UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets

PL 24668/0173-6

UKPAR

TABLE OF CONTENTS
Lay Summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 13

Steps taken after authorisation – summary Page 14

Summary of Product Characteristics

Product Information Leaflet

Labelling
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets

PL 24668/0173-6

LAY SUMMARY

On 22nd December 2009, the MHRA granted Caduceus Pharma Limited Marketing
Authorisations (licences) for Lercanidipine Hydrochloride 10mg and 20mg Film-Coated
Tablets (PL 24668/0173-6).

This medicine is used to treat mild to moderate high blood pressure, also known as
hypertension.
This medicine contains lercanidipine hydrochloride. Lercanidipine belongs to a group of
medicines called calcium channel blockers. These work by blocking the entry of calcium
into the muscle cells of the heart and the blood vessels that carry blood away from the
heart.
It is the entry of calcium into these cells that causes the heart to contract and blood vessels
to narrow. By blocking the entry of calcium, calcium channel blockers decrease contraction
of the heart and widen the blood vessels, and the blood pressure is reduced.

No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Lercanidipine Hydrochloride 10mg and 20mg Film-
Coated Tablets outweigh the risks; hence Marketing Authorisations have been granted.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets

PL 24668/0173-6

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS
Introduction Page 4

Pharmaceutical assessment Page 5

Preclinical assessment Page 8

Clinical assessment (including statistical assessment) Page 9

Overall conclusions and risk benefit assessment Page 11

UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

INTRODUCTION

The UK granted Caduceus Pharma Limited Marketing Authorisations for the medicinal
products Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets (PL
24668/0173-6) on 22nd December 2009. The products are prescription only medicines
(POM) indicated in adults (over 18 years of age) for the treatment of mild to moderate
essential hypertension.

These applications for Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets
are submitted as abridged applications according to Article 10.1 of Directive 2001/83/EC,
claiming to be generic medicinal products to Zanidip 10mg and 20mg Tablets, first
authorised in the UK to Recordati Industria Chimica e Farmaceutica S.p.A. in March 1996.

There are two duplicate applications for Lercanidipine 10mg and 20mg Film-Coated
Tablets which have been approved. The information for both sets of licences are identical.

The product contains lercanidipine which is a selective calcium channel blocker (with
mainly vascular effects).

Lercanidipine hydrochloride is a third generation dihydropyridine calcium antagonist.

Lercanidipine exists as a racemate, with anti-hypertensive activity residing primarily in the
S-enantiomer. The R-enantiomer and S-enantiomers show similar plasma profiles. No
interconversion of the enantiomers occurs in vivo.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

PHARMACEUTICAL ASSESSMENT
DRUG SUBSTANCE
Lercanidipine hydrochloride
INN: Lercanidipine hydrochloride
Chemical name: 1,4 - Dihydro - 2,6 - dimethyl - 4 - (3 -nitrophenyl) - 3,5 —
pyridinedicarboxylic acid - 2 -[(3,3 - diphenylpropyl) methylamino]
— 1,1 - dimethylethyl methyl ester hydrochloride

Structure:

Physical form: A yellow powder (crystalline form).

Solubility: Soluble in methanol and practically insoluble in water.

Molecular formula: C36H41N3O6 . HCl

Molecular weight: 648.19

Lercanidipine hydrochloride complies with in-house specifications.

A Drug Master File (DMF) has been provided covering the manufacture and control of the
drug substance lercanidipine hydrochloride.

Synthesis of the drug substance from the designated starting materials has been adequately
described, and appropriate in-process controls and intermediate specifications are applied.

Satisfactory specification tests are in place for all starting materials and reagents, and these
are supported by relevant certificates of analysis.

All potential known impurities have been identified and characterised. Appropriate proof of
structure data has been supplied for the drug substance.

An appropriate specification is provided for lercanidipine hydrochloride, with suitable test

methods and limits. Analytical methods have been appropriately validated and are
satisfactory for ensuring compliance with the relevant specifications. Batch analysis data
are provided and comply with the proposed specifications.

Satisfactory specifications and certificates of analysis have been provided for all aspects of
the container-closure system. A declaration has been provided that the primary packaging
complies with current regulations concerning contact with foodstuff.

Suitable certificates of analysis have been provided for all reference standards used.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Appropriate stability data have been generated showing lercanidipine hydrochloride to be

physically and chemically stable drugs, and supporting an appropriate retest period.

DRUG PRODUCT
Other ingredients
Other ingredients inside the tablet core are pharmaceutical excipients magnesium stearate,
povidone, sodium starch glycolate (Type A), lactose monohydrate and microcrystalline
cellulose.

The tablet film-coating consists of pharmaceutical excipients macrogol, polyvinyl alcohol,

talc, titanium dioxide (E 171) and yellow iron oxide (E 172).

For the film-coating of the 20mg Film-Coated Tablets there is an additional excipient of red
iron oxide (E 172)

All of the excipients with the exception of the excipients in the tablet film-coating comply
with their relevant European Pharmacopoeia monographs. The tablet film-coating
excipients comply with in-house specifications.

None of the excipients used contain material of animal or human origin.

The magnesium stearate contained in this product is sourced from vegetable origin and
therefore no European Pharmacopoeia Certificates of suitability for TSE is required.

The applicant has provided a declaration that milk used in the production of lactose
monohydrate is sourced from healthy animals under the same conditions as those intended
for human consumption.

No genetically modified organisms (GMO) have been used in the preparation of these
products.

Product development
The objective of the development programme was to produce products that could be
considered generic medicinal products of Zanidip 10mg and 20mg Tablets (Recordati
Industria Chimica e Farmaceutica S.p.A.).

The applicant has provided a suitable product development section. Justifications for the
use and amounts of each excipient have been provided and are valid. Comparative
dissolution and impurity profiles have been provided for the finished product versus the
reference products.

Manufacture
A description and flow-chart of the manufacturing method has been provided.

In-process controls are satisfactory based on process validation data and controls on the
finished product. Process validation has been carried out on pilot scale batches of finished
product and the results appear satisfactory. The applicant has committed to perform process
validation on future commercial-scale batches.

Finished product specification

The finished product specifications are satisfactory. Test methods have been described and
have been adequately validated, as appropriate. Batch data have been provided and comply
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

with the release specifications. Certificates of analysis for all working standards used have
been provided and are satisfactory.

Container-Closure System
The product is packaged in two types of blister packs consisting of polyvinylchloride and
aluminium, and polyvinylidene chloride and aluminium, both with push-through foil.
The product comes in pack sizes of 7, 10, 14, 20, 28, 30, 35, 50, 56, 60, 98 and 100
film-coated tablets.
The 20mg dose product has the extra pack size of 42 film-coated tablets.

Specifications and certificates of analysis have been provided. All primary product
packaging complies with EU legislation regarding contact with food.

Stability
Finished product stability studies have been conducted in accordance with current
guidelines. Based on the results, a shelf life of 2 years has been set, with storage conditions
‘Do not store above 25oC’ and ‘Store in the original package in order to protect from
moisture’. This is satisfactory.

ADMINISTRATIVE
Expert Report
A pharmaceutical expert report has been written by a suitably qualified person and is
satisfactory.

Summary of Product Characteristics (SPC)

These are pharmaceutically satisfactory.

Labelling
These are pharmaceutically satisfactory.

Patient Information Leaflet (PIL)

This is pharmaceutically satisfactory.

