Download Introduction

Public Assessment Report
Scientific discussion
LADYBON
tibolone
CZ/H/0131/001/MR
Applicant: Zentiva a.s., Prague, Czech Republic
This module reflects the scientific discussion for the approval of Ladybon. The procedures were
finalised at 25-09-2006.
INTRODUCTION
The application was submitted as abridged application according to article 10.1 (a)(iii) of
Directive 2001/83/EC, claiming essential similarity to the original products Livial tablets,
N.V.Organon, The Netherlands authorised in the Czech Republic since 1991, marketing
authorisation number 54/249/91- C.
The first Mutual Recognition Procedure was finished on 25.9.2006 with Estonia, Hungary,
Latvia, Lithuania and Slovak Republic as CMS. Originally this medicinal product was
approved nationally in the Czech Republic on 23.02.2006.
2nd wave of Mutual Recognition Procedure was finished on 16th July 2008, the Concerned
Member State was Poland.
The product contains the active ingredient Tibolone, a synthetic steroid that has estrogenic,
progestagenic and androgenic properties. It is used for hormone replacement therapy (HRT)
in the treatment of menopausal vasomotor symptoms and prevention of postmenopausal
osteoporosis. The usual dose is 2,5 mg daily.
QUALITY ASPECTS
Introduction
Ladybone is presented in the form of uncoated tablets containing 2.5 mg of tibolone. The
excipients are lactose monohydrate, potato starch, ascorbyl palmitate and magnesium stearate.
The product is packed into blisters made of thermoformed PVC/PVDC transparent foils
laminated with aluminium foils. Blisters are placed, together with a package leaflet, into a
paper folding box.
Drug substance
The active substance tibolone is not described in the European Pharmacopoeia. Tibolone is a
white or almost white crystalline powder, soluble in acetone, methanol and ethanol, slightly
soluble in water, melting point is165 to 169°C, tibolone presents 6 chiral centers and exhibits
two crystalline forms and also an amorphous form. At this time the quality of the drug
substance corresponds to the European Pharmacopoeia. This change of specifications has
been approved.
Starting material for the manufacturing of the active substance is purchased from one
manufacturer, other manufacturer and six testing facilities are involved in manufacturing of
tibolone. The DMF and Letter of Access were submitted.
The specification was proposed in accordance with ICH Q6A guideline. Satisfactory
Certificates of Analysis have been provided which demonstrate compliance with the stated
specification.
All components of the primary packaging for the active substance are in line with Directive
2002/72/EC and with Ph.Eur. monographs.
Based on stability results the re-test period (date) was set for 2 years.
Medicinal Product
The development of medical product has been sufficiently described; the essential similarity,
based on comparison of dissolution profiles, impurity profiles and bioequivalence with brand
leader Livial, has been documented.
Tablets are formulated using excipients described in the current Ph Eur. The content of the
anti-oxidant ascorbyl palmitate is justified. Certificates of analysis have been provided.
Lactose monohydrate is the only material of animal origin used in manufacture of the tablets.
TSE risk is minimised in line with EMEA/CPMP/571/02.
The manufacturing process has been presented with its critical steps and with in process
controls. The validation of manufacturing process confirms that the process is reproducible,
and demonstrates accordance with the specification. The tests and limits are considered
appropriate to justified the quality of the medicinal product. The analytical methods have been
sufficiently described and validated.
Batch analysis data have demonstrated compliance with the proposed release specification
The safety of proposed packaging material has been documented.
Stability studies under ICH conditions have been performed and data presented. Based on the
result obtained from this stability study and evaluation of stability data, the shelf life of 2
years can be approved for Ladybon 2,5 mg when stored at temperature bellow 25°C in the
original package (blister) with the precaution ”Keep blister in the outer carton” to protect the
product from light and air humidity.
STEPS TAKEN AFTER AUTHORISATION – SUMMARY
Application type and scope
Variation IA/11a:
Change in batch size of active substance – up to 10-fold.
Variation IB/7c:
Replacement of or additional manufacturing site for part or all of the manufacturing process
of the finished product – all other manufacturing operations except batch release.
Variation IA/38a:
Change in test procedure of the finished product – Minor change to an approved test
procedure.
Variation IB/38c:
Change in the test procedure of the finished product – Other changes to a test procedure
Variation IA/37a:
Change in the specification of the finished product – Tightening of specification limits.
Variation IB/25a1:
Change of specification(s) of a former non-Eur. Pharmacopoeial substance to comply with
Ph.Eur. – Active Substance.
Variation IA/12a:
Change in the specification of the active substance – Tightening of specification limits.
Variation IA/4:
Change in the name of a manufacturer of the active substance where no Ph.Eur. certificate of
suitability is available.
Variation IB/33:
Minor change in the manufacture of the finished product.
Variation II:
Change to Module 2 (Update of the Clinical Overview).
Variation IA/13a:
Change in test procedure for active substance – Minor changes to an approved test
procedure.
CLINICAL ASPECTS
Based on the review of data on quality, safety and efficacy, the RMS considered that the
application for Ladybon, tablets, in the treatment of estrogen deficiency symptoms in women
and in prevention of osteoporosis in postmenopausal women with a high risk of future
fractures, could be approved.
