Instructions for Lercanidipine-Teva tablets 20 mg No. 28
Composition
active ingredient: lercanidipine hydrochloride, which is equivalent to lercanidipine;
1 film-coated tablet contains lercanidipine hydrochloride 10 mg (equivalent to 9.4 mg lercanidipine) or lercanidipine hydrochloride 20 mg (equivalent to 18.8 mg lercanidipine);
excipients:
10 mg tablets: povidone, sodium starch glycolate (type A), lactose monohydrate, microcrystalline cellulose, magnesium stearate, partially hydrolyzed polyvinyl alcohol*, titanium dioxide (E 171)*, macrogol*, talc*, iron oxide yellow (E 172)*
*includes Opadry II Yellow 85F32553.
20 mg tablets: povidone, sodium starch glycolate (type A), lactose monohydrate, microcrystalline cellulose, magnesium stearate, partially hydrolyzed polyvinyl alcohol*, titanium dioxide (E 171)*, macrogol*, talc*, yellow iron oxide (E 172)*, red iron oxide (E 172)*.
*includes Opadry II Pink 85F34564.
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex yellow or pink, coated tablets with a diameter of 6.5 ± 0.3 mm or 8.5 ± 0.4 mm, with a score on one side, a stamp "L" on the other side.
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 vascular peripheral 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.
The results of an 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 patients taking the drug 20 mg 1 time per day and 56% - in those taking 10 mg 2 times per day. In a double-blind randomized placebo-controlled study of the effect of lercanidipine on systolic blood pressure, an effective reduction in systolic blood pressure from 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg was recorded.
Pharmacokinetics
Lercanidipine is completely absorbed after oral administration of 10–20 mg, with peak plasma concentrations occurring approximately 1.5–3 hours later.
Due to high first-pass metabolism, the absolute bioavailability of lercanidipine administered to a patient after a meal is approximately 10%, although it was reduced to ⅓ of this value when administered to healthy volunteers on an empty stomach. If the drug is taken within 2 hours of a high-fat meal, its bioavailability increases 4-fold. Therefore, lercanidipine should be taken before meals.
Distribution from blood plasma to tissues and organs is rapid and extensive. The degree of binding of lercanidipine to plasma proteins exceeds 98%. The free fraction of the drug may increase in patients with severe renal and hepatic impairment, as the level of protein in the blood plasma decreases.
Lercanidipine is extensively metabolized by the CYP3A4 isoenzyme. It is mainly converted to inactive metabolites, approximately 50% of the administered dose is excreted in the urine. Elimination occurs mainly by biotransformation. The average 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.
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.
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 the active substance, to other dihydropyridines or to any component of the drug.
Obstruction of the vessels leaving the left ventricle.
Untreated congestive heart failure.
Unstable angina.
The period within 1 month after myocardial infarction.
Severe liver or kidney dysfunction.
Simultaneous use with:
- strong CYP3A4 inhibitors;
- cyclosporine;
- grapefruit juice.
Pregnancy and breastfeeding.
Women of reproductive age, unless they use effective contraception.
Interaction with other medicinal products and other types of interactions
Lercanidipine is metabolized by the enzyme CYP3A4, therefore inhibitors and inducers of this enzyme used concomitantly with lercanidipine may affect the metabolism and elimination of lercanidipine. The concomitant use of lercanidipine with CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided, as this leads to an increase in lercanidipine plasma levels.
The simultaneous use of cyclosporine and lercanidipine is contraindicated, as it leads to an increase in the level of both substances in the blood plasma.
Lercanidipine and grapefruit juice should not be taken simultaneously, as this leads to inhibition of the metabolism of lercanidipine, as well as other dihydropyridines, and causes an increase in the hypotensive effect.
When 20 mg of lercanidipine and midazolam are administered simultaneously in elderly patients, the absorption of lercanidipine is increased; the concentration of midazolam does not change.