A package leaflet has been submitted to the MHRA along with results of consultations with
target patient groups ("user testing"), in accordance with Article 59 of Council Directive
2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and
organised, easy to understand and written in a comprehensive manner. The test shows that
the patients/users are able to act upon the information that it contains.

MAA Form
These are pharmaceutically satisfactory.

Conclusion
It is recommended that Marketing Authorisations are granted for these applications.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

PRECLINICAL ASSESSMENT
These applications for Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets are
submitted as abridged standard applications according to Article 10.1 of Directive 2001/83/EC,
claiming to be a generic medicinal products of Zanidip 10mg and 20mg Tablets, first
authorised in the UK to Recordati Industria Chimica e Farmaceutica S.p.A. in March 1996.

No new preclinical data have been supplied with these applications and none are required for
applications of this type.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY
To support the applications, the marketing authorisation holder has included a single
bioequivalence study:

An open-label, randomized, 2-treatment, 4-period, 2 sequence, single dose, crossover

bioequivalence study comparing the pharmacokinetics of Lercanidipine Hydrochloride
20mg Film-Coated Tablets (Test) versus Corifeo 20mg Tablets (Reference) under fasted
conditions.

Corifeo 20 mg Tablets licensed in Germany were used as the reference product in the
bioequivalence study. This is considered to be equivalent to the UK reference product,
Zanidip 20 mg Tablets

Blood sampling was performed pre- drug administration, during the study and up to 48 hours
post dose in each treatment period. There was a washout period of 7 days. Pharmacokinetic
parameters were measured from the plasma and statistically analysed.

Results from this study are presented below as log-transformed values:

Geometric Least Mean Squares and 90% Confidence Interval

Treatment AUC0-t AUC0-∞ Cmax

(pg/ml/h) (pg/ml/h) (pg/ml)
S-Lercanidipine:
Test (1st administration) 24773.64 25779.04 5396.34
Test (2nd administration) 35554.92 37273.53 8128.96

Reference (1st administration) 28512.33 29470.77 5885.96

Reference (2nd administration) 34096.52 35625.31 7043.96

Ratio (90% CI) 0.94 0.95 1.02

(0.86 – 1.04) (0.86 – 1.05) (0.89 – 1.16)

Treatment AUC0-t AUC0-∞ Cmax

(pg/ml/h) (pg/ml/h) (pg/ml)
R-Lercanidipine:
Test (1st administration) 26453.99 27683.67 5313.90
Test (2nd administration) 37137.92 39476.96 7896.60

Reference (1st administration) 29533.13 31229.65 5669.19

Reference (2nd administration) 35151.10 37087.59 6771.79

Ratio (90% CI) 0.97 0.97 1.03

(0.87 – 1.08) (0.87 – 1.07) (0.90 – 1.18)

The results for the primary variables indicated that the 90% confidence intervals test/reference
ratio of geometric means for AUC0-t and Cmax for both enantiomers S- and R- lercanidipine lie
within 80-125% boundaries. Thus, bioequivalence has been shown between the test and
reference products in this study.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

EFFICACY
No new data has been provided.

SAFETY
No new data has been provided.

EXPERT REPORTS
The clinical expert report has been written by a suitably qualified person and is satisfactory.

PATIENT INFORMATION LEAFLET (PIL)

This is consistent with that for the reference product and is satisfactory.

LABELLING
These are satisfactory.

APPLICATION FORMS (MAA)

These are satisfactory.

SUMMARY OF PRODUCT CHARACTERISTICS (SPC)

These are consistent with those for the reference products and are satisfactory.

DISCUSSION
The applicant has satisfactorily demonstrated bioequivalence between the test and reference
products.

MEDICAL CONCLUSION
The bioequivalence study submitted has shown that Lercanidipine Hydrochloride 10mg and
20mg Film-Coated Tablets can be considered as generic medicinal products to the originator
products Zanidip 10mg and 20mg Tablets (Recordati Industria Chimica e Farmaceutica S.p.A.).

The grant of marketing authorisations is recommended for these applications.

UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY
The important quality characteristics of Lercanidipine Hydrochloride 10mg and 20mg
Film-Coated Tablets are well-defined and controlled. The specifications and batch analytical
results indicate consistency from batch to batch. There are no outstanding quality issues that
would have a negative impact on the benefit/risk balance.

PRECLINICAL
No new preclinical data were submitted and none are required for applications of this type.

EFFICACY
Bioequivalence has been demonstrated between the applicant’s Lercanidipine Hydrochloride
20mg Film-Coated Tablets and the reference product. As these products meet all the criteria as
specified in the Note for Guidance on the investigation of bioavailability and bioequivalence
(CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study on the
Lercanidipine Hydrochloride 20mg Film-Coated Tablets can be extrapolated to Lercanidipine
Hydrochloride 10mg Film-Coated Tablets

No new or unexpected safety concerns arise from these applications.

The SPC, PIL and labelling are satisfactory and consistent with those for the reference
products.

RISK BENEFIT ASSESSMENT

The quality of the products is acceptable and no new preclinical or clinical safety concerns
have been identified. The bioequivalence study supports the claim that the applicant’s products
and the reference products are interchangeable. Extensive clinical experience with lercanidipine
is considered to have demonstrated the therapeutic value of the compound. The benefit/risk is,
therefore, considered to be positive.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets

PL 24668/0173-6

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation applications on 26th February

2008.

2 Following standard checks and communication with the applicant the MHRA
considered the applications valid on 13th March 2008.

3 Following assessment of the applications, the MHRA requested further

information on the clinical sections of the dossier on 4th August 2008 and 31st
March 2009.

4 The applicant responded to the MHRA’s requests, providing further information

on the clinical sections of the dossier on 27th January 2009 and 23rd June 2009.

5 The applications were determined on 22nd December 2009.

UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets

PL 24668/0173-6

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date Application Scope Outcome

submitted type
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lercanidipine Hydrochloride 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 10 mg lercanidipine hydrochloride, equivalent to 9.4 mg lercanidipine.
Excipient:
Lercanidipine Hydrochloride 10 mg film-coated tablets: Lactose monohydrate 30 mg
For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Film-coated tablets
Lercanidipine Hydrochloride 10 mg film-coated tablets: Yellow, round, biconvex 6.5 mm film-coated
tablets, scored on one side, marked 'L' on the other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Lercanidipine is indicated for the treatment of mild to moderate essential hypertension.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be
increased to 20 mg depending on the individual patient's response.

Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive
effect is apparent.

Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the
addition of lercandipine to therapy with a beta-adrenoreceptor blocking drug, a diuretic
(hydrochlorothiazide) or an angiotensin converting enzyme inhibitor.

Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that
efficacy will be improved by higher doses; whereas side effects may increase.

Elderly
Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage
is required, special care should be exercised when initiating treatment in the elderly.

Children and adolescents

Lercanidipine is not recommended for use in children and adolescents below the age of 18 years as there
is no clinical experience.

Renal insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate renal
impairment. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20mg daily must be approached with caution.
Lercanidipine is not recommended for use in patients with severe renal impairment (GFR < 30 ml/min).

Hepatic insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate hepatic
dysfunction. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients
with hepatic impairment and consequently an adjustment of the dosage should be considered.

Administration
The tablets should be taken with some water before a meal.