This is an abridged application. The applicant claims essential similarity, under article 10.1
(a)(iii) 1st par.of Directive 2001/83/EC, to Livial, tablets, N.V.Organon, Oss, Netherlands,
authorised for more than 10 years in Europe. Livial has been authorised in the Czech Republic
since 1991 (MANo 54/249/91-C, marketing authorisation holder N.V.Organon, Oss,
Netherlands).
Tibolone is a synthetic steroid that acts on estrogen, progesterone, and androgen receptors
either directly or indirectly through its metabolites, with a different pattern according to the
target tissue. Tibolone is used in the treatment of estrogen deficiency symptoms, prevents
bone loss as second line therapy for prevention of osteoporosis in postmenopausal women
(who are intolerant to other medicinal products), and reduces menopausal symptoms
(including vasomotor complaints, depressed mood, decreased libido) without causing
estrogen-like stimulation of the endometrium and breast.
No new preclinical studies and no clinical studies were conducted, which is acceptable given
that the applications were based on essential similarity to a product that has been licensed for
more than 10 years. The application contains an adequate review of published clinical data.
One single-dose bioequivalence study at fasted state has been conducted for 2,5 mg strength.
Essential similarity has been sufficiently proven by the bioequivalence study that complies
with current requirements and by comparison of dissolution and impurity profiles.
Quality of the product Ladybon tablets and GMP standards of manufacture have been
sufficiently demonstrated.
The SmPC of product Ladybon tablets corresponds to the SmPC of reference product. The
Package leaflet has been shown to provide the tested consumers with all required information
in a clear and comprehensive form and the Readability testing was performed according to the
guidelines.
The quality of the product Ladybon, tablets, is satisfactory in relation to its safety and
efficacy. The data have demonstrated the efficacy and safety of Ladybon tablets, to the extent
that the overall risk/benefit of the products is favourable for the proposed indications.
To support the application, the applicant has submitted as report one bioequivalence study.
A single-dose, randomized, two-period, two-treatment, two-sequence, crossover
bioequivalence study on tibolone preparations Ladybon 2.5 mg tablets (Zentiva a.s., Czech
Republic) versus Livial 2.5 mg tablets (N.V. Organon, The Netherlands) in healthy
postmenopausal women. Investigator: I. Ulč, M.D.,Ph.D., Site of the clinical and analytical
parts: Cepha s.r.o., Pilsen, CZ; January/ February 2005; Study code: CPA 221-04/Zentiva
16/04/TIB/BSD, EudraCT No.: 2004-004132-31; Sponsor: Zentiva a.s., Prague 10, CZ
The objective of the study was to compare bioavailability of two tibolone formulations on the
request of Zentiva a.s., Prague: Ladybon 2.5 mg tablets with Livial 2.5 mg tablets (Organon,
NL). This was an open (laboratory blind), single-dose, randomised, two-way cross-over study.
The assessment of bioequivalence was based on pharmacokinetic parameters derived from
3-hydroxytibolone, 3-hydroxytibolone and tibolone concentrations analysed in individual
plasma samples.
After a 10.5 hour fasting period, each subject was administered orally a single dose (one 2.5
mg tablet) of one of the two tibolone formulations with 200 ml water. The fasting period
continued 4 hours after the dosing. 21 blood samples were taken predose and up to 30.0 hours
after dosing. The subjects were confined at the study centre from the evening prior to each
study phase until collection of the 30-hour blood sample. There was a six-day washout period
between doses. Vital signs were measured before dosing and at 1, 3, 8, 12, 24, and 30 hours
after drug administration.
The total twenty-four (24) + four (4) alternates healthy female volunteers initiated and
completed the study. Their ages ranged from 48 to 65 years (median age 55 years), and their
body weight was between 56.9 and 81.3 kg (median 66.5 kg).
Plasma samples for 3-hydroxytibolone, 3-hydroxytibolone, and tibolone concentrations
were planned to be analysed by means of validated HPLC-MS/MS method in CEPHA
bioanalytical laboratory. The lower limit of quantification was 0.20 ng/mL for 3hydroxytibolone, and 0.19 ng/mL for 3-hydroxytibolone. The determination of parent drug
tibolone has been performed after the Clinical Study Report and was issued as a Supplement
to Clinical Study Report. Tibolone plasma levels were determined in CEPHA bioanalytical
laboratory by the validated HPLC-MS/MS method with the lower limit of quantitation 0.30
ng/ml.
Bioequivalence of tibolone products, assessed in this study, was based on the pharmacokinetic
parameters of active drug metabolite 3-hydroxytibolone as a primary parameter and 3hydroxytibolone and parent drug tibolone as a secondary parameters, analysed in individual
plasma samples.
Based on the pharmacokinetic parameters of of the active metabolites 3-hydroxytibolone and 3hydroxytibolone and the parent drug tibolone, the reference and test 2.5 mg tablet formulations are
bioequivalent with respect to the extent and rate of absorption. The 90% confidence intervals
calculated for AUC (0-last), AUC (0-inf) and Cmax were within the range of acceptability.
Based on the presented bioequivalence study, Ladybon 2.5 mg tablets is considered
bioequivalent to Livial 2.5 mg tablets.