Toridip 20

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORIDIP 10, TORIDIP 20 (TORIDIP 10, TORIDIP 20)

Composition:

Active substance: lercanidipine hydrochloride;

One film-coated tablet contains lercanidipine hydrochloride 10 mg or 20 mg;

Excipients:

for 10 mg: maize starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, microcrystalline cellulose, poloxamer, sodium stearyl fumarate, polyethylene glycol 6000, hypromellose, iron oxide yellow (E 172), titanium dioxide (E 171);

for 20 mg: maize starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, microcrystalline cellulose, sodium stearyl fumarate, povidone, hypromellose, polyethylene glycol 6000, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics:

10 mg tablets: round, biconvex, film-coated tablets, yellow in color, with a break line on one side and smooth on the other;

20 mg tablets: round, biconvex, film-coated tablets, pink in color, with a break line on one side and smooth on the other.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant vascular action. ATC code C08CA13.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle cells. Its mechanism of action is due to a direct vasorelaxant effect on vascular muscles, resulting in a reduction of total peripheral vascular resistance.

Pharmacodynamic effects

Despite its short elimination half-life, lercanidipine has a prolonged antihypertensive effect due to its high membrane partition coefficient and lacks negative inotropic activity owing to its high vascular selectivity. Since vasodilation induced by lercanidipine occurs gradually, acute arterial hypotension with reflex tachycardia is rarely observed in patients with arterial hypertension.

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

Clinical efficacy and safety

The clinical efficacy and safety of lercanidipine at doses of 10 to 20 mg once daily were evaluated in double-blind, placebo-controlled clinical trials (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo) and in long-term, uncontrolled clinical studies with an active comparator drug involving 3676 patients with arterial hypertension.

Most clinical trials were conducted in patients with mild to moderate essential hypertension (including elderly patients and patients with diabetes), who received lercanidipine as monotherapy or in combination with ACE inhibitors, diuretics, or beta-blockers.

In addition to the clinical trials conducted to confirm therapeutic indications, one small uncontrolled but randomized study was performed in patients with severe hypertension (mean ± standard deviation of diastolic blood pressure was 114.5 ± 3.7 mm Hg). In this study, blood pressure normalized in 40% of 25 patients receiving 20 mg of lercanidipine hydrochloride once daily and in 56% of 25 patients receiving 10 mg of lercanidipine hydrochloride twice daily. In a double-blind, randomized, controlled trial in patients with systolic hypertension, lercanidipine hydrochloride effectively reduced systolic blood pressure from a mean of 172.6 ± 5.6 mm Hg to 140.2 ± 8.7 mm Hg.

Pediatric population

Clinical studies in children have not been conducted.

Pharmacokinetics.

Absorption

Lercanidipine is completely absorbed after oral administration of 10–20 mg, and maximum plasma concentrations of 3.30 ng/mL ± 2.09 standard deviation and 7.66 ng/mL ± 5.90 standard deviation, respectively, are reached within

1.5 hours after intake.

Both enantiomers of lercanidipine exhibit a similar plasma concentration profile: time to reach maximum plasma concentration is identical, maximum plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer, and the elimination half-life of both enantiomers is mainly similar. Interconversion of enantiomers in in vivo studies has not been observed.

Due to high first-pass hepatic metabolism, the absolute bioavailability of lercanidipine administered after food intake is approximately 10%, and it decreases to one-third of this value when administered to healthy volunteers on an empty stomach.

The bioavailability of lercanidipine after oral administration increases fourfold if taken no later than 2 hours after a high-fat meal; therefore, the drug should be taken on an empty stomach.

Distribution

Distribution from plasma to tissues and organs is rapid and extensive.

The degree 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 be increased.

Biotransformation

Lercanidipine hydrochloride is actively metabolized by the CYP3A4 enzyme; unchanged drug is not detected in urine or feces. It is primarily converted into inactive metabolites, and approximately 50% of the administered dose is excreted in urine.

In vitro experiments with human liver microsomes have demonstrated that lercanidipine slightly inhibits CYP3A4 and CYP2D6 at concentrations 160 and 40 times higher, respectively, than its peak plasma concentrations achieved after a 20 mg dose. Furthermore, interaction studies in humans have shown that lercanidipine does not modify plasma levels of midazolam, a typical CYP3A4 substrate, or metoprolol, a typical CYP2D6 substrate; thus, inhibition of biotransformation of drugs metabolized by CYP3A4 or CYP2D6 is not expected with therapeutic doses of lercanidipine hydrochloride.

Elimination

Elimination occurs primarily via biotransformation. The mean elimination half-life is 8–10 hours, and the therapeutic effect lasts 24 hours due to the high degree of lercanidipine binding to the lipid membrane. No accumulation was observed 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, 20, and 40 mg, observed maximum plasma concentrations had a ratio of 1:3:8, and areas under the plasma concentration-time curves had a ratio of 1:4:18, indicating progressive saturation of first-pass metabolism. Thus, lercanidipine bioavailability increases with dose escalation.

