Zanidip

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZANIDIP® (ZANIDIP®)

Composition:

Active substance: 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;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

tablets containing 20 mg lercanidipine hydrochloride – pink, film-coated, round, biconvex tablets with a notch on one side.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular action. Dihydropyridine derivatives. ATC code C08CA13.

Pharmacological properties.

Pharmacodynamics.

Lercanidipine is a calcium antagonist of the dihydropyridine group. It inhibits the transmembrane influx of calcium into cardiomyocytes and vascular smooth muscle cells. The mechanism of lercanidipine's antihypertensive action is due to its direct vasorelaxant effect on vascular smooth muscles, thereby reducing total peripheral vascular resistance. Despite its short plasma half-life, lercanidipine exerts a prolonged antihypertensive effect owing to its high membrane partition coefficient. Due to its high vascular selectivity, the drug does not exert a negative inotropic effect. Acute arterial hypotension with reflex tachycardia rarely occurs because of the gradual onset of vasodilation following lercanidipine administration.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is primarily attributable to its S-enantiomer.

The clinical efficacy and safety of lercanidipine at doses of 10–20 mg once daily have been evaluated in a double-blind, placebo-controlled clinical trial (in which 1200 patients received lercanidipine and 603 patients received placebo) and in active-controlled and uncontrolled long-term clinical trials involving a total of 3676 hypertensive patients.

Most studies included patients with mild to moderate essential hypertension (including elderly patients and those with diabetes mellitus), treated with lercanidipine either as monotherapy or in combination with ACE inhibitors, diuretics, or beta-blockers.

In addition to clinical trials conducted to confirm therapeutic indications, a further small, uncontrolled but randomized study in patients with severe arterial hypertension (mean ± standard deviation diastolic blood pressure of 114.5 ± 3.7 mm Hg) demonstrated blood pressure normalization in 40% of 25 patients receiving Zanidip® 20 mg once daily and in 56% of 25 patients receiving Zanidip® 10 mg twice daily. 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 doses of 10–20 mg, with peak plasma concentrations of 3.30 ng/mL ± 2.09 SD and 7.66 ng/mL ± 5.90 SD, respectively, reached approximately 1.5–3 hours after intake.

The two enantiomers of lercanidipine exhibit a similar plasma concentration profile: time to reach maximum plasma concentration is identical, while peak concentration and AUC are on average 1.2 times higher for the S-enantiomer; the elimination half-life of both enantiomers is essentially the same. In vivo interconversion of enantiomers has not been observed.

Due to extensive first-pass metabolism in the liver, the absolute bioavailability of orally administered lercanidipine is approximately 10% when taken after food, although it decreases to one-third 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 fourfold. Therefore, lercanidipine should be taken before meals.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive. The extent of lercanidipine binding to plasma proteins exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic impairment, the free fraction of the drug may increase.

Biotransformation

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

In vitro experiments using human liver microsomes indicate that lercanidipine weakly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its maximum plasma concentration achieved after a 20 mg dose. Furthermore, drug interaction studies in humans have demonstrated that lercanidipine does not alter plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate. Thus, when lercanidipine is used at therapeutic doses, clinically significant inhibition of the biotransformation of drugs metabolized by CYP3A4 or CYP2D6 is not expected.

Elimination

Elimination occurs primarily via biotransformation. The mean terminal half-life is 8–10 hours, while the therapeutic effect lasts 24 hours due to the high degree of lercanidipine binding to cellular membrane lipids. No accumulation occurs with repeated administration.

Linearity/Non-linearity

After oral administration, lercanidipine plasma concentrations are not directly proportional to the administered dose (non-linear kinetics). Following doses of 10 mg, 20 mg, and 40 mg, observed maximum plasma concentrations showed a ratio of 1:3:8, while the area under the plasma concentration-time curves (AUC) showed a ratio of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, the bioavailability of lercanidipine increases with increasing dose.

Additional information in specific patient groups

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic dysfunction are similar to those observed in the general patient population. In patients with severe renal impairment or those dependent on dialysis, drug concentrations were higher (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as it is predominantly metabolized in the liver.

Clinical characteristics.

Indications.

Mild to moderate essential hypertension.

Contraindications.

• Hypersensitivity to lercanidipine or to any component of the medicinal product.
• Obstruction of the left ventricular outflow tract.
• Uncompensated congestive heart failure.
• Unstable angina or recent (within 1 month) myocardial infarction.
• Severe hepatic impairment.
• Severe renal impairment (creatinine clearance < 30 mL/min), including patients on hemodialysis.
• Concomitant use with strong CYP3A4 inhibitors, cyclosporine, grapefruit or grapefruit juice.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated

CYP3A4 inhibitors

Lercanidipine is metabolized by the CYP3A4 enzyme; therefore, concomitant administration of CYP3A4 inhibitors or inducers may affect the metabolism and elimination of lercanidipine. Interaction studies between lercanidipine and the potent CYP3A4 inhibitor ketoconazole demonstrated a marked increase in plasma lercanidipine levels (15-fold increase in AUC and 8-fold increase in maximum concentration of the S-enantiomer of lercanidipine).