4.3 CONTRAINDICATIONS
- Hypersensitivity to lercanidipine, to any dihydropyridine or to any of the excipients.
- Left ventricular outflow tract obstruction.
- Untreated congestive cardiac failure.
- Unstable angina pectoris.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

- Within 1 month of a myocardial infarction.

- Severe renal or hepatic impairment.
- Pregnancy and lactation (see section 4.6).
- Women of child-bearing potential unless effective contraception is used.
- Strong inhibitors of CYP3A4 (see section 4.5).
- Cyclosporin (see section 4.5).
- Grapefruit juice (see section 4.5).

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Sick sinus syndrome
Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a
pacemaker is not in situ). Although hemodynamic controlled studies revealed no impairment of
ventricular function, care is also required in patients with LV dysfunction. It has been suggested that
some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with
ischaemic heart disease. Although lercanidipine is long-acting caution is required in such patients.

Angina pectoris
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.
Isolated cases of myocardial infarction may be observed (see 4.8).

Use in renal or hepatic dysfunction:

Special care should be exercised when treatment is commenced in patients with mild to moderate renal or
hepatic dysfunction. Although the usually recommended dose schedule may be tolerated by these
subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive
effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the
dosage should be considered.

Lercanidipine is not recommended for use in patients with severe hepatic impairment or in patients with
severe renal impairment (GFR < 30 ml/min) (see 4.2).
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see
4.5).

CYP3A4 inducers
Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce
lercanidipine's plasma levels and therefore the efficacy of lercanidipine may be less than expected (see
section 4.5).

This medicinal product contains lactose monohydrate and therefore should not be administered to patients
with Lapp lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION
Metabolic interactions
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and, therefore, inhibitors and inducers
of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine.

CYP3A4 inhibitors
Co-administration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir,
erythromycin, troleandomycin) should be avoided (see 4.3).
An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in
plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the
eutomer S-lercanidipine).

Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant
administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3
hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of
ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has
caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice,

with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should
not be taken with grapefruit juice.

When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers,

lercanidipine's absorption was increased (by approximately 40%) and the rate of absorption was
decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.

CYP3A4 inducers
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin,
carbamazepine), rifampicin should be approached with caution since the antihypertensive effect may be
reduced and blood pressure should be monitored more frequently than usual.

CYP3A4 substrates
Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a
mean increase of 33% in digoxin Cmax , while AUC and renal clearance were not significantly modified.
Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin
toxicity.
Co-administration of 20 mg lercanidipine in patients chronically treated with b-methyldigoxin showed no
evidence of pharmacokinetic interaction.

Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in
plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the
hypotensive effect of lercanidipine may be increased.

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of
an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the
pharmacokinetics of lercanidipine.

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the
pharmacokinetics of warfarin.

Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like
terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine.

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Other interactions
When lercanidipine was co-administered with metoprolol, β-blocker eliminated mainly by the liver, the
bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This
effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore
occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta-
adrenoceptor blocking drugs, but dose adjustment may be required.

When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the

AUC of lercanidipine was not significantly modified, while simvastatin's AUC increased by 56% and that
of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance.
No interaction is expected when lercanidipine is administered in the morning and simvastatin in the
evening, as indicated for such drug.

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

4.6 PREGNANCY AND LACTATION

Pregnancy
There are no adequate data from the use of lercanidipine in pregnant women. Non-clinical data provide
no evidence of a teratogenic effect in the rat and the rabbit and reproductive performance in the rat was
unimpaired. Since other dihydropyridine compounds have been found teratogenic in animals,
lercanidipine should not be administered during pregnancy or to women with child-bearing potential
unless effective contraception is used.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Lactation
Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore, it should
not be administered to nursing mothers.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Lercanidipine has no or negligible influence on the ability to drive and use machines. However, caution
should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

4.8 UNDESIRABLE EFFECTS

The following undesirable effects have been reported in clinical studies and in the post-marketing phase:

Assessment of frequencies:
Very common: ≥1/10
Common: ≥ 1/100, < 1/10
Uncommon: ≥ 1/1,000, < 1/100
Rare: ≥ 1/10,000, < 1/1,000
Very rare: < 1/10,000, cannot be estimated from the available data

Investigations
Very rare: reversible increases in serum levels of hepatic transaminases

Cardiac disorders
Uncommon: tachycardia; palpitations, peripheral oedema
Rare: angina pectoris
Very rare: chest pain, myocardial infarction, hypotension
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.

Nervous system disorders

Uncommon: headache; dizziness

Gastrointestinal disorders
Rare: nausea; dyspepsia; diarrhoea; abdominal pain; vomiting
Very rare: gingival hypertrophy

Renal and urinary disorders

Rare: polyuria
Very rare: urinary frequency

Skin and subcutaneous tissue disorders

Rare: rash

Musculoskeletal and connective tissue disorders

Rare: myalgia

Vascular disorders
Uncommon: flushing

General disorders and administration site conditions

Rare: asthenia; fatigue

Immune system disorders

Very rare: hypersensitivity

Psychiatric disorders
Rare: somnolence

Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

4.9 OVERDOSE
In the post-marketing experience, three cases of overdose were reported (150 mg, 280 mg and 800 mg of
lercanidipine, respectively, ingested in an attempt to commit suicide).
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Dose level Signs/Symptoms Management Outcome

150 mg Sleepiness Gastric lavage Recovered
+ Active charcoal
undefined
amount of
alcohol
280 mg Cardiogenic shock High-dose catecholamines Recovered
+ Severe myocardial ischaemia Furosemide
5.6 mg Mild renal failure Digitalis
moxonidine Parenteral plasma expanders

800 mg Emesis Active charcoal Recovered

Hypotention Cathartics
Dopamine i.v.

As with other dihydropyridines, overdosage might be expected to cause excessive peripheral

vasodilatation with marked hypotension and reflex tachycardia. In case of severe hypotension,
bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for
bradycardia.

In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular
status of patients who take an overdose is monitored for 24 hours at least. There is no information on the
value of dialysis. Since the drug is highly lipophilic, it is most probable that plasma levels are no guide to
the duration of the period of risk and dialysis may not be effective.

5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects
ATC Code: C08CA13

Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx
of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a
direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its
short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive
activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due
to its high vascular selectivity.

Since the vasodilatation induced by lercanidipine is gradual in onset, acute hypotension with reflex
tachycardia has rarely been observed in hypertensive patients.

As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due
to its (S)-enantiomer.

In addition to the clinical studies conducted to support the therapeutic indications, a further small
uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood
pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on
20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a
double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension
lercanidipine was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6
mmHg to 140.2 ± 8.7 mmHg.

5.2 PHARMACOKINETIC PROPERTIES

Absorption
Lercanidipine is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30
ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. respectively, occur about 1.5-3 hours after dosing.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma
concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for
the (S) enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No "in
vivo" interconversion of enantiomers is observed.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Due to the high first pass metabolism, the absolute bioavailability of lercanidipine orally administered to
patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy
volunteers under fasting conditions.

Oral administration of lercanidipine leads to plasma levels of lercanidipine not directly proportional to
dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the
ratio 1:3:8 and areas under plasma concentration-time curves in the ratio 1:4:18, suggesting a progressive
saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high
fat meal. Accordingly, lercanidipine should be taken before meals.

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

The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are
reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be
increased.

