enantiomers of lercanidipine show a similar plasma level profile: the time to reach Cmax is the same, (Cmax) and AUC (area under the pharmacokinetic concentration-time curve) 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 administered to a patient after food intake is approximately 10%, although it was reduced to 1/3 of this value when administered to healthy volunteers 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 food.
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 level of plasma protein is reduced in patients with severe renal and hepatic impairment, the free fraction of the drug may increase.
Biotransformation
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.
Breeding
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/nonlinearity
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 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 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 CYP3A4 inhibitors, cyclosporine, grapefruit and grapefruit juice.
Interaction with other medicinal products and other types of interactions
Concomitant use is contraindicated.
CYP3A4 inhibitors
Lercanidipine is metabolized by the CYP3A4 enzyme, 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 Cmax of the S-lercanidipine eutomer).
The concomitant use of lercanidipine with CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided.
Cyclosporine
Concomitant administration of lercanidipine and cyclosporine increases the plasma levels of both substances. A study in young healthy volunteers showed that administration of cyclosporine 3 hours after lercanidipine did not alter the plasma levels of lercanidipine, while the AUC of cyclosporine increased by 27%. However, concomitant administration of lercanidipine and cyclosporine resulted in a 3-fold increase in plasma levels of lercanidipine and a 21% increase in the AUC of cyclosporine.
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, leading to increased systemic availability of lercanidipine and increased hypotensive effect. Lercanidipine and grapefruit or grapefruit juice should not be taken simultaneously.
Concomitant use is not recommended.
CYP3A4 inducers
Caution should be exercised when lercanidipine is 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 using lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine, sotalol.
Midazolam
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 may be 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 administered with β-blockers, but a dose adjustment may be necessary.
Digoxin
When lercanidipine 20 mg was co-administered to patients receiving β-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 monitored more closely for signs of digoxin intoxication.
Concomitant use with other medicines
Fluoxetine
An interaction study with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) in volunteers aged 65 ± 7 years (mean ± s.e.) revealed no 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 β-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, angiotensin-converting enzyme (ACE) inhibitors
Lercanidipine can be used concomitantly with diuretics and ACE inhibitors.
Other medicines that affect blood pressure
As with all antihypertensive drugs, an increase in the hypotensive effect is possible when lercanidipine is used concomitantly with other drugs 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 deterioration of ventricular function, caution should be exercised in patients with left ventricular dysfunction.
Coronary heart disease
It has been suggested that some short-acting dihydropyridines may be associated with an increased cardiovascular risk in patients with coronary heart disease. Although EZANTAL is a long-acting drug, it should be used with caution in such patients. Some dihydropyridines may rarely cause precordial pain or angina pectoris. Very rarely, in patients with pre-existing angina pectoris, an increase in the frequency, duration or severity of these attacks may occur. Isolated cases of myocardial infarction may occur.
Peritoneal dialysis
The use of lercanidipine has been associated with the development of opacification of the peritoneal fluid in patients undergoing peritoneal dialysis. The opacification is due to an increased concentration of triglycerides in the peritoneal fluid. 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 fluid may be mistaken for infectious peritonitis, leading to unnecessary hospitalization and empirical administration of antibiotics.
Lactose
This medicine contains lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy
There is no clinical experience with lercanidipine during pregnancy. Animal studies have not shown a teratogenic effect, but this has been observed with other dihydropyridine compounds. Lercanidipine is not recommended for use during pregnancy or in women of childbearing potential unless they are using effective contraception.
Breastfeeding period
It is not known whether lercanidipine or its metabolites pass into breast milk, therefore a risk to the child cannot be excluded. Lercanidipine should not be used during breast-feeding.
Fertility
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
The recommended dose is 10 mg orally once daily, taken at least 15 minutes before meals. 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 after 2 weeks of treatment.
Patients whose blood pressure is not adequately controlled with antihypertensive drugs alone may be offered the addition of EZANTAL 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, the drug EZANTAL can be used in elderly patients without special dose adjustment, but treatment in elderly patients should be initiated under the supervision of a physician.
Patients with renal or hepatic insufficiency
Patients with mild to moderate renal or hepatic impairment should start taking EZANTAL under medical supervision. The usual recommended dose of 10 mg is usually well tolerated by patients in these subgroups, 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.
Lercanidipine is contraindicated in patients with severe hepatic dysfunction or severe renal dysfunction (creatinine clearance < 30 ml/min), including patients on hemodialysis.
Method of application
Before using the drug EZANTAL, it is necessary to consider 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 and grapefruit juice.
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 the post-marketing period, some cases of overdose (from 30-40 mg to 800 mg, including a suicide attempt) have been reported with lercanidipine.
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 status 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.
Adverse reactions
According to clinical studies and post-marketing experience, the most common adverse reactions are peripheral edema, headache, flushing, tachycardia, and palpitations.
The table below lists adverse reactions reported during clinical trials and post-marketing use worldwide and for which a causal relationship with the use of the drug was established. Adverse reactions are listed according to MedDRA classification and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available information). Within each grouping, the frequency of occurrence of the reaction is presented in order of decreasing seriousness.
MedDRA
classification of systems and organs
Often
Infrequently
Rarely
Frequency unknown
On the part of the immune system
Increased sensitivity
From the nervous system
Headache
Dizziness
Drowsiness, fainting
From the heart
Tachycardia, rapid heartbeat
Angina pectoris
From the vascular side
Tides
Hypotension
Dyspepsia, nausea, upper abdominal pain
Vomiting, diarrhea
Gingival hypertrophy*, opacification of peritoneal exudate*
Hepatobiliary system
Increased serum transaminases*
Skin and subcutaneous tissue disorders
Rash, itching
Rash
Edema*
Musculoskeletal and connective tissue disorders
Myalgia
From the urinary system
Polyuria
Pollakiuria
General disorders and administration site conditions
Peripheral edema
Asthenia,
elevated
fatigue
Chest pain
*Adverse reactions from spontaneous reports during post-marketing use worldwide.
Lercanidipine does not adversely affect blood sugar levels and serum lipid levels.
In placebo-controlled clinical trials, peripheral oedema occurred in 0.9% of patients receiving lercanidipine 10-20 mg and 0.83% of patients receiving placebo. This incidence reached 2% in the overall study population, including long-term clinical trials.
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 observed.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging
10 tablets in a blister, 3 or 6 blisters together with instructions for medical use in a cardboard pack.
30 or 60 tablets in a jar, 1 jar together with instructions for medical use in a cardboard pack.
Vacation category
According to the recipe.
Producer
LLC NVF "MICROCHEM".
Location of the manufacturer and address of its place of business
Ukraine, 93400, Luhansk region, Severodonetsk city, Promyslova st., building 24-v.
Applicant
LLC NVF "MICROCHEM".
Applicant's location
Ukraine, 93000, Luhansk region, Rubizhne, Lenina st., building 33.