Concomitant use of lercanidipine with CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided.

Cyclosporine

Concomitant administration of lercanidipine and cyclosporine increases plasma levels of both substances. A study in young healthy volunteers showed that administration of cyclosporine 3 hours after lercanidipine intake did not alter lercanidipine plasma levels, while the AUC of cyclosporine increased by 27%. However, simultaneous administration of lercanidipine and cyclosporine leads to a 3-fold increase in lercanidipine plasma levels and a 21% increase in cyclosporine AUC.

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, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect. Concomitant intake of lercanidipine with grapefruit or grapefruit juice should be avoided.

Concomitant use is not recommended

CYP3A4 inducers

Lercanidipine should be used with caution when administered concomitantly with CYP3A4 inducers such as anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin, due to the possible reduction of the antihypertensive effect of lercanidipine. In such cases, more frequent blood pressure monitoring is recommended.

Alcohol

Alcohol consumption should be avoided due to the potential potentiation of the vasodilatory effect of antihypertensive medicinal products.

Interactions requiring dose adjustment

CYP3A4 substrates

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

Midazolam

In elderly volunteers, concomitant administration of 20 mg lercanidipine and midazolam resulted in increased absorption of lercanidipine (approximately by 40%) and reduced rate of absorption (tmax prolonged from 1.75 to 3 hours). Midazolam concentration was not altered.

Metoprolol

Concomitant administration of lercanidipine with metoprolol, a β-blocker primarily eliminated via the liver, does not alter the bioavailability of metoprolol but reduces the bioavailability of lercanidipine by 50%. This effect may be due to reduced hepatic blood flow caused by β-blockers and may therefore occur when used with other agents in this class. Thus, lercanidipine may be used with β-adrenergic blockers, but dose adjustment may be necessary.

Digoxin

When 20 mg lercanidipine was administered concomitantly to patients on chronic β-methyldigoxin therapy, no evidence of pharmacokinetic interaction was observed. However, an average increase in digoxin Cmax by 33% was noted, while AUC and renal clearance were not significantly altered. Patients receiving digoxin concomitantly should be closely monitored for signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

A study investigating interaction with fluoxetine (an inhibitor of CYP2D6 and CYP3A4) in volunteers aged 65 ± 7 years (mean ± SD) showed 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 lercanidipine plasma concentration. However, caution is advised with higher doses due to the potential for increased bioavailability and antihypertensive effect of lercanidipine.

Simvastatin

When lercanidipine 20 mg was administered concomitantly with 40 mg simvastatin, the AUC of lercanidipine was not significantly altered, whereas the AUC of simvastatin increased by 56% and that of its active metabolite β-hydroxyacid by 28%. Such 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 recommended for this product.

Diuretics and ACE inhibitors

Lercanidipine may be used concomitantly with diuretics and angiotensin-converting enzyme (ACE) inhibitors.

Other medicinal products affecting blood pressure

As with all antihypertensive agents, an enhanced hypotensive effect may occur when lercanidipine is used concomitantly with other medicinal products affecting blood pressure, such as α-blockers used for symptomatic treatment of bladder disorders, tricyclic antidepressants, and neuroleptics.

Conversely, a reduced antihypertensive effect may be observed when lercanidipine is used concomitantly with corticosteroids.

Special precautions for use

Sinus node weakness syndrome

Lercanidipine should be used with caution in patients with sinus node weakness syndrome (without an implanted cardiac pacemaker).

Left ventricular dysfunction

Although hemodynamically controlled studies have not shown worsening of ventricular function, the drug should be prescribed with caution in patients with left ventricular dysfunction.

Ischemic heart disease

It has been hypothesized that some short-acting dihydropyridines may be associated with an increased cardiovascular risk in patients with ischemic heart disease. Although Zanidip® is a long-acting formulation, the drug should still be used with caution in such patients. Some dihydropyridines may rarely cause precordial pain or angina. Very rarely, in patients with pre-existing angina, an increase in frequency, duration, or severity of angina attacks may occur. Isolated cases of myocardial infarction have been reported.

Peritoneal dialysis

The use of lercanidipine has been associated with turbidity of peritoneal dialysate in patients undergoing peritoneal dialysis. This turbidity is due to elevated triglyceride concentrations in the peritoneal exudate. Although the mechanism is not known, this effect tends to resolve shortly after discontinuation of lercanidipine. This association should be taken into account to avoid situations where turbidity of the peritoneal dialysate may be mistakenly interpreted as infectious peritonitis, leading to unnecessary hospitalization and empirical antibiotic therapy.

Lactose

This medicinal product contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding

There is no clinical experience with the use of lercanidipine during pregnancy. Animal studies have not revealed teratogenic effects; however, such effects have been observed with other dihydropyridine compounds. Lercanidipine is not recommended for use in pregnant women or in women of childbearing potential who are not using effective contraception.