Metabolism
Lercanidipine is extensively metabolised by CYP3A4; no parent drug is found in the urine or the faeces.
It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine.

In vitro-experiments with human liver microsomes have demonstrated that lercanidipine shows some
degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher
than those reached at peak in the plasma after the dose of 20 mg.

Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels
of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6.
Therefore, inhibition of biotransformation of drugs metabolised by CYP3A4 and CYP2D6 by
lercanidipine is not expected at therapeutic doses.

Elimination
Elimination occurs essentially by biotransformation.
A mean terminal elimination half life of 8-10 hours was calculated and the therapeutical activity lasts for
24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated
administration.

Elderly, renal and hepatic insufficiency

In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic
impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in
the general patient population; patients with severe renal dysfunction or dialysis-dependent patients
showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment,
the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally
metabolised extensively in the liver.

5.3 PRECLINICAL SAFETY DATA

Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the
central nervous system or on gastrointestinal function at antihypertensive doses.

The relevant effects which have been observed in long-term studies in rats and dogs were related, directly
or indirectly, to the known effects of high doses of Ca-antagonists, predominantly reflecting exaggerated
pharmacodynamic activity.

Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard.

Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine.
There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high
dose levels induced pre- and post- implantation losses and delay in foetal development.
Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced
dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast
milk have not been investigated.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Metabolites have not been evaluated separately in toxicity studies.

6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Tablet core:
Magnesium stearate
Povidone
Sodium starch glycolate (Type A)
Lactose monohydrate
Cellulose, microcrystalline

Film-coating:
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E 171)
Yellow iron oxide (E 172)

6.2 INCOMPATIBILITIES
Not applicable.

6.3 SHELF LIFE

2 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Al/PVC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.
Al/PVDC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 NATURE AND CONTENTS OF CONTAINER

Blister pack (Aluminium/PVC) with push-through foil.
Blister pack (Aluminium/PVDC) with push-through foil.

Pack sizes: 7, 10, 14, 20, 28, 30, 35, 50, 56, 60, 98, 100 film-coated tablets
Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Ltd
6th Floor
94 Wigmore Street
London
W1U 3RF
UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0173

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/2009

10 DATE OF REVISION OF THE TEXT

22/12/2009
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

1 NAME OF THE MEDICINAL PRODUCT

Lercanidipine Hydrochloride 20 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 20 mg lercanidipine hydrochloride, equivalent to 18.8 mg lercanidipine.
Excipient:
Lercanidipine Hydrochloride 20 mg film-coated tablets: Lactose monohydrate 60 mg
For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Film-coated tablets
Lercanidipine Hydrochloride 20 mg film-coated tablets: Pink, round, biconvex 8.5 mm film-coated
tablets, scored on one side, marked 'L' on the other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Lercanidipine is indicated for the treatment of mild to moderate essential hypertension.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be
increased to 20 mg depending on the individual patient's response.

Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive
effect is apparent.

Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the
addition of lercandipine to therapy with a beta-adrenoreceptor blocking drug, a diuretic
(hydrochlorothiazide) or an angiotensin converting enzyme inhibitor.

Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that
efficacy will be improved by higher doses; whereas side effects may increase.

Elderly
Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage
is required, special care should be exercised when initiating treatment in the elderly.

Children and adolescents

Lercanidipine is not recommended for use in children and adolescents below the age of 18 years as there
is no clinical experience.

Renal insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate renal
impairment. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20mg daily must be approached with caution.
Lercanidipine is not recommended for use in patients with severe renal impairment (GFR < 30 ml/min).

Hepatic insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate hepatic
dysfunction. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients
with hepatic impairment and consequently an adjustment of the dosage should be considered.

Administration
The tablets should be taken with some water before a meal.

4.3 CONTRAINDICATIONS
- Hypersensitivity to lercanidipine, to any dihydropyridine or to any of the excipients.
- Left ventricular outflow tract obstruction.
- Untreated congestive cardiac failure.
- Unstable angina pectoris.
- Within 1 month of a myocardial infarction.
- Severe renal or hepatic impairment.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

- Pregnancy and lactation (see section 4.6).

- Women of child-bearing potential unless effective contraception is used.
- Strong inhibitors of CYP3A4 (see section 4.5).
- Cyclosporin (see section 4.5).
- Grapefruit juice (see section 4.5).

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Sick sinus syndrome
Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a
pacemaker is not in situ). Although hemodynamic controlled studies revealed no impairment of
ventricular function, care is also required in patients with LV dysfunction. It has been suggested that
some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with
ischaemic heart disease. Although lercanidipine is long-acting caution is required in such patients.

Angina pectoris
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.
Isolated cases of myocardial infarction may be observed (see 4.8).

Use in renal or hepatic dysfunction:

Special care should be exercised when treatment is commenced in patients with mild to moderate renal or
hepatic dysfunction. Although the usually recommended dose schedule may be tolerated by these
subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive
effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the
dosage should be considered.

Lercanidipine is not recommended for use in patients with severe hepatic impairment or in patients with
severe renal impairment (GFR < 30 ml/min) (see 4.2).
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see
4.5).

CYP3A4 inducers
Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce
lercanidipine's plasma levels and therefore the efficacy of lercanidipine may be less than expected (see
section 4.5).

This medicinal product contains lactose monohydrate and therefore should not be administered to patients
with Lapp lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION
Metabolic interactions
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and, therefore, inhibitors and inducers
of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine.

CYP3A4 inhibitors
Co-administration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir,
erythromycin, troleandomycin) should be avoided (see 4.3).
An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in
plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the
eutomer S-lercanidipine).

Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant
administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3
hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of
ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has
caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together.

As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice,

with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should
not be taken with grapefruit juice.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers,

lercanidipine's absorption was increased (by approximately 40%) and the rate of absorption was
decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.

CYP3A4 inducers
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin,
carbamazepine), rifampicin should be approached with caution since the antihypertensive effect may be
reduced and blood pressure should be monitored more frequently than usual.

CYP3A4 substrates
Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a
mean increase of 33% in digoxin Cmax , while AUC and renal clearance were not significantly modified.
Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin
toxicity.
Co-administration of 20 mg lercanidipine in patients chronically treated with b-methyldigoxin showed no
evidence of pharmacokinetic interaction.

Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in
plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the
hypotensive effect of lercanidipine may be increased.

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of
an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the
pharmacokinetics of lercanidipine.

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the
pharmacokinetics of warfarin.

Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like
terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine.

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Other interactions
When lercanidipine was co-administered with metoprolol, β-blocker eliminated mainly by the liver, the
bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This
effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore
occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta-
adrenoceptor blocking drugs, but dose adjustment may be required.

When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the

AUC of lercanidipine was not significantly modified, while simvastatin's AUC increased by 56% and that
of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance.
No interaction is expected when lercanidipine is administered in the morning and simvastatin in the
evening, as indicated for such drug.

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

4.6 PREGNANCY AND LACTATION

Pregnancy
There are no adequate data from the use of lercanidipine in pregnant women. Non-clinical data provide
no evidence of a teratogenic effect in the rat and the rabbit and reproductive performance in the rat was
unimpaired. Since other dihydropyridine compounds have been found teratogenic in animals,
lercanidipine should not be administered during pregnancy or to women with child-bearing potential
unless effective contraception is used.

