Public Assessment Report
Scientific discussion
Sibutramine Teva 10mg, 15mg Capsules
Sibutramine Hydrochloride Monohydrate
CZ/H/0142/01-02/DC
Applicant: TEVA Pharma B.V. , Czech Republic
This module reflects the scientific discussion for the approval of Sibutramine Teva 10
and 15mg Capsules. The procedures were finalised at 08-02-2008.
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INTRODUCTION
Sibutramine TEVA 10 mg and 15 mg hard gelatine capsules are generic medicinal products
containing sibutramine hydrochloride monohydrate as the active substance. The reference
product Reductil (in the Czech marketed under the name Meridia) 10 mg and 15 mg hard
gelatine capsules has been authorized in 1999.
Sibutramine hydrochloride monohydrate is a serotonin and noradrenalin reuptake inhibitor, it
also inhibits dopamine reuptake but to a lesser extent. The product is used for management of
obesity. It may be also used in overweight patients if other risk factors such as hypertension,
diabetes mellitus, or hyperlipidaemias are present.
QUALITY ASPECTS
Introduction
Sibutramine TEVA exists as 10 and 15 mg hard gelatine capsules.
It contains sibutramine hydrochloride monohydrate as the active substance. The excipients
used are the following excipients microcrystalline cellulose, lactose monohydrate, colloidal
anhydrous silica, magnesium stearate, and gelatine capsules. One capsule contains 10 (15) mg
of sibutramine hydrochloride monohydrate equivalent to 8.37 (12.55) mg of sibutramine.
Product is presented in PVC/PVdC aluminium blisters (of 7, 28, 30, 56, 60, 98, and 100
capsules). Approved storage conditions are “Do not store above 25 º C. Store blister in the
original package to protect from humidity”. Approved shelf life of the product is 2 years.
Active Substance
The active substance sibutramine hydrochloride monohydrate (chemical name: N-1-(1-(4Chlorophenyl)cyclobutyl)-3-methylbutyl-N,N-dimethylamine hydrochloride mono-hydrate) is
a white to almost white crystalline powder. Physical-chemical properties have been
adequately described.
There have been no literature reports of polymorphism for Sibutramine Hydrochloride
Monohydrate. There is one chiral centre present in Sibutramine HCl Monohydrate. The
chemical structure was sufficiently characterized.
The scientific information has been submitted in form of a Drug Master File.
Manufacture has been described in details.
The applicant has provided an in-house monograph since sibutramine hydrochloride
monohydrate is not described in any pharmacopoeia. Satisfactory specification is provided.
Appropriate discussion has been presented on organic and inorganic impurities including
residual solvents.
The applicant has provided an in-house monograph since sibutramine hydrochloride
monohydrate is not described in any pharmacopoeia. Analytical methods have been described
and validated when non-compendial in accordance with ICH requirements.
The substance is packed in double clear colorless PE bags. The bags are placed in fibre drums
tightly covered with lids.
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Certificates of analysis have been provided for three full scale batches. Results comply with
the proposed specification and confirm the consistency of the process.
Stability studies have been carried out on three batches in the proposed packaging under ICH
conditions. The re-test period is justified based on the stability results when substance is kept
in the proposed packaging.
Medicinal Product
Sibutramine TEVA 10 and 15 mg exists as hard gelatine capsules. The qualitative and
quantitative composition is detailed for the capsules shell and ink used for imprinting.

Pharmaceutical Development
The objective was to obtain sibutramine capsules achieving pharmaceutical equivalence and
bioequivalence with the product of reference Meridia 10 and 15 mg capsules.
Common excipients have been chosen for Sibutramine hard gelatine capsules formulation. No
compatibility issue could be identified between active substance and the excipients.
Adequate formulation development has been presented and the ratio between the excipients
and the active substance is identical for the both strengths. All of used excipients with the
exception of gelatin capsules are the subject of monographs in the Ph. Eur. For empty hard
gelatin capsules a satisfactory specification has been provided.
Satisfactory Certificates of analysis of all excipients have been provided.
In order to demonstrate the equivalence of the Sibutramine TEVA capsules and the reference
product Meridia capsules, comparative dissolution data between the proposed and reference
products (both strengths) have been provided including the biobatches.
The impurity profile comparison of proposed product with reference product from different
EU markets has been provided with comparable results.
Satisfactory TSE Certificates of suitability for gelatine have been provided.

