Active ingredients: Lercanidipine (lercanidipine hydrochloride)
ZANEDIP 10 mg film-coated tablets ZANEDIP 20 mg film-coated tablets
Indications Why is Zanedip used? What is it for?
Zanedip, lercanidipine hydrochloride, belongs to a group of drugs called calcium channel blockers (dihydropyridine derivatives) that reduce blood pressure.
Zanedip is used to treat high blood pressure, also known as hypertension, in adults over the age of 18 (not recommended in children under the age of 18).
Contraindications When Zanedip should not be used
Do not take Zanedip
- If you are allergic (hypersensitive) to lercanidipine hydrochloride or any of the other ingredients of Zanedip tablets.
- If you have had allergic reactions to medicines similar to Zanedip tablets (for example amlodipine, nicardipine, felodipine, isradipine, nifedipine or lacidipine).
- If you suffer from certain heart diseases such as: uncontrolled heart failure; obstruction of blood flow from the heart; unstable angina (angina at rest or that gets progressively worse); heart attack less than a month old.
- If you have severe liver or kidney problems.
- If you are taking medicines that are inhibitors of the CYP3A4 isoenzyme such as: antifungals (for example ketoconazole or itraconazole); macrolide antibiotics (for example erythromycin or troleandomycin): antivirals (for example ritonavir).
- If you are taking another medicine called cyclosporine (used after transplants to prevent organ rejection).
- With grapefruit or grapefruit juice.
Do not take Zanedip if you are pregnant or breastfeeding (see Pregnancy, breast-feeding and fertility section for more information).
Precautions for use What you need to know before taking Zanedip
Talk to your doctor or pharmacist before taking Zanedip:
- If you have other heart diseases that have not been treated with the insertion of a pacemaker or have pre-existing angina.
- If you have liver or kidney problems or are on dialysis.
You should tell your doctor if you think you are (or may become) pregnant or are breast-feeding (see section Pregnancy, breast-feeding and fertility).
Children and adolescents
The safety and efficacy of Zanedip in children up to 18 years of age have not been established. There are no data available.
Interactions Which drugs or foods can modify the effect of Zanedip
Other medicines and Zanedip
Tell your doctor or pharmacist if:
- You are taking or have recently taken any other medicines, including medicines obtained without a prescription.
- You are taking beta-blockers such as metoprolol, diuretics or ACE inhibitors (medicines to treat high blood pressure).
- You are taking cimetidine (more than 800 mg, a medicine for ulcer, indigestion or heartburn).
- You are taking digoxin (a medicine to treat heart problems).
- You are taking midazolam (a medicine that helps you sleep).
- You are taking rifampicin (a drug to treat tuberculosis).
- You are taking astemizole or terfenadine (medicines to treat allergies).
- You are taking amiodarone or quinidine (medicines to treat tachycardia).
- You are taking phenytoin or carbamazepine (medicines for epilepsy). Your doctor will want to monitor your blood pressure more frequently than usual.
Zanedip with food, drink and alcohol
- Do not drink alcohol while taking Zanedip tablets as it may increase the effect of the drug.
- Do not take Zanedip tablets with grapefruit or grapefruit juice.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
Zanedip must not be used if you are pregnant, think you may be pregnant or are planning to become pregnant, or if you are breast-feeding or are not using any contraceptive methods. Ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
Caution should be exercised as dizziness, weakness, tiredness and rarely somnolence may occur. Do not drive or operate machinery until you know what influence Zanedip has on you.
Zanedip contains lactose
If you have been told by your doctor that you have intolerance to some sugars, for example lactose intolerance, galactosemia or glucose / galactose malabsorption syndrome, contact your doctor before taking this medicine as the tablets contain lactose.
Dose, Method and Time of Administration How to use Zanedip: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Adults: The recommended dose is 10 mg once a day, taken at the same time each day, preferably in the morning at least 15 minutes before breakfast, as a high-fat meal significantly increases blood levels of the drug. If necessary, your doctor may advise you to increase the dose to Zanedip 20 mg once a day. The tablets should preferably be swallowed whole with some water.
Use in children: This medicine should not be used in children under 18 years of age.