Lactation
Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore, it should
not be administered to nursing mothers.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Lercanidipine has no or negligible influence on the ability to drive and use machines. However, caution
should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

4.8 UNDESIRABLE EFFECTS

The following undesirable effects have been reported in clinical studies and in the post-marketing phase:

Assessment of frequencies:
Very common: ≥1/10
Common: ≥ 1/100, < 1/10
Uncommon: ≥ 1/1,000, < 1/100
Rare: ≥ 1/10,000, < 1/1,000
Very rare: < 1/10,000, cannot be estimated from the available data

Investigations
Very rare: reversible increases in serum levels of hepatic transaminases

Cardiac disorders
Uncommon: tachycardia; palpitations, peripheral oedema
Rare: angina pectoris
Very rare: chest pain, myocardial infarction, hypotension
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.

Nervous system disorders

Uncommon: headache; dizziness

Gastrointestinal disorders
Rare: nausea; dyspepsia; diarrhoea; abdominal pain; vomiting
Very rare: gingival hypertrophy

Renal and urinary disorders

Rare: polyuria
Very rare: urinary frequency

Skin and subcutaneous tissue disorders

Rare: rash

Musculoskeletal and connective tissue disorders

Rare: myalgia

Vascular disorders
Uncommon: flushing

General disorders and administration site conditions

Rare: asthenia; fatigue

Immune system disorders

Very rare: hypersensitivity

Psychiatric disorders
Rare: somnolence

Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

4.9 OVERDOSE
In the post-marketing experience, three cases of overdose were reported (150 mg, 280 mg and 800 mg of
lercanidipine, respectively, ingested in an attempt to commit suicide).

Dose level Signs/Symptoms Management Outcome

150 mg Sleepiness Gastric lavage Recovered
+ Active charcoal
undefined
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

amount of
alcohol
280 mg Cardiogenic shock High-dose catecholamines Recovered
+ Severe myocardial ischaemia Furosemide
5.6 mg Mild renal failure Digitalis
moxonidine Parenteral plasma expanders

800 mg Emesis Active charcoal Recovered

Hypotention Cathartics
Dopamine i.v.

As with other dihydropyridines, overdosage might be expected to cause excessive peripheral

vasodilatation with marked hypotension and reflex tachycardia. In case of severe hypotension,
bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for
bradycardia.

In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular
status of patients who take an overdose is monitored for 24 hours at least. There is no information on the
value of dialysis. Since the drug is highly lipophilic, it is most probable that plasma levels are no guide to
the duration of the period of risk and dialysis may not be effective.

5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects
ATC Code: C08CA13

Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx
of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a
direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its
short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive
activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due
to its high vascular selectivity.

Since the vasodilatation induced by lercanidipine is gradual in onset, acute hypotension with reflex
tachycardia has rarely been observed in hypertensive patients.

As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due
to its (S)-enantiomer.

In addition to the clinical studies conducted to support the therapeutic indications, a further small
uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood
pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on
20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a
double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension
lercanidipine was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6
mmHg to 140.2 ± 8.7 mmHg.

5.2 PHARMACOKINETIC PROPERTIES

Absorption
Lercanidipine is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30
ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. respectively, occur about 1.5-3 hours after dosing.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma
concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for
the (S) enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No "in
vivo" interconversion of enantiomers is observed.

Due to the high first pass metabolism, the absolute bioavailability of lercanidipine orally administered to
patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy
volunteers under fasting conditions.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Oral administration of lercanidipine leads to plasma levels of lercanidipine not directly proportional to
dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the
ratio 1:3:8 and areas under plasma concentration-time curves in the ratio 1:4:18, suggesting a progressive
saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high
fat meal. Accordingly, lercanidipine should be taken before meals.

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

The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are
reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be
increased.

Metabolism
Lercanidipine is extensively metabolised by CYP3A4; no parent drug is found in the urine or the faeces.
It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine.

In vitro-experiments with human liver microsomes have demonstrated that lercanidipine shows some
degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher
than those reached at peak in the plasma after the dose of 20 mg.

Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels
of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6.
Therefore, inhibition of biotransformation of drugs metabolised by CYP3A4 and CYP2D6 by
lercanidipine is not expected at therapeutic doses.

Elimination
Elimination occurs essentially by biotransformation.
A mean terminal elimination half life of 8-10 hours was calculated and the therapeutical activity lasts for
24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated
administration.

Elderly, renal and hepatic insufficiency

In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic
impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in
the general patient population; patients with severe renal dysfunction or dialysis-dependent patients
showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment,
the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally
metabolised extensively in the liver.

5.3 PRECLINICAL SAFETY DATA

Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the
central nervous system or on gastrointestinal function at antihypertensive doses.

The relevant effects which have been observed in long-term studies in rats and dogs were related, directly
or indirectly, to the known effects of high doses of Ca-antagonists, predominantly reflecting exaggerated
pharmacodynamic activity.

Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard.

Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine.
There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high
dose levels induced pre- and post- implantation losses and delay in foetal development.
Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced
dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast
milk have not been investigated.
Metabolites have not been evaluated separately in toxicity studies.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Tablet core:
Magnesium stearate
Povidone
Sodium starch glycolate (Type A)
Lactose monohydrate
Cellulose, microcrystalline

Film-coating:
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E 171)
Iron oxide, yellow (E 172)
Iron oxide, red (E 172)

6.2 INCOMPATIBILITIES
Not applicable.

6.3 SHELF LIFE

2 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Al/PVC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.
Al/PVDC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 NATURE AND CONTENTS OF CONTAINER

Blister pack (Aluminium/PVC) with push-through foil.
Blister pack (Aluminium/PVDC) with push-through foil.

Pack sizes: 7, 10, 14, 20, 28, 30, 35, 42, 50, 56, 60, 98, 100 film-coated tablets
Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Ltd
6th Floor
94 Wigmore Street
London
W1U 3RF
UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0174

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/2009

10 DATE OF REVISION OF THE TEXT

22/12/2009
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

1 NAME OF THE MEDICINAL PRODUCT

Lercanidipine Hydrochloride 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 10 mg lercanidipine hydrochloride, equivalent to 9.4 mg lercanidipine.
Excipient:
Lercanidipine Hydrochloride 10 mg film-coated tablets: Lactose monohydrate 30 mg
For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Film-coated tablets
Lercanidipine Hydrochloride 10 mg film-coated tablets: Yellow, round, biconvex 6.5 mm film-coated
tablets, scored on one side, marked 'L' on the other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Lercanidipine is indicated for the treatment of mild to moderate essential hypertension.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be
increased to 20 mg depending on the individual patient's response.

Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive
effect is apparent.

Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the
addition of lercandipine to therapy with a beta-adrenoreceptor blocking drug, a diuretic
(hydrochlorothiazide) or an angiotensin converting enzyme inhibitor.

Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that
efficacy will be improved by higher doses; whereas side effects may increase.

Elderly
Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage
is required, special care should be exercised when initiating treatment in the elderly.

Children and adolescents

Lercanidipine is not recommended for use in children and adolescents below the age of 18 years as there
is no clinical experience.

Renal insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate renal
impairment. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20mg daily must be approached with caution.
Lercanidipine is not recommended for use in patients with severe renal impairment (GFR < 30 ml/min).

Hepatic insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate hepatic
dysfunction. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients
with hepatic impairment and consequently an adjustment of the dosage should be considered.

Administration
The tablets should be taken with some water before a meal.