Special patient groups

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic impairment have been shown to be similar to those in the general population. In patients with severe renal dysfunction or undergoing hemodialysis, drug concentrations were higher (approximately 70%). In patients with moderate or severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as it is primarily metabolized in the liver.

Preclinical safety data

Data obtained from standard preclinical safety pharmacology studies, repeated-dose toxicity studies, genotoxicity, carcinogenic potential, and reproductive toxicity studies indicate no special hazard for humans.

Safety pharmacology studies conducted in animals showed no effect on the autonomic nervous system, central nervous system, or gastrointestinal function at antihypertensive doses.

Significant effects observed in long-term studies in rats and dogs were directly or indirectly related to the known effects of high doses of calcium antagonists, i.e., resulting from excessively high pharmacodynamic activity.

Lercanidipine is not genotoxic and shows no carcinogenic risk.

Lercanidipine had no effect on fertility or general reproductive performance in rats.

Lercanidipine treatment showed no teratogenic effects in rats and rabbits; however, administration of high doses in rats led to pre- and post-implantation loss and delayed intrauterine development.

Administration of high doses of lercanidipine hydrochloride (12 mg/kg/day) during delivery may lead to dystocia. Distribution of lercanidipine and/or its metabolites in pregnant animals and their penetration into breast milk has not been studied.

Metabolites were not separately evaluated in toxicological studies.

Clinical characteristics.

Indications.

Mild to moderate essential hypertension.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section «Composition»).
• Left ventricular outflow tract obstruction.
• Untreated congestive heart failure.
• Unstable angina or recent (within the last month) myocardial infarction.
• Severe hepatic impairment.
• Severe renal impairment (GFR < 30 mL/min), including patients on dialysis.
• Concomitant use with strong CYP3A4 inhibitors, cyclosporine, grapefruit or grapefruit juice (see section «Interaction with other medicinal products and other forms of interaction»).

Interaction with other medicinal products and other forms of interaction.

Contraindications for concomitant use

CYP3A4 inhibitors

Lercanidipine is known to be metabolized by the CYP3A4 enzyme; therefore, concomitant administration of CYP3A4 inhibitors and inducers may affect its metabolism and elimination.

Interaction studies with the strong CYP3A4 inhibitor ketoconazole have shown a marked increase in plasma concentrations of lercanidipine (a 15-fold increase in AUC [area under the curve] and an 8-fold increase in Cmax of the S-lercanidipine eutomer).

Concomitant use of lercanidipine with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (see section «Contraindications»).

Cyclosporine

When lercanidipine and cyclosporine are used concomitantly, plasma concentrations of both drugs increase. When cyclosporine is administered within 3 hours after lercanidipine intake, lercanidipine plasma concentration remains unchanged, while the AUC of cyclosporine increases by 27%. However, concomitant administration of lercanidipine and cyclosporine increases lercanidipine plasma concentration by 3-fold and the AUC of cyclosporine by 21%.

Lercanidipine and cyclosporine should not be used together (see section «Contraindications»).

Grapefruit or grapefruit juice

As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit or grapefruit juice, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section «Contraindications»).

Concomitant use not recommended

CYP3A4 inducers

Concomitant use of lercanidipine with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution, as antihypertensive efficacy may be reduced; blood pressure should be monitored more frequently than usual (see section «Special precautions for use»).

Alcohol

Alcohol consumption should be avoided, as it may potentiate the effect of vasodilating antihypertensive agents (see section «Special precautions for use»).

Safety measures, including dose adjustment

CYP3A4 substrates

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

Midazolam

Concomitant administration of midazolam and lercanidipine 20 mg resulted in increased absorption of lercanidipine (by approximately 40%) and reduced rate of absorption (3 hours vs. 1.75 hours), while midazolam concentration remained unchanged.

Metoprolol

Concomitant administration of metoprolol (a β-blocker primarily metabolized in the liver) with lercanidipine did not alter the bioavailability of metoprolol, whereas the bioavailability of lercanidipine decreased by 50%, likely due to reduced hepatic blood flow caused by β-blockers. Therefore, lercanidipine can be used with β-blockers without restrictions, but dose adjustment of lercanidipine may be required.

Digoxin

Concomitant administration of digoxin and lercanidipine 20 mg increases digoxin plasma concentration by 33%. Therefore, patients receiving both digoxin and lercanidipine should be monitored more closely for signs of digoxin toxicity.

Concomitant use with other medicinal products

Fluoxetine

An interaction study with fluoxetine, an inhibitor of CYP2D6 and CYP3A4, conducted in healthy volunteers aged 65 ± 7 years (mean ± standard deviation) did not reveal any clinically significant changes 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 at higher doses, as increased bioavailability and antihypertensive effect of lercanidipine may occur.