Elderly patients: No daily dose adjustment is required. However, particular attention should be paid to the initiation of treatment.
Patients with liver or kidney problems: Particular attention is needed when initiating treatment in these patients and an increase in the daily dose to 20 mg should be carefully considered.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Zanedip
If you take more Zanedip than you should
Do not exceed the dose that has been prescribed for you.
If you take a higher dose than prescribed or if you have an overdose, consult your doctor immediately and, if possible, take your tablets and / or the pack with you.
Taking more than the recommended dose may cause an excessive reduction in blood pressure and the appearance of irregular heart rhythms or tachycardia. This can also lead to unconsciousness.
If you forget to take Zanedip
If you forget to take a tablet, simply skip the missed dose and then continue taking it as prescribed the next day.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Zanedip
If you stop taking Zanedip your blood pressure may rise again. Consult your doctor before stopping treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Zanedip
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be serious:
If you experience any of the following side effects, consult your doctor immediately.
Rare (affects less than 1 in 1,000 patients): angina pectoris (chest pain caused by insufficient blood supply to the heart).
Very rare (affects less than 1 in 10,000 patients): chest pain, excessive pressure reduction, fainting and allergic reactions (symptoms include itching, rash, hives).
If you have pre-existing angina pectoris, an increase in the frequency, duration and severity of angina attacks may occur with the group of medicines to which Zanedip belongs. Isolated cases of myocardial infarction can be observed.
Other possible side effects:
Uncommon (affecting less than 1 in 100 patients): headache, dizziness, tachycardia, palpitations (disordered or racing heart), sudden flushing of the face, neck and upper chest, swelling of the ankles.
Rare (affects less than 1 in 1,000 patients): drowsiness, feeling sick, vomiting, heartburn, stomach pain, diarrhea, redness of the skin, muscle pain, increased amount of urine, tiredness.
Very rare (affects less than 1 in 10,000 patients): swelling of the gums, abnormal liver function values (detected by blood tests), frequent urge to urinate.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
Store in the original package to protect the medicine from light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Zanedip contains
The active ingredient is lercanidipine hydrochloride.
Each film-coated 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).
The other ingredients are:
Tablet core: lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, povidone K30, magnesium stearate.
Film-coating: hypromellose, talc, titanium dioxide (E171), macrogol 6000, iron oxide (E172).
Description of the appearance of Zanedip and contents of the package
Zanedip 10 mg: yellow, circular, biconvex, film-coated tablet with a score line on one side. The score line on the tablet is to facilitate breaking for easier swallowing and not to divide into equal doses.
Zanedip 20 mg: Pink, circular, biconvex, film-coated tablet with a score line on one side.
ZANEDIP is available in packs of 7, 14, 28, 35, 42, 50, 56, 98 and 100 tablets. Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ZANEDIP 10 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 10 mg of lercanidipine hydrochloride (equivalent to 9.4 mg of lercanidipine).
One film-coated tablet contains 30 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow, circular, biconvex tablet, scored on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ZANEDIP is indicated in adults for the treatment of mild to moderate essential hypertension.
04.2 Posology and method of administration
Dosage
The recommended dose is 10 mg once daily orally, at least 15 minutes before meals; the dose can be increased to 20 mg, depending on the individual patient response.
Dose adjustment should be gradual as the maximum antihypertensive effect occurs within approximately 2 weeks.
In the case of patients not adequately controlled by antihypertensive monotherapy, it is possible to combine the administration of ZANEDIP with beta-blocking drugs (atenolol), diuretics (hydrochlorothiazide) or ACE inhibitors (captopril or enalapril).
Since the dose-response curve is steep and has a "plateau" at doses between 20 and 30 mg, higher doses are unlikely to induce greater efficacy while, conversely, an increase in undesirable effects may occur.
Elderly patients: Although pharmacokinetic studies and specific clinical experience did not reveal the need to modify the daily dose, particular attention is nevertheless recommended at the initiation of treatment in the elderly.
Pediatric population: The safety and efficacy of ZANEDIP in children up to 18 years of age have not been established.
No data are available.