Caution should be exercised when administering lercanidipine concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmic drugs such as amiodarone, quinidine.
CYP3A4 inducers, such as anticonvulsants (carbamazepine, phenytoin) or rifampicin, reduce the plasma levels of lercanidipine, thereby reducing its antihypertensive effect. In these cases, more frequent monitoring of blood pressure is recommended.
Concomitant use of lercanidipine with metoprolol, a β-adrenergic blocker that is mainly eliminated by the liver, results in a 50% reduction in the bioavailability of lercanidipine, which may require dose adjustment. The bioavailability of metoprolol is not altered. This effect may be due to the reduction in hepatic blood flow caused by β-adrenergic blockers, and may therefore occur with other drugs of this group. Therefore, lercanidipine can be administered with β-adrenergic blockers, but dose adjustment may be required.
When co-administered with fluoxetine (a CYP2D6 and CYP3A4 inhibitor) in elderly patients, no clinically significant modification of the pharmacokinetics of lercanidipine was observed.
Concomitant administration of cimetidine at 800 mg per day does not cause significant changes in lercanidipine plasma concentrations, but caution should be exercised when using higher doses, as the bioavailability and antihypertensive effect of lercanidipine may increase.
When lercanidipine 20 mg was administered to patients who were taking β-methyldigoxin continuously, no pharmacokinetic interaction was observed. Concomitant administration with digoxin showed an increase in Cmax of digoxin, but not in AUC (area under the concentration-time curve). Patients who are concurrently prescribed digoxin should be monitored more closely for signs of digoxin intoxication.
When lercanidipine 20 mg was co-administered with simvastatin 40 mg, the AUC of lercanidipine was slightly 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 clinically significant. No interaction between these drugs is expected if lercanidipine is administered in the morning and simvastatin in the evening, as indicated for this drug.
Studies have shown that with the simultaneous use of lercanidipine at a dose of 20 mg on an empty stomach and warfarin, no changes in the pharmacokinetics of the latter were observed.
Lercanidipine can be used concomitantly with diuretics and angiotensin-converting enzyme (ACE) inhibitors.
Alcohol consumption should be avoided while taking lercanidipine as it may lead to increased vasodilating effects.
Application features
Some short-acting dihydropyridines can cause pain in the heart and angina pectoris. Patients with angina pectoris may experience an increase in the frequency, duration and severity of its attacks. In some cases, myocardial infarction may occur, so the use of lercanidipine in such patients requires caution, although Lercanidipine-Teva has a prolonged effect.
Lercanidipine does not have an adverse effect on blood glucose levels or plasma lipid levels.
Lercanidipine can be used in elderly patients, but caution should be exercised at the beginning of treatment.
Lercanidipine should be used with caution in patients with mild to moderate renal or hepatic impairment. Usually, a tolerable dose titration is well tolerated in these subgroups, but increasing the dose to 20 mg requires greater attention and caution.
Concomitant alcohol consumption should be avoided as it may enhance the vasodilatory effect of antihypertensive drugs.
1 tablet of Lercanidipine-Teva with a dosage of 10 mg contains 30 mg of lactose, 1 tablet with a dosage of 20 mg contains 60 mg of lactose, therefore this drug should not be used in case of Lapp lactase deficiency, galactosemia or glucose/galactose malabsorption syndrome.
CYP3A4 inducers (carbamazepine, phenytoin, rifampicin) reduce the level of lercanidipine in the blood plasma, therefore its effectiveness may be lower than expected.
Caution should be exercised when treating patients with sick sinus syndrome (unless a pacemaker is implanted). The drug should be prescribed with caution in cases of left ventricular dysfunction, although hemodynamically controlled studies have not revealed deterioration of ventricular function.
Some short-acting dihydropyridines are associated with an increased cardiovascular risk in the treatment of patients with coronary heart disease. Lercanidipine-Teva is a long-acting drug, but the drug should be used with caution in such patients.