Simvastatin

When lercanidipine 20 mg was administered concomitantly with simvastatin 40 mg, the AUC of lercanidipine changed only slightly, whereas the AUC of simvastatin increased by 56% and the AUC of its active metabolite β-hydroxyacid by 28%. Such changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening.

Diuretics and ACE inhibitors

Lercanidipine can be safely used concomitantly with diuretics and ACE inhibitors.

Other medicinal products affecting blood pressure

As with other antihypertensive agents, enhanced hypotensive effects may occur when lercanidipine is used concomitantly with other agents affecting blood pressure, such as alpha-blockers for relief of urinary symptoms, tricyclic antidepressants, and neuroleptics. Conversely, reduced antihypertensive effect may occur when used concomitantly with corticosteroids.

Special precautions for use.

Sinus node dysfunction

Lercanidipine should be used with caution in patients with sinus node dysfunction who do not have a cardiac pacemaker implanted.

Left ventricular dysfunction

Lercanidipine should be administered with caution in patients with left ventricular dysfunction, despite the fact that hemodynamically controlled studies have not revealed any disturbances in ventricular function.

Ischemic heart disease

It is believed that the use of certain short-acting dihydropyridines may increase the risk of cardiovascular complications in patients with ischemic heart disease. Therefore, lercanidipine should be used with caution in such patients, even though lercanidipine has a prolonged duration of action.

Some dihydropyridines may in isolated cases provoke chest pain and angina. Very rarely, patients with angina may experience an increase in frequency, duration, and severity of angina attacks. In individual cases, myocardial infarction may occur (see section «Adverse reactions»).

Use in renal and hepatic impairment

Extreme caution is required when initiating treatment in patients with mild or moderate renal or hepatic impairment. Although such patients generally tolerate the usual recommended dosage regimen well, dose escalation up to 20 mg daily should be performed with caution. The antihypertensive effect of the drug may be enhanced in patients with hepatic impairment, and dose adjustment may therefore be necessary. The drug is contraindicated in patients with severe hepatic impairment or severe renal dysfunction (glomerular filtration rate < 30 mL/min), including patients undergoing hemodialysis (see sections «Dosage and administration» and «Contraindications»).

Peritoneal dialysis

The use of lercanidipine has been associated with turbidity of peritoneal dialysate effluent in patients undergoing peritoneal dialysis. This turbidity is related to increased triglyceride concentration in the peritoneal effluent. Although the mechanism is not known, the turbidity resolves shortly after discontinuation of lercanidipine. This association should be taken into account, as turbidity of the peritoneal effluent may be mistakenly interpreted as infectious peritonitis, potentially leading to unnecessary hospitalization and empirical antibiotic therapy.

CYP3A4 inducers

CYP3A4 inducers, such as anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin, may reduce plasma concentrations of lercanidipine, and thus the efficacy of lercanidipine may be lower than expected (see section «Interaction with other medicinal products and other forms of interaction»).

Alcohol

Concomitant consumption of alcohol should be avoided, as it may lead to an enhanced vasodilatory antihypertensive effect of the medicinal product (see section «Interaction with other medicinal products and other forms of interaction»).

Pediatric population

The safety and efficacy of lercanidipine in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of lercanidipine in pregnant women. Animal studies have not revealed teratogenic effects (see non-clinical safety data), although such effects have been observed with other dihydropyridine derivatives. Lercanidipine is not recommended during pregnancy or in women of childbearing potential who are not using contraception.

Breastfeeding

It is unknown whether lercanidipine or its metabolites are excreted in human breast milk. A risk to newborns/infants cannot be excluded. Lercanidipine should not be used during breastfeeding.

Fertility

Clinical data on lercanidipine are lacking. In some patients treated with calcium channel blockers, reversible biochemical changes in the sperm head have been reported, which may negatively affect fertilization. In cases of repeated failed attempts at in vitro fertilization and in the absence of other explanations, the possibility that calcium channel blockers may be the cause of such failures should be considered.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience with lercanidipine indicates that impairment of the ability to drive or operate machinery is unlikely. However, caution is advised, as dizziness, asthenia, fatigue, and somnolence may occur.

Method of Administration and Dosage

Method of Administration

Precautions to be followed when taking the medicinal product or handling it:

• The medicinal product should preferably be taken in the morning, at least 15 minutes before breakfast.
• This medicinal product should not be taken with grapefruit juice (see sections «Contraindications», «Interaction with other medicinal products and other forms of interaction»).