Patients with impaired liver or kidney function: Particular caution is recommended when initiating treatment of patients with mild to moderate hepatic or renal dysfunction. The recommended posology was well tolerated by these patients, however increasing the daily dose to 20 mg should be carefully considered. In patients with hepatic impairment the antihypertensive effect may be increased and therefore a dosage adjustment should be considered.
Treatment with ZANEDIP is not recommended in patients with severe hepatic impairment or in patients with severe renal impairment (glomerular filtration rate
Method of administration
Precautions to be taken before handling or administering the medicinal product:
- The treatment should preferably be administered in the morning at least 15 minutes before breakfast.
- This product must not be administered with grapefruit juice (see sections 4.3 and 4.5).
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Pregnancy and lactation (see section 4.6).
• Women of childbearing age who do not use effective birth control coverage.
• Left ventricular ejection obstruction.
• Untreated congestive heart failure.
• Unstable angina pectoris.
• Severe changes in liver or kidney function.
• Patients who have had a heart attack for less than a month.
• Concomitant treatment with:
- potent CYP3A4 inhibitors (see section 4.5),
- ciclosporin (see section 4.5),
- grapefruit juice (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Sinus node dysfunction syndromes
Particular caution is required when ZANEDIP is administered to patients with sinus node dysfunction syndromes (without a pacemaker).
Left ventricular dysfunction and cardiac ischemia
Although controlled hemodynamic studies have shown no impairment of ventricular function, caution is required in patients with left ventricular dysfunction. It has been suggested that some short-acting dihydropyridines may increase the risk of cardiovascular morbidity in patients with cardiac ischaemia. Although ZANEDIP is a long-acting drug in such patients, caution is required.
Some dihydropyridines may rarely cause precordial pain or angina pectoris. Very rarely, there may be an increase in the frequency, duration and severity of acute anginal episodes in patients with pre-existing angina pectoris. Isolated cases of myocardial infarction may be observed (see section 4.8).
Liver or kidney dysfunction
Particular caution is recommended when initiating treatment of patients with mild to moderate hepatic or renal dysfunction. The recommended posology was well tolerated by these patients, however the increase of the daily dose to 20 mg should be carefully considered. In patients with hepatic impairment the antihypertensive effect may be increased and therefore a dosage adjustment should be considered.
Treatment with ZANEDIP is not recommended in patients with severe hepatic impairment or in patients with severe renal impairment (glomerular filtration rate
CYP3A4 inducers
CYP3A4 inducers such as anticonvulsants (eg phenytoin, carbamazepine) and rifampicin may decrease the plasma levels of lercanidipine and therefore the efficacy of lercanidipine may be less than expected (see section 4.5).
Pediatric population
The safety and efficacy of ZANEDIP have not been demonstrated in children.
Alcohol
Alcohol intake should be avoided as it may potentiate the vasodilating effect of antihypertensive drugs (see section 4.5).
Lactose
1 tablet contains 30 mg of lactose and therefore should not be administered to patients with Lapp lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
CYP3A4 inhibitors
Since lercanidipine is metabolised by the CYP3A4 enzyme, inhibitors and inducers of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine.
It should be avoided that ZANEDIP is administered concomitantly with CYP3A4 inhibitors (eg ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) (see section 4.3).
An interaction study with ketoconazole, a potent CYP3A4 inhibitor, showed a considerable increase in the plasma concentrations of lercanidipine (a 15-fold increase in AUC and 8-fold in C for the eutomer S-lercanidipine).
Cyclosporine
Ciclosporin and lercanidipine must not be administered together (see section 4.3).
Following the concomitant administration of lercanidipine and cyclosporine, an increase in plasma levels of both active substances was observed. A study in young healthy volunteers has shown that when cyclosporine is administered 3 hours after lercanidipine intake, the plasma levels of lercanidipine do not change, while the cyclosporine AUC increases by 27%. However, co-administration of ZANEDIP with cyclosporine caused a 3-fold increase in plasma levels of lercanidipine and a 21% increase in cyclosporine AUC.
Grapefruit juice
Lercanidipine must not be taken with grapefruit juice (see section 4.3).