It is not definitively known whether lercanidipine or its metabolites are excreted in human breast milk. Therefore, a risk to the infant cannot be excluded. Lercanidipine should not be used during breastfeeding.

Fertility

Clinical data on the effect of lercanidipine on fertility are lacking. Available data indicate reversible biochemical changes in the sperm head that may affect fertilizing capacity in patients treated with calcium channel blockers. In cases of repeated failure of in vitro fertilization and in the absence of other explanations, the use of calcium channel blockers should be considered as a possible cause.

Effect on ability to drive and use machines

The effect of lercanidipine on the ability to drive or operate machinery is negligible. However, one should take into account the possibility of dizziness, weakness, increased fatigue, and rarely – somnolence.

Method of Administration and Dosage

The recommended dose is 10 mg orally once daily, taken at least 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 over 2 weeks of treatment.

For patients whose blood pressure is not adequately controlled on monotherapy with antihypertensive agents, addition of Zanidip® to treatment regimens containing β-adrenoblockers (atenolol), diuretics (hydrochlorothiazide), or ACE inhibitors (captopril or enalapril) may be considered.

Since the dose–response curve plateaus within the dose range of 20–30 mg, it is unlikely that efficacy will increase with higher doses, whereas the risk of adverse effects may rise.

Elderly Patients

According to pharmacokinetic and clinical studies, Zanidip® can be administered to elderly patients without specific dose adjustment; however, treatment initiation in elderly patients should be under medical supervision.

Patients with Renal or Hepatic Impairment

Treatment with Zanidip® in patients with mild to moderate renal or hepatic impairment should be initiated under medical supervision. The usual recommended dose of 10 mg is generally well tolerated in these patient subgroups, but dose escalation to 20 mg requires caution.

In patients with hepatic impairment, an enhanced antihypertensive effect of the drug may occur, necessitating dose adjustment.

Lercanidipine is contraindicated in patients with severe hepatic dysfunction or severe renal impairment (creatinine clearance < 30 mL/min), including patients on hemodialysis.

Method of Administration

Prior to administration, the following should be considered:

• The drug should preferably be taken in the morning, at least 15 minutes before breakfast.
• This medicinal product must not be taken with grapefruit juice.

Children

The safety and efficacy of this medicinal product in children under 18 years of age have not been studied; data on use in pediatric patients are lacking.

Overdose

During the post-marketing period, several cases of overdose have been reported (from 30–40 mg to 800 mg, including a suicide attempt).

Symptoms
By analogy with other dihydropyridines, overdose with lercanidipine is expected to cause excessive peripheral vasodilation and marked arterial hypotension, along with reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, potentially leading to bradycardia and a negative inotropic effect. The most common adverse reactions associated with overdose are hypotension, dizziness, headache, and palpitations.

Treatment
In cases of severe arterial hypotension, active cardiovascular support measures are required, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated lower limbs, fluid status monitoring, and assessment of urinary output. Due to the prolonged pharmacological action of lercanidipine, cardiovascular monitoring of such patients is necessary for at least 24 hours after overdose. Because of the high protein binding of lercanidipine, dialysis may be ineffective. Patients with anticipated moderate or severe intoxication should be managed under intensive care conditions.

Adverse Reactions

According to data from clinical studies and post-marketing use, the most commonly reported adverse reactions are peripheral edema, headache, flushing, tachycardia, and palpitations.

The table below lists adverse reactions reported during clinical trials and post-marketing use of the drug worldwide, for which a causal relationship with the drug's use was considered reasonable. Adverse reactions are listed by MedDRA classification system and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each group, reactions are listed in decreasing order of severity according to frequency.

1Adverse reactions from spontaneous reports during post-marketing use worldwide.

Lercanidipine does not negatively affect blood glucose levels or serum lipid levels.

In placebo-controlled clinical trials, peripheral edema occurred in 0.9% of patients receiving lercanidipine 10–20 mg and in 0.83% of those receiving placebo. This frequency reached 2% in the overall study population, including long-term clinical trials.

The use of some dihydropyridines may occasionally cause precordial pain or angina; in rare cases, in patients with angina pectoris, the frequency, duration, or severity of attacks may increase. Isolated cases of myocardial infarction have also been reported.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging. Keep out of reach of children.

Packaging.

Tablets containing 10 mg of lercanidipine hydrochloride.

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

Tablets containing 20 mg of lercanidipine hydrochloride.

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

Prescription category. Prescription only.

Manufacturer. Recordati Industria Chimica e Farmaceutica S.p.A.

Manufacturer's address. Via M. Civitali 1, 20148 Milan, Italy.

Marketing Authorization Holder. Recordati Ireland Ltd.

Address of the Marketing Authorization Holder. Rincol East, Ringaskiddy, Co. Cork, Ireland.