Dosage

The recommended dose for adults is 10 mg (using Toridip 10) once daily, taken at least 15 minutes before a meal; the dose may be increased to 20 mg (using Toridip 20) depending on the individual patient's sensitivity. Dosage should be titrated gradually, as the maximum antihypertensive effect may not be achieved until 2 weeks after initiation of treatment.

For some patients in whom blood pressure cannot be adequately controlled with a single antihypertensive agent, combination therapy with lercanidipine hydrochloride together with a β-adrenoreceptor blocker (atenolol), a diuretic (hydrochlorothiazide), or an angiotensin-converting enzyme inhibitor (captopril or enalapril) may be appropriate.

Since the dose-response curve is steep and plateaus at doses of 20–30 mg, it is unlikely that higher doses will provide greater efficacy; however, the incidence of adverse effects may increase.

Elderly patients. Dose adjustment is not required, but caution should be exercised when initiating treatment in elderly patients.

Use in renal or hepatic impairment. Extreme caution should be exercised when initiating treatment in patients with mild to moderate renal or hepatic impairment. Although such patients generally tolerate the recommended dosage, dose escalation to 20 mg daily should be done cautiously. The antihypertensive effect of the drug may be enhanced in patients with hepatic impairment, and therefore dose adjustment may be necessary.

Lercanidipine hydrochloride is contraindicated in patients with severe renal impairment (glomerular filtration rate < 30 mL/min) or severe hepatic impairment, including patients on dialysis (see sections «Contraindications» and «Special precautions for use»).

Children.

The use of lercanidipine in children is not recommended due to lack of clinical experience.

Overdose.

Post-marketing experience with lercanidipine includes several cases of overdose (dose range from 30–40 mg to 800 mg, including a suicide attempt report).

Symptoms

As with other dihydropyridines, overdose of lercanidipine leads to excessive peripheral vasodilation resulting in pronounced arterial hypotension and reflex tachycardia. However, with very high doses, loss of peripheral selectivity may occur, leading to bradycardia and negative inotropic effects. The most common adverse reactions associated with overdose were arterial hypotension, dizziness, headache, and palpitations.

Treatment

Patients with clinically significant arterial hypotension require active cardiovascular support, including frequent monitoring of cardiac and respiratory function, supine position with elevated lower limbs, monitoring of circulating fluid volume and diuresis. Due to the prolonged pharmacological action of lercanidipine, monitoring of the cardiovascular system should continue for at least 24 hours. Since the drug is highly protein-bound, dialysis is unlikely to be effective. In cases of suspected moderate or severe poisoning, patients should be monitored in an intensive care unit.

Adverse reactions

Overall safety profile

The safety of lercanidipine administered at a dose of 10 to 20 mg once daily was evaluated during a double-blind, placebo-controlled clinical study (involving 1200 patients receiving lercanidipine and 603 patients receiving placebo), as well as during long-term, uncontrolled clinical studies with an active comparator drug involving 3676 patients with arterial hypertension who received lercanidipine.

Adverse reactions most frequently reported during clinical studies and post-marketing surveillance: peripheral edema, headache, facial flushing, tachycardia, and palpitations.

Adverse reaction table

The table below lists adverse reactions reported during clinical studies and worldwide post-marketing experience, for which a reasonable causal relationship with the use of the drug has been established. The reactions are categorized by organ systems according to MedDRA and by 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 frequency category, adverse reactions are listed in order of decreasing severity.

MedDRA System Organ Class	Common	Uncommon	Rare	Not known
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness	Somnolence, syncope
Cardiac disorders	Tachycardia, palpitations		Angina pectoris
Vascular disorders	Facial flushing	Hypotension
Gastrointestinal disorders		Dyspepsia, nausea, upper abdominal pain	Vomiting, diarrhea	Gingival hyperplasia1, clouding of peritoneal dialysate1
Hepatobiliary disorders				Increased serum transaminase1
Skin and subcutaneous tissue disorders		Rash, pruritus	Urticaria	Angioedema1
Connective tissue, musculoskeletal and bone disorders		Myalgia
Renal and urinary disorders		Polyuria	Pollakiuria
General disorders and administration site conditions	Peripheral edema	Asthenia, fatigue	Chest pain

1 Adverse reactions reported spontaneously during post-marketing surveillance worldwide.

Description of selected adverse reactions

In placebo-controlled clinical trials, the incidence of peripheral edema was 0.9% with lercanidipine at doses of 10 to 20 mg and 0.83% with placebo. In the overall study population, including long-term clinical trials, the incidence was 2%.

Lercanidipine has no adverse effect on blood glucose levels or serum lipids.

Some dihydropyridines may rarely cause chest pain or angina. Very rarely, in patients with pre-existing angina, the frequency, duration, or severity of episodes may increase. Isolated cases of myocardial infarction may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 3 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

TORRENT PHARMACEUTICALS Ltd.

Manufacturer's address and location of manufacturing site.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana, Gujarat 382721, India.