As with other dihydropyridines, lercanidipine is sensitive to the metabolic inhibition caused by grapefruit juice, resulting in an increase in its systemic availability and an increase in its hypotensive effect.
Midazolam
When administered at a dose of 20 mg concomitantly with midazolam orally in elderly subjects, the absorption of lercanidipine is increased (by approximately 40%) and the rate of absorption decreases (tmax is delayed by 1.75 to 3 hours). Midazolam concentrations are remained unchanged.
CYP3A4 substrates
Caution should be exercised when ZANEDIP is prescribed together with other CYP3A4 substrates, such as: terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone and quinidine.
CYP3A4 inducers
Concomitant administration of ZANEDIP with CYP3A4 inducers such as anticonvulsant drugs (eg phenytoin, carbamazepine) and rifampicin should be done with caution as the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual.
Metoprolol
When ZANEDIP is administered with metoprolol, a beta-blocker eliminated primarily by the liver, the bioavailability of metoprolol is not changed, while that of lercanidipine is reduced by 50%. This effect may be due to the reduction in hepatic blood flow caused by beta-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine can be administered with beta-adrenergic receptor blockers, but the dose may need to be adjusted.
Fluoxetine
An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers aged 65 ± 7 years (mean ± s.d.), showed no clinically relevant changes in the pharmacokinetics of lercanidipine.
Cimetidine
Plasma levels of lercanidipine are not significantly changed in patients receiving concomitant treatment with cimetidine 800 mg / day, but caution is recommended at higher doses as the bioavailability and hypotensive effect of lercanidipine may increase.
Digoxin
In patients undergoing chronic treatment with b-methyldigoxine, co-administration of 20 mg of lercanidipine did not result in any pharmacokinetic interaction. Healthy volunteers treated with digoxin, following a 20 mg dose of lercanidipine administered in the fasted state, showed a mean increase of 33% in digoxin Cmax, while AUC and renal clearance were not significantly changed. Patients should be carefully monitored. concomitantly treated with digoxin to detect any signs of digoxin toxicity.
Simvastatin
Following repeated co-administration of a 20 mg dose of ZANEDIP with 40 mg of simvastatin, the AUC of lercanidipine was not significantly changed, while the AUC of simvastatin increased by 56% and that of its active metabolite. - 28% hydroxy acid. These changes are unlikely to be of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening as indicated for these medicinal products.
Warfarin
Co-administration of 20 mg of lercanidipine taken by fasted healthy volunteers does not alter the pharmacokinetics of warfarin.
Diuretics and ACE inhibitors
ZANEDIP administered with diuretics and ACE inhibitors was well tolerated.
Alcohol
Alcohol intake should be avoided as it may potentiate the vasodilating effect of antihypertensive drugs (see section 4.4).
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and breastfeeding
Pregnancy
The results of studies performed in rats and rabbits did not show a teratogenic effect of lercanidipine in these animal species, and there was no impairment of reproductive function in the rat. However, due to the lack of clinical data on the use of lercanidipine in pregnancy and lactation, and other compounds belonging to the dihydropyridine class have been shown to be teratogenic in animals, ZANEDIP should not be administered during pregnancy or to women of childbearing potential who are not using effective contraceptive coverage.
Feeding time
It is unknown whether lercanidipine / metabolites are excreted in human milk. A risk to the newborns / infants cannot be excluded. ZANEDIP is contraindicated during lactation (see section 4.3).
Fertility
No clinical data are available with lercanidipine. Reversible biochemical changes in the head of spermatozoa, which could impair fertilization, have been reported in some patients treated with calcium channel blockers. In the face of repeated unsuccessful in-vitro fertilization, and in the absence of other explanations, it is possible to attribute the cause to calcium channel blockers.
04.7 Effects on ability to drive and use machines
ZANEDIP has minor effects on the ability to drive and use machines. Therefore caution is required as dizziness, asthenia, a sense of fatigue and, more rarely, drowsiness may occur.
04.8 Undesirable effects
Adverse reactions occurred in approximately 1.8% of treated patients.