The anesthesiologist should be informed that the patient is taking lercanidipine.
Use during pregnancy or breastfeeding
Available data indicate that lercanidipine was not teratogenic in animals and did not affect their reproductive function. However, due to the lack of clinical experience during pregnancy or lactation, and the presence of data on the teratogenic effects of other dihydropyridines in animal experiments, the drug is not recommended for use during pregnancy or in women of childbearing potential if they are planning a pregnancy and are not using effective contraception.
The risk of lercanidipine or its metabolites passing into breast milk cannot be excluded.
Given the above information, the drug is contraindicated during pregnancy or breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug is unlikely to affect the ability to drive or operate machinery. However, it is necessary to take into account the possible development of dizziness, weakness, increased fatigue, and rarely drowsiness. In these conditions, driving or operating machinery is contraindicated.
Method of administration and doses
Adults. For oral use. The recommended dose is 10 mg once daily, preferably in the morning, at least 15 minutes before meals. Depending on the individual sensitivity of the patient, the dose may be increased to 20 mg.
Dose titration should be gradual, as the maximum antihypertensive effect develops after 2 weeks of treatment.
According to the dose-response study, it is unlikely that increasing the dose above 20 mg per day will increase the effectiveness of the drug, but at the same time the risk of side effects increases.
Patients whose blood pressure is not adequately controlled with monotherapy with β-adrenergic blockers or diuretics (hydrochlorothiazide), or ACE inhibitors (captopril or enalapril), may be offered the addition of Lercanidipine to their treatment regimens.
Children.
The use of the drug in children is not recommended due to the lack of clinical experience.
Overdose
During post-marketing use, some cases of overdose (from 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 should be expected in case of overdose.
Treatment. In case of severe hypotension, bradycardia and loss of consciousness, cardiovascular drugs should be administered; in case of bradycardia, intravenous atropine should be administered. In view of the prolonged pharmacological action of lercanidipine, in case of overdose, hemodynamic monitoring of such patients is necessary for at least 24 hours. There is no information on the use of dialysis. Given the high lipophilicity of the drug, it is most likely that the plasma level is not representative for determining the period of risk and dialysis may be ineffective.
Adverse reactions
Adverse reactions were observed in approximately 1.8% of patients.
The following table lists adverse reactions that may be associated with the use of the drug according to the MedDRA classification. The data are arranged according to the frequency of occurrence of reactions (uncommon, rare, very rare), within each grouping the reactions are listed in order of decreasing incidence.
According to clinical trial data, the most commonly reported reactions were headache, dizziness, peripheral edema, tachycardia, palpitations, and hot flashes, each of which occurred in less than 1% of patients.
MedDRA classification regarding the impact on systems and organs | Infrequently (≥1/1000 to | Rarely (≥1/10,000 to | Very rare ( |
| On the part of the immune system | Increased sensitivity | | |
| From the nervous system | Headache Dizziness | Drowsiness | Faint |
| From the heart | Tachycardia
Increased heartbeat
Angina pectoris | |
| From the vascular system | Tides | | |
| Gastrointestinal tract | Epigastric pain Diarrhea Dyspepsia Nausea Vomiting | | |
| Skin and Appendages | Rash | | |
| Musculoskeletal, connective tissue and bone disorders | Myalgia | | |
| Renal and urinary tract disorders | Polyuria | | |
| General disorders and administration site conditions | Peripheral edema | Asthenia Increased fatigue | |
During the post-marketing period, isolated adverse reactions have been reported (
Lercanidipine does not have an adverse effect on blood glucose levels or plasma lipid levels.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture, out of the reach of children.
Packaging
14 tablets in a blister, 2 or 4 blisters in a box.
Vacation category
According to the recipe.
Producer
Balkanpharma-Dupnitsa AT.
Address
3 Samokovskoe Shose St., Dupnitsa, 2600, Bulgaria.
