Download Public Assessment Report

Public Assessment Report
Scientific discussion
LINDAXA 10 mg
LINDAXA 15 mg
Sibutramine hydrochloride monohydrate
CZ/H/0128/001/MR
CZ/H/0128/002/MR
Applicant: Zentiva, a.s., Prague, Czech Republic
This module reflects the scientific discussion for the approval of Lindaxa 10mg, 15mg. The
procedures were finalised at 17-12-2007.
Introduction
Lindaxa 10 mg and 15 mg hard capsules are generic medicinal products containing
sibutramine hydrochloride monohydrate as the active substance. Original products are
Reductil 10 and 15 mg hard capsules from Abbott GmbH and Co. KG, Germany, first
authorization was granted in Germany in 1999. The original products have been marketed in
the Czech Republic since 1999 under the name Meridia 10 and 15 mg, hard capsules. The
product Meridia (15 mg strength) is used also for bioequivalence studies.
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
Lindaxa exists as 10 and 15 mg hard gelatine capsules.
It contains sibutramine hydrochloride monohydrate as the active substance. Excipients are
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 30 or 90 capsules). Approved
storage conditions are “Do not store above 30 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 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 which enables existence of two enantiomers. The chemical structure was
sufficiently characterized.
The scientific information has been submitted in form of an Active Substance 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.
Certificates of analysis have been provided for pilot and full scale batches. Results comply
with the proposed specification and confirm the consistency of the process.
Substance is packed in LDPE bag bound with a cotton string. The bags comply with the
provisions of Ph.Eur. The bags are placed inside a polyethylene pot with a lid and/or a 3layer and pasteboard box.
Appropriate stability studies have been carried out. Results showed no significant change and
remained within the specification. Therefore the proposed re-test period is justified based on
the stability results when substance is kept in the proposed packaging.
Medicinal Product
Lindaxa 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.
The drug substance is compatible with most of the commonly used excipients – this has been
either described in the literature or has been observed in stability tests of the finished product.
All of used excipients with the exception of gelatin capsules are the subject of monographs in
the Ph. Eur. For empty hard gelatin capsules an appropriate specification has been submitted.
Satisfactory Certificates of analysis of all excipients have been provided.
Magnesium stearate is of vegetal origin.
Lactose monohydrate is of animal origin and is manufactured in compliance with CPMP
guideline EMEA/410/01.Rev.2.
Satisfactory TSE Certificates of suitability for gelatine have been provided.
In order to demonstrate the equivalence of the Lindaxa 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.
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.
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.
Results of analysis for six 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.
The materials comply with the Ph.Eur. and with 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.
STEPS TAKEN AFTER AUTHORISATION – SUMMARY
Application type and scope
Variation II
Change to Module 3 – addition of new API
source
Variation II
Change to Module 1 – update of SPC, PIL
Clinical aspects
This MRP application concerns a generic version of Sibutramine HCl monohydrate, under the
name Lindaxa 10/15mg (formerly Verona 10/15mg).
The originator product is Meridia (10/15 mg capsules) by Abbot
since 4th August 1999 in the Czech Republic.
To support the application, the applicant has submitted two bioequivalence studies, both
conducted with 15 mg strength.
A single dose, randomised, two-period, two-treatment, two-sequence, crossover
bioequivalence study on sibutramine hydrochloride monohydrate 15 mg capsules Verona 15
versus Meridia 15 mg capsules in healthy volunteers.
Subjects accepted for inclusion participated in a randomized, two-way, two sequence
crossover study. Following an overnight fasting period (at least 10 hours) healthy volunteers
received a single oral 15 mg sibutramine dose with 200 mL water on two separate occasion
with washout period of at least 7 days.
In each phase, a total 18 blood samples were taken at pre-dose and at 0.25, 0.50, 1.00, 1.50,
2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 16.0, 24.0, 32.0, 48.0, and 72.0 hours after dosing.
Plasma
concentrations
of
N-mono-desmethyl-sibutramine
(M1),
and
N-didesmethylsibutramine (M2) were determined and the pharmacokinetic parameters Cmax,
tmax, AUC0-last, AUC0-inf, residual area, and t1/2 were calculated.
Statement of compliance with GCP and GLP is presented.
28 subjects were enrolled. No subject was withdrawn or dropped out from the study.
They were healthy subjects of either sex, 18-55 years old, BMI within the normal range,
without alcohol or drug abuse, non-smokers or moderate smokers (less then 11 cigarettes),
screened for suitability.
In the group of 28 subjects employed for the bioequivalence assessment there were 