4.3 CONTRAINDICATIONS
- Hypersensitivity to lercanidipine, to any dihydropyridine or to any of the excipients.
- Left ventricular outflow tract obstruction.
- Untreated congestive cardiac failure.
- Unstable angina pectoris.
- Within 1 month of a myocardial infarction.
- Severe renal or hepatic impairment.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

- Pregnancy and lactation (see section 4.6).

- Women of child-bearing potential unless effective contraception is used.
- Strong inhibitors of CYP3A4 (see section 4.5).
- Cyclosporin (see section 4.5).
- Grapefruit juice (see section 4.5).

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Sick sinus syndrome
Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a
pacemaker is not in situ). Although hemodynamic controlled studies revealed no impairment of
ventricular function, care is also required in patients with LV dysfunction. It has been suggested that
some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with
ischaemic heart disease. Although lercanidipine is long-acting caution is required in such patients.

Angina pectoris
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.
Isolated cases of myocardial infarction may be observed (see 4.8).

Use in renal or hepatic dysfunction:

Special care should be exercised when treatment is commenced in patients with mild to moderate renal or
hepatic dysfunction. Although the usually recommended dose schedule may be tolerated by these
subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive
effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the
dosage should be considered.

Lercanidipine is not recommended for use in patients with severe hepatic impairment or in patients with
severe renal impairment (GFR < 30 ml/min) (see 4.2).
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see
4.5).

CYP3A4 inducers
Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce
lercanidipine's plasma levels and therefore the efficacy of lercanidipine may be less than expected (see
section 4.5).

This medicinal product contains lactose monohydrate and therefore should not be administered to patients
with Lapp lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION
Metabolic interactions
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and, therefore, inhibitors and inducers
of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine.

CYP3A4 inhibitors
Co-administration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir,
erythromycin, troleandomycin) should be avoided (see 4.3).
An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in
plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the
eutomer S-lercanidipine).

Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant
administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3
hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of
ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has
caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together.

As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice,

with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should
not be taken with grapefruit juice.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers,

lercanidipine's absorption was increased (by approximately 40%) and the rate of absorption was
decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.

CYP3A4 inducers
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin,
carbamazepine), rifampicin should be approached with caution since the antihypertensive effect may be
reduced and blood pressure should be monitored more frequently than usual.

CYP3A4 substrates
Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a
mean increase of 33% in digoxin Cmax , while AUC and renal clearance were not significantly modified.
Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin
toxicity.
Co-administration of 20 mg lercanidipine in patients chronically treated with b-methyldigoxin showed no
evidence of pharmacokinetic interaction.

Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in
plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the
hypotensive effect of lercanidipine may be increased.

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of
an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the
pharmacokinetics of lercanidipine.

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the
pharmacokinetics of warfarin.

Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like
terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine.

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Other interactions
When lercanidipine was co-administered with metoprolol, β-blocker eliminated mainly by the liver, the
bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This
effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore
occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta-
adrenoceptor blocking drugs, but dose adjustment may be required.

When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the

AUC of lercanidipine was not significantly modified, while simvastatin's AUC increased by 56% and that
of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance.
No interaction is expected when lercanidipine is administered in the morning and simvastatin in the
evening, as indicated for such drug.

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

4.6 PREGNANCY AND LACTATION

Pregnancy
There are no adequate data from the use of lercanidipine in pregnant women. Non-clinical data provide
no evidence of a teratogenic effect in the rat and the rabbit and reproductive performance in the rat was
unimpaired. Since other dihydropyridine compounds have been found teratogenic in animals,
lercanidipine should not be administered during pregnancy or to women with child-bearing potential
unless effective contraception is used.

Lactation
Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore, it should
not be administered to nursing mothers.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Lercanidipine has no or negligible influence on the ability to drive and use machines. However, caution
should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

4.8 UNDESIRABLE EFFECTS

The following undesirable effects have been reported in clinical studies and in the post-marketing phase:

Assessment of frequencies:
Very common: ≥1/10
Common: ≥ 1/100, < 1/10
Uncommon: ≥ 1/1,000, < 1/100
Rare: ≥ 1/10,000, < 1/1,000
Very rare: < 1/10,000, cannot be estimated from the available data

Investigations
Very rare: reversible increases in serum levels of hepatic transaminases

Cardiac disorders
Uncommon: tachycardia; palpitations, peripheral oedema
Rare: angina pectoris
Very rare: chest pain, myocardial infarction, hypotension
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.

Nervous system disorders

Uncommon: headache; dizziness

Gastrointestinal disorders
Rare: nausea; dyspepsia; diarrhoea; abdominal pain; vomiting
Very rare: gingival hypertrophy

Renal and urinary disorders

Rare: polyuria
Very rare: urinary frequency

Skin and subcutaneous tissue disorders

Rare: rash

Musculoskeletal and connective tissue disorders

Rare: myalgia

Vascular disorders
Uncommon: flushing

General disorders and administration site conditions

Rare: asthenia; fatigue

Immune system disorders

Very rare: hypersensitivity

Psychiatric disorders
Rare: somnolence

Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

4.9 OVERDOSE
In the post-marketing experience, three cases of overdose were reported (150 mg, 280 mg and 800 mg of
lercanidipine, respectively, ingested in an attempt to commit suicide).

Dose level Signs/Symptoms Management Outcome

150 mg Sleepiness Gastric lavage Recovered
+ Active charcoal
undefined
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

amount of
alcohol
280 mg Cardiogenic shock High-dose catecholamines Recovered
+ Severe myocardial ischaemia Furosemide
5.6 mg Mild renal failure Digitalis
moxonidine Parenteral plasma expanders

800 mg Emesis Active charcoal Recovered

Hypotention Cathartics
Dopamine i.v.

As with other dihydropyridines, overdosage might be expected to cause excessive peripheral

vasodilatation with marked hypotension and reflex tachycardia. In case of severe hypotension,
bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for
bradycardia.

In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular
status of patients who take an overdose is monitored for 24 hours at least. There is no information on the
value of dialysis. Since the drug is highly lipophilic, it is most probable that plasma levels are no guide to
the duration of the period of risk and dialysis may not be effective.

5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects
ATC Code: C08CA13

Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx
of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a
direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its
short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive
activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due
to its high vascular selectivity.

Since the vasodilatation induced by lercanidipine is gradual in onset, acute hypotension with reflex
tachycardia has rarely been observed in hypertensive patients.

As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due
to its (S)-enantiomer.

In addition to the clinical studies conducted to support the therapeutic indications, a further small
uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood
pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on
20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a
double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension
lercanidipine was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6
mmHg to 140.2 ± 8.7 mmHg.

5.2 PHARMACOKINETIC PROPERTIES

Absorption
Lercanidipine is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30
ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. respectively, occur about 1.5-3 hours after dosing.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma
concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for
the (S) enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No "in
vivo" interconversion of enantiomers is observed.

Due to the high first pass metabolism, the absolute bioavailability of lercanidipine orally administered to
patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy
volunteers under fasting conditions.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

Oral administration of lercanidipine leads to plasma levels of lercanidipine not directly proportional to
dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the
ratio 1:3:8 and areas under plasma concentration-time curves in the ratio 1:4:18, suggesting a progressive
saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high
fat meal. Accordingly, lercanidipine should be taken before meals.

