Zanidip film-coated tablets 20 mg blister No. 98

Instructions Zanidip film-coated tablets 20 mg blister No. 98

Composition

active ingredient: 1 tablet contains 10 mg of lercanidipine hydrochloride (equivalent to 9.4 mg of lercanidipine) or 20 mg of lercanidipine hydrochloride (equivalent to 18.8 mg of lercanidipine);

excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K30, magnesium stearate;

shell for a tablet with a dosage of 10 mg: film-coating mixture (hypromellose, talc, titanium dioxide (E 171), macrogol 6000, iron oxide yellow (E 172));

shell for a tablet with a dosage of 20 mg: film-coating mixture (hypromellose, talc, titanium dioxide (E 171), macrogol 6000, red iron oxide (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties:

tablets containing 10 mg of lercanidipine hydrochloride – film-coated tablets, yellow, round, biconvex, with a notch on one side;

tablets containing 20 mg of lercanidipine hydrochloride are film-coated tablets, pink in color, round, biconvex, with a notch on one 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.

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 hypertensive patients.

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 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 Zanidip® at a dose of 20 mg 1 time per day and in 56% of 25 patients taking Zanidip® at a dose of 10 mg 2 times per day. In a double-blind, randomized, placebo-controlled study in patients with isolated systolic hypertension, Zanidip® effectively reduced systolic blood pressure from a mean baseline value of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.

Clinical studies in the pediatric population have not been conducted.

Pharmacokinetics.

Absorption

Zanidip® is completely absorbed after oral administration at a dose of 10–20 mg, maximum plasma concentrations of 3.30 ng/ml ± 2.09 s.u. and 7.66 ng/ml ± 5.90 s.u., respectively, are recorded after approximately 1.5–3 hours.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma concentration is the same, the maximum concentration and 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 was reduced to ⅓ of this value when the drug was 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 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 the level of plasma protein is reduced in patients with severe renal and hepatic impairment, the free fraction of the drug may increase.

Zanidip® is extensively metabolized by the CYP3A4 isoenzyme, unchanged drug is not detected in urine or feces. It is converted mainly to inactive metabolites, approximately 50% of the administered dose is excreted in the urine.

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 concentration 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. Therefore, 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.

Left ventricular outflow tract obstruction.

Untreated congestive heart failure.

Unstable angina or recent (within 1 month) myocardial infarction.

Severe liver failure.

Severe renal impairment (creatinine clearance < 30 ml/min), including patients on hemodialysis.

Concomitant 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 simultaneously with lercanidipine, may affect the metabolism and excretion 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

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 lercanidipine is used concomitantly with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics such as amiodarone, quinidine, sotalol.

When 20 mg of lercanidipine and midazolam were co-administered to elderly volunteers, the absorption of lercanidipine was increased (by approximately 40%) and the rate of absorption was reduced (tmax was prolonged from 1.75 to 3 hours). Midazolam concentrations were not affected.

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 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 concomitant digoxin should be carefully monitored for signs of digoxin intoxication.

Concomitant use with other medicines

Fluoxetine

An interaction study with fluoxetine (CYP2D6 and CYP3A4 inhibitor) in volunteers aged 65 ± 7 years (mean ± SD) 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 altered, 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 taken in the morning and simvastatin in the evening, as indicated for this drug.

Diuretics and ACE inhibitors

Lercanidipine can be used concomitantly with diuretics and angiotensin-converting enzyme 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 Zanidip® 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 be observed.

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

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 in pregnant women and women of childbearing potential unless they use effective contraception.

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.

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.

The ability to influence the reaction speed when driving or working with 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 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 within 2 weeks of treatment.

Patients whose blood pressure is not adequately controlled with antihypertensive drugs alone may be offered the addition of Zanidip® to treatment regimens with b-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 study data, Zanidip® 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 Zanidip® under close supervision. The usual recommended dose of 10 mg is generally well tolerated by patients 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.

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, 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.

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

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 the 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 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each grouping, the frequency of reactions is presented in order of decreasing seriousness.

1Adverse 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

3 years.

Storage conditions

Store at a temperature not exceeding 30 ° C in the original packaging. Keep out of the reach of children.

Packaging

Tablets containing 10 mg of lercanidipine hydrochloride.

14 or 28, or 56, or 98 tablets in blisters in a cardboard box.

Tablets containing 20 mg of lercanidipine hydrochloride.

14 or 28, or 56, or 98 tablets in blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Records of Industria Chimica e Farmaceutica S.p.A.

Address

Rehins East, Ringeskiddie, Co. Cork, Ireland.

Applicant

Recordate Island Ltd.