The table below shows the incidence of adverse reactions, with at least possible causation, grouped by MedDRA system organ class and sorted by frequency: very common (≥1 / 10); common (≥1 / 100,
As shown in the table, the most commonly observed adverse reactions reported in controlled clinical trials are headache, dizziness, peripheral edema, tachycardia, palpitations, flushing, each occurring in less than 1% of patients.
In the post-marketing experience, from the spontaneous reports received, the following undesirable effects have been reported very rarely (gingival hypertrophy, reversible increase in serum levels of hepatic transaminases, hypotension, urinary frequency and chest pain.
Some dihydropyridines may rarely cause precordial pain or angina pectoris. Very rarely, there may be an increase in the frequency, duration and severity of acute anginal episodes in patients with pre-existing angina pectoris. Isolated cases of myocardial infarction can be observed.
There are no negative effects of lercanidipine on blood glucose or lipemia.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In post-marketing experience, some cases of overdose (40 to 800 mg of lercanidipine, including reports of suicide attempts) have been reported.
Symptoms
As with other dihydropyridines, it is assumed that an overdose may result in excessive peripheral vasodilation. Symptoms associated with overdose include marked hypotension and reflex tachycardia.
Treatment
In case of severe hypotension, bradycardia and loss of consciousness, cardiovascular support therapy may be necessary, with intravenous administration of atropine in case of bradycardia.
Given the prolonged pharmacological effect of lercanidipine, it is essential to monitor for at least 24 hours the cardiovascular function of the patient who has taken an excessive dose of the drug. No information is available on the possible beneficial effects of dialysis. Given the high lipophilicity of the drug, it is It is very likely that plasma levels cannot be used as benchmarks for the duration of the risk period and that dialysis has no efficacy.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective calcium channel blockers with predominantly vascular effect - Dihydropyridine derivatives. ATC code: C08CA13.
Mechanism of action
Lercanidipine is a calcium channel blocker belonging to the dihydropyridine group which inhibits the flow of calcium across the cell membrane of smooth muscle and heart. The mechanism of its antihypertensive action is due to a direct relaxing effect on vascular smooth muscle, with a consequent lowering of total peripheral resistance.
Pharmacodynamic effects
Despite its short plasma half-life, lercanidipine has a prolonged antihypertensive activity, due to the high partition coefficient in the membrane, and does not cause negative inotropic effects thanks to its high vascular selectivity.
Since the vasodilation induced by ZANEDIP is characterized by a gradual onset of the effect, acute hypotension with reflex tachycardia has only rarely occurred in hypertensive patients.
As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S) -enantiomer.
Clinical efficacy and safety
In addition to clinical studies performed to support the therapeutic indication, a further randomized study in patients with severe hypertension (mean diastolic blood pressure ± sd of 114.5 ± 3.7 mmHg) showed that blood pressure normalized in 40% of 25 patients treated with a dosage of 20 mg, in a single daily administration of ZANEDIP, and in 56% of the 25 patients treated with a dosage of 10 mg twice a day. In a randomized, double-blind, placebo-controlled clinical trial in patients with isolated systolic hypertension, ZANEDIP was shown to be effective in lowering systolic blood pressure from an initial mean value of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg.
05.2 Pharmacokinetic properties
Absorption
ZANEDIP is completely absorbed after oral administration of 10-20 mg and plasma peaks of 3.30 ng / ml ± 2.09 s.d. respectively. and 7.66 ng / ml ± 5.90 d.s., are reached approximately 1.5-3 hours after administration.
The two enantiomers of lercanidipine show a similar plasma level profile: the time to obtain the maximum plasma concentration is identical, the maximum plasma concentration and AUC are, on average, 1.2 times higher for the (S) enantiomer. and the elimination half-life of the two enantiomers is essentially the same. No "in vivo" interconversion of the enantiomers was observed.
Following an elevated pre-systemic metabolism, the absolute bioavailability of ZANEDIP, given orally to fed patients, is approximately 10% and decreases to one third (1/3) when administered to healthy volunteers in the fasted state.
The availability of lercanidipine, given orally, quadruples when ZANEDIP is ingested up to 2 hours after a high-fat meal. Consequently, ZANEDIP should be administered before meals.