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

The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are
reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be
increased.

Metabolism
Lercanidipine is extensively metabolised by CYP3A4; no parent drug is found in the urine or the faeces.
It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine.

In vitro-experiments with human liver microsomes have demonstrated that lercanidipine shows some
degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher
than those reached at peak in the plasma after the dose of 20 mg.

Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels
of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6.
Therefore, inhibition of biotransformation of drugs metabolised by CYP3A4 and CYP2D6 by
lercanidipine is not expected at therapeutic doses.

Elimination
Elimination occurs essentially by biotransformation.
A mean terminal elimination half life of 8-10 hours was calculated and the therapeutical activity lasts for
24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated
administration.

Elderly, renal and hepatic insufficiency

In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic
impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in
the general patient population; patients with severe renal dysfunction or dialysis-dependent patients
showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment,
the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally
metabolised extensively in the liver.

5.3 PRECLINICAL SAFETY DATA

Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the
central nervous system or on gastrointestinal function at antihypertensive doses.

The relevant effects which have been observed in long-term studies in rats and dogs were related, directly
or indirectly, to the known effects of high doses of Ca-antagonists, predominantly reflecting exaggerated
pharmacodynamic activity.

Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard.

Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine.
There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high
dose levels induced pre- and post- implantation losses and delay in foetal development.
Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced
dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast
milk have not been investigated.
Metabolites have not been evaluated separately in toxicity studies.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Tablet core:
Magnesium stearate
Povidone
Sodium starch glycolate (Type A)
Lactose monohydrate
Cellulose, microcrystalline

Film-coating:
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E 171)
Yellow iron oxide (E 172)

6.2 INCOMPATIBILITIES
Not applicable.

6.3 SHELF LIFE

2 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Al/PVC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.
Al/PVDC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 NATURE AND CONTENTS OF CONTAINER

Blister pack (Aluminium/PVC) with push-through foil.
Blister pack (Aluminium/PVDC) with push-through foil.

Pack sizes: 7, 10, 14, 20, 28, 30, 35, 50, 56, 60, 98, 100 film-coated tablets
Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Ltd
6th Floor
94 Wigmore Street
London
W1U 3RF
UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0175

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/2009

10 DATE OF REVISION OF THE TEXT

22/12/2009
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

1 NAME OF THE MEDICINAL PRODUCT

Lercanidipine Hydrochloride 20 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 20 mg lercanidipine hydrochloride, equivalent to 18.8 mg lercanidipine.
Excipient:
Lercanidipine Hydrochloride 20 mg film-coated tablets: Lactose monohydrate 60 mg
For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Film-coated tablets
Lercanidipine Hydrochloride 20 mg film-coated tablets: Pink, round, biconvex 8.5 mm film-coated
tablets, scored on one side, marked 'L' on the other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Lercanidipine is indicated for the treatment of mild to moderate essential hypertension.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION

The recommended dosage is 10 mg orally once a day at least 15 minutes before meals; the dose may be
increased to 20 mg depending on the individual patient's response.

Dose titration should be gradual, because it may take about 2 weeks before the maximal antihypertensive
effect is apparent.

Some individuals, not adequately controlled on a single antihypertensive agent, may benefit from the
addition of lercandipine to therapy with a beta-adrenoreceptor blocking drug, a diuretic
(hydrochlorothiazide) or an angiotensin converting enzyme inhibitor.

Since the dose-response curve is steep with a plateau at doses between 20-30 mg, it is unlikely that
efficacy will be improved by higher doses; whereas side effects may increase.

Elderly
Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dosage
is required, special care should be exercised when initiating treatment in the elderly.

Children and adolescents

Lercanidipine is not recommended for use in children and adolescents below the age of 18 years as there
is no clinical experience.

Renal insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate renal
impairment. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20mg daily must be approached with caution.
Lercanidipine is not recommended for use in patients with severe renal impairment (GFR < 30 ml/min).

Hepatic insufficiency
Special care should be exercised when treatment is commenced in patients with mild to moderate hepatic
dysfunction. Although the usually recommended dose schedule may be tolerated, an increase in dose to
20 mg daily must be approached with caution. The antihypertensive effect may be enhanced in patients
with hepatic impairment and consequently an adjustment of the dosage should be considered.

Administration
The tablets should be taken with some water before a meal.

4.3 CONTRAINDICATIONS
- Hypersensitivity to lercanidipine, to any dihydropyridine or to any of the excipients.
- Left ventricular outflow tract obstruction.
- Untreated congestive cardiac failure.
- Unstable angina pectoris.
- Within 1 month of a myocardial infarction.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

- Severe renal or hepatic impairment.

- Pregnancy and lactation (see section 4.6).
- Women of child-bearing potential unless effective contraception is used.
- Strong inhibitors of CYP3A4 (see section 4.5).
- Cyclosporin (see section 4.5).
- Grapefruit juice (see section 4.5).

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Sick sinus syndrome
Special care should be exercised when lercanidipine is used in patients with sick sinus syndrome (if a
pacemaker is not in situ). Although hemodynamic controlled studies revealed no impairment of
ventricular function, care is also required in patients with LV dysfunction. It has been suggested that
some short-acting dihydropyridines may be associated with increased cardiovascular risk in patients with
ischaemic heart disease. Although lercanidipine is long-acting caution is required in such patients.

Angina pectoris
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.
Isolated cases of myocardial infarction may be observed (see 4.8).

Use in renal or hepatic dysfunction:

Special care should be exercised when treatment is commenced in patients with mild to moderate renal or
hepatic dysfunction. Although the usually recommended dose schedule may be tolerated by these
subgroups, an increase in dose to 20 mg daily must be approached with caution. The antihypertensive
effect may be enhanced in patients with hepatic impairment and consequently an adjustment of the
dosage should be considered.

Lercanidipine is not recommended for use in patients with severe hepatic impairment or in patients with
severe renal impairment (GFR < 30 ml/min) (see 4.2).
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see
4.5).

CYP3A4 inducers
Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce
lercanidipine's plasma levels and therefore the efficacy of lercanidipine may be less than expected (see
section 4.5).

This medicinal product contains lactose monohydrate and therefore should not be administered to patients
with Lapp lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF

INTERACTION
Metabolic interactions
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and, therefore, inhibitors and inducers
of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine.

CYP3A4 inhibitors
Co-administration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir,
erythromycin, troleandomycin) should be avoided (see 4.3).
An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in
plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the
eutomer S-lercanidipine).

Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant
administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3
hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of
ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has
caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together.

As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice,

with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should
not be taken with grapefruit juice.
UKPAR Lercanidipine Hydrochloride 10mg and 20mg Film-Coated Tablets PL 24668/0173-6

When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers,

lercanidipine's absorption was increased (by approximately 40%) and the rate of absorption was
decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.

CYP3A4 inducers
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin,
carbamazepine), rifampicin should be approached with caution since the antihypertensive effect may be
reduced and blood pressure should be monitored more frequently than usual.

CYP3A4 substrates
Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a
mean increase of 33% in digoxin Cmax , while AUC and renal clearance were not significantly modified.
Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin
toxicity.
Co-administration of 20 mg lercanidipine in patients chronically treated with b-methyldigoxin showed no
evidence of pharmacokinetic interaction.

Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in
plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the
hypotensive effect of lercanidipine may be increased.

An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of
an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the
pharmacokinetics of lercanidipine.