Manufacturing of the product
The manufacturing process can be considered as standard. The manufacture and in-process
controls are fully described in the dossier. Results of process validation for both strengths
have been submitted and showed the process is adequately controlled and reproducible. A
satisfactory validation plan has been presented for the validation of the process on commercial
batches. Results of process validation for both strengths have been submitted and showed the
process is adequately controlled and reproducible.
Product specification
The approved proposed specifications are acceptable. Satisfactory control tests are applied at
time of release and during the shelf-life. Release and shelf life limits for the assay of
sibutramine hydrochloride monohydrate are in line with batch and stability data. Limits for
related substances comply with ICH guidelines.
Analytical methods have been satisfactorily described and validated in accordance to
regulatory requirements.
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Results of analysis for two pilot batches were given in documentation. All results complied
with the specifications.
The packaging material is a blister made of PVC/PVdC/Al foil, packed in cardboard cartons.
Satisfactory specifications for blisters have been provided as well as IR identification and
certificates of analysis. The packaging material complies with Ph. Eur. and EU directives.
Stability of the product
The stability of the drug product was tested and evaluated in several stability studies in
accordance with the predefined individual stability protocols.
Based on the data, proposed shelf life and storage conditions were accepted.
Discussion on chemical and pharmaceutical aspects
Information on development, manufacture and control of the drug substance and drug product
has been presented in a satisfactory manner. The results of tests carried out indicate
satisfactory consistency and uniformity of important product quality characteristics, and these
in turn lead to the conclusion that the product should have a satisfactory and uniform
performance in the clinic.
CLINICAL ASPECTS
This decentralised application concerns a generic version of Sibutramine HCl monohydrate,
under Sibutramine Teva 10/15 mg Capsules. In this Assessment Report, the name
Sibutramine Teva is used.
The originator product is Meridia (10/15 mg capsules) by
since 4 August 1999 in the Czech Republic.
authorised
To support the application, the applicant has submitted one bioequivalence study.
A single-dose, randomized, three-period, six-sequence, three-treatment, crossover
comparative bioavailability study of three formulations of sibutramine hydrochloride
monohydrate 15 mg capsules administered to healthy, non-smoking, male and female subjects
under fasting conditions. The wash-out period was 14 days.
Test product (A): Novo-Sibutramine (sibutramine hydrochloride mohohydrate) 15 mg
capsules by Novopharm Limited,has been compared to two references:
- Reference Product 2(C): Reductil (sibutramine hydrochloride mohohydrate) 15 mg capsules
by Abbott Scandinavia AB, Sweden
Each subject received a single dose of respective formulation in each period with 240 ml of
tap water after an overnight fast.
Forty-two healthy, non-smoking, male and female subjects were enrolled into the study when
fulfilling inclusion criteria, and not fulfilling any of exclusion criteria as specified in the study
protocol.
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One volunteer elected to withdraw from the study prior to drug administration in Period 2 due
to personal reasons.
Therefore, forty-one subjects completed the whole study and were included in the PK
evaluation.
Mean age of the analysed 41 subjects was 38 ± 10 years; mean height 166.6 ± 7.9 cm; mean
weight 69.0 ± 9.7 kg; and mean BMI 24.9 ± 2.7 kg/m2.
Plasma concentration of sibutramine and its metabolites mono-desmethylsibutramine and didesmethyl sibutramine were determined. The technical, analytical staffs were blinded as to
formulation identity. A validation report of the analytical technique is provided. Freeze-thaw
short term and long term stability for sibutramine and both metabolites have been verified.
ANOVA was carried out on log transformed AUC0-last, AUC0-∞, Cmax values and non
transformed Tmax, Kel, and T½ values. The treatment, period, sequence and subject in
sequence terms were included in the model. Computer output corresponds with that model.
Results
The results with the reference product for the EU market (reference 2 - C) are discussed
below.
The extrapolated part of AUCinf was below 20% for all three analytes.
The ratios (90% CI) of AUC0-t, AUCinf, Cmax log-transformed values of all three analytes
are within the standard limits of 80-125%.
Several statistically significant differences were detected in ANOVA, mainly for the
metabolites. The applicant has discussed these issues. Since the 90% confidence intervals of
all parameters are entirely within the 80-125% range, this was considered acceptable with no
clinical relevance.
Safety
No serious adverse events were reported.
Test and reference formulations showed similar adverse event profile.
Pharmacokinetic conclusion
The bioequivalence has been sufficiently proven.
The results of study with 15mg formulation can be extrapolated to other strength 10 mg,
according to conditions in Note for Guidance on the Investigation of Bioavailability and
Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4.
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