Distribution
Distribution from plasma to tissues and organs is rapid and extensive.
Plasma protein binding of lercanidipine is greater than 98%. In patients with severe renal or hepatic dysfunction, plasma protein levels are reduced and the free fraction of the drug may increase.
Biotransformation
ZANEDIP is extensively metabolised by CYP3A4; the drug was not detected in the urine or faeces. It is predominantly converted to inactive metabolites and approximately 50% of the dose is excreted in the urine.
"In vitro" experiments with human liver microsomes have shown that lercanidipine exerts some degree of inhibition of CYP3A4 and CYP2D6, but at concentrations 160 and 40 times, respectively, higher than those reached at peak in plasma after administration of a dose of 20 mg.
Furthermore, interaction studies in humans have shown that lercanidipine does not modify the plasma levels of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6. Therefore, at therapeutic doses, ZANEDIP is not expected to inhibit the biotransformation of drugs metabolised by CYP3A4 and CYP2D6.
Elimination
Elimination occurs essentially by biotransformation.
The mean plasma half-life that can be calculated from the terminal elimination phase is 8-10 hours and the therapeutic activity lasts 24 hours thanks to the high binding to the lipid membranes. No accumulation was found after repeated administration.
Linearity / Non-linearity
Oral administration of ZANEDIP leads to plasma levels of lercanidipine not directly proportional to dosage (non-linear kinetics). After taking 10, 20 or 40 mg the maximum plasma concentrations observed were in a ratio of 1: 3: 8 and the plasma concentration AUCs over time in a ratio of 1: 4: 18, indicating a progressive saturation of the pre-systemic metabolism Consequently, availability increases with increasing dosage.
Additional information on special populations
In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment, the pharmacokinetic behavior of lercanidipine was similar to that observed in the general patient population; higher levels (of about 70%) of the drug were found in patients with severe renal dysfunction or in dialysis patients. In patients with moderate to severe hepatic impairment, an increase in the systemic bioavailability of lercanidipine is likely as the drug is normally extensively metabolised in the liver.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.
Pharmacotoxicological studies in animals have shown no effect on the autonomic nervous system, central nervous system or gastrointestinal function at the doses commonly used to obtain the antihypertensive effect.
The relevant effects observed in long-term studies in rats and dogs are to be considered directly or indirectly related to the already known effects following the use of high doses of calcium channel blockers and mainly reflect excessive pharmacodynamic activity.
Lercanidipine is not genotoxic and has been shown to have no carcinogenic potential.
Fertility and reproductive function in the rat were not affected by lercanidipine treatment.
No teratogenic effects were found in rats and rabbits; however, lercanidipine, given in high doses in rats, induced pre- and post-implantation losses and delayed fetal development.
When given in high doses (12 mg / kg / day of the hydrochloride) during labor, lercanidipine induced dystocia.
The distribution of lercanidipine and / or its metabolites in pregnant animals and their excretion into breast milk have not been evaluated.
The metabolites have not been evaluated separately in toxicity studies.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Lactose monohydrate; microcrystalline cellulose; sodium carboxymethyl starch; povidone K30; magnesium stearate.
Coating film:
Hypromellose; talc; titanium dioxide (E171); macrogol 6000; iron oxide (E172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC and aluminum blisters.
Packs of 7, 14, 28, 35, 50, 56, 98 and 100 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
RECORDATI Chemical and Pharmaceutical Industries S.p.A. - Via Matteo Civitali 1, 20148 Milan - ITALY
08.0 MARKETING AUTHORIZATION NUMBER
ZANEDIP 14 film-coated tablets of 10 mg - AIC: 033224015
ZANEDIP 28 film-coated tablets of 10 mg - AIC: 033224027
ZANEDIP 35 film-coated tablets of 10 mg - AIC: 033224039
ZANEDIP 50 film-coated tablets of 10 mg - AIC: 033224041
ZANEDIP 100 film-coated tablets of 10 mg - AIC: 033224054
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 18 March 1997
Date of most recent renewal: 05 July 2006
10.0 DATE OF REVISION OF THE TEXT
June 2014