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the
pharmacokinetics of warfarin.

Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like
terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine.

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.

Other interactions
When lercanidipine was co-administered with metoprolol, β-blocker eliminated mainly by the liver, the
bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This
effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore
occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta-
adrenoceptor blocking drugs, but dose adjustment may be required.

When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the

AUC of lercanidipine was not significantly modified, while simvastatin's AUC increased by 56% and that
of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance.
No interaction is expected when lercanidipine is administered in the morning and simvastatin in the
evening, as indicated for such drug.

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

4.6 PREGNANCY AND LACTATION

Pregnancy
There are no adequate data from the use of lercanidipine in pregnant women. Non-clinical data provide
no evidence of a teratogenic effect in the rat and the rabbit and reproductive performance in the rat was
unimpaired. Since other dihydropyridine compounds have been found teratogenic in animals,
lercanidipine should not be administered during pregnancy or to women with child-bearing potential
unless effective contraception is used.

Lactation
Because of high lipophilicity of lercanidipine, distribution in milk may be expected. Therefore, it should
not be administered to nursing mothers.
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4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Lercanidipine has no or negligible influence on the ability to drive and use machines. However, caution
should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

4.8 UNDESIRABLE EFFECTS

The following undesirable effects have been reported in clinical studies and in the post-marketing phase:

Assessment of frequencies:
Very common: ≥1/10
Common: ≥ 1/100, < 1/10
Uncommon: ≥ 1/1,000, < 1/100
Rare: ≥ 1/10,000, < 1/1,000
Very rare: < 1/10,000, cannot be estimated from the available data

Investigations
Very rare: reversible increases in serum levels of hepatic transaminases

Cardiac disorders
Uncommon: tachycardia; palpitations, peripheral oedema
Rare: angina pectoris
Very rare: chest pain, myocardial infarction, hypotension
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with
pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.

Nervous system disorders

Uncommon: headache; dizziness

Gastrointestinal disorders
Rare: nausea; dyspepsia; diarrhoea; abdominal pain; vomiting
Very rare: gingival hypertrophy

Renal and urinary disorders

Rare: polyuria
Very rare: urinary frequency

Skin and subcutaneous tissue disorders

Rare: rash

Musculoskeletal and connective tissue disorders

Rare: myalgia

Vascular disorders
Uncommon: flushing

General disorders and administration site conditions

Rare: asthenia; fatigue

Immune system disorders

Very rare: hypersensitivity

Psychiatric disorders
Rare: somnolence

Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

4.9 OVERDOSE
In the post-marketing experience, three cases of overdose were reported (150 mg, 280 mg and 800 mg of
lercanidipine, respectively, ingested in an attempt to commit suicide).

Dose level Signs/Symptoms Management Outcome

150 mg Sleepiness Gastric lavage Recovered
+ Active charcoal
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amount of
alcohol
280 mg Cardiogenic shock High-dose catecholamines Recovered
+ Severe myocardial ischaemia Furosemide
5.6 mg Mild renal failure Digitalis
moxonidine Parenteral plasma expanders

800 mg Emesis Active charcoal Recovered

Hypotention Cathartics
Dopamine i.v.

As with other dihydropyridines, overdosage might be expected to cause excessive peripheral

vasodilatation with marked hypotension and reflex tachycardia. In case of severe hypotension,
bradycardia and unconsciousness, cardiovascular support could be helpful, with intravenous atropine for
bradycardia.

In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular
status of patients who take an overdose is monitored for 24 hours at least. There is no information on the
value of dialysis. Since the drug is highly lipophilic, it is most probable that plasma levels are no guide to
the duration of the period of risk and dialysis may not be effective.

5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects
ATC Code: C08CA13

Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx
of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a
direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance. Despite its
short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive
activity because of its high membrane partition coefficient, and is devoid of negative inotropic effects due
to its high vascular selectivity.

Since the vasodilatation induced by lercanidipine is gradual in onset, acute hypotension with reflex
tachycardia has rarely been observed in hypertensive patients.

As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due
to its (S)-enantiomer.

In addition to the clinical studies conducted to support the therapeutic indications, a further small
uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood
pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on
20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a
double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension
lercanidipine was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6
mmHg to 140.2 ± 8.7 mmHg.

5.2 PHARMACOKINETIC PROPERTIES

Absorption
Lercanidipine is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30
ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. respectively, occur about 1.5-3 hours after dosing.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma
concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for
the (S) enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No "in
vivo" interconversion of enantiomers is observed.

Due to the high first pass metabolism, the absolute bioavailability of lercanidipine orally administered to
patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy
volunteers under fasting conditions.
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Oral administration of lercanidipine leads to plasma levels of lercanidipine not directly proportional to
dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the
ratio 1:3:8 and areas under plasma concentration-time curves in the ratio 1:4:18, suggesting a progressive
saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high
fat meal. Accordingly, lercanidipine should be taken before meals.

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

The degree of serum protein binding of lercanidipine exceeds 98%. Since plasma protein levels are
reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be
increased.

Metabolism
Lercanidipine is extensively metabolised by CYP3A4; no parent drug is found in the urine or the faeces.
It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine.

In vitro-experiments with human liver microsomes have demonstrated that lercanidipine shows some
degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher
than those reached at peak in the plasma after the dose of 20 mg.

Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels
of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6.
Therefore, inhibition of biotransformation of drugs metabolised by CYP3A4 and CYP2D6 by
lercanidipine is not expected at therapeutic doses.

Elimination
Elimination occurs essentially by biotransformation.
A mean terminal elimination half life of 8-10 hours was calculated and the therapeutical activity lasts for
24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated
administration.

Elderly, renal and hepatic insufficiency

In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic
impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in
the general patient population; patients with severe renal dysfunction or dialysis-dependent patients
showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment,
the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally
metabolised extensively in the liver.

5.3 PRECLINICAL SAFETY DATA

Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the
central nervous system or on gastrointestinal function at antihypertensive doses.

The relevant effects which have been observed in long-term studies in rats and dogs were related, directly
or indirectly, to the known effects of high doses of Ca-antagonists, predominantly reflecting exaggerated
pharmacodynamic activity.

Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard.

Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine.
There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high
dose levels induced pre- and post- implantation losses and delay in foetal development.
Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced
dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast
milk have not been investigated.
Metabolites have not been evaluated separately in toxicity studies.
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6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Tablet core:
Magnesium stearate
Povidone
Sodium starch glycolate (Type A)
Lactose monohydrate
Cellulose, microcrystalline

Film-coating:
Macrogol
Polyvinyl alcohol
Talc
Titanium dioxide (E 171)
Iron oxide, yellow (E 172)
Iron oxide, red (E 172)

6.2 INCOMPATIBILITIES
Not applicable.

6.3 SHELF LIFE

2 years

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Al/PVC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.
Al/PVDC blister:
Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 NATURE AND CONTENTS OF CONTAINER

Blister pack (Aluminium/PVC) with push-through foil.
Blister pack (Aluminium/PVDC) with push-through foil.

Pack sizes: 7, 10, 14, 20, 28, 30, 35, 42, 50, 56, 60, 98, 100 film-coated tablets
Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Ltd
6th Floor
94 Wigmore Street
London
W1U 3RF
UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0176

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/2009

10 DATE OF REVISION OF THE TEXT

22/12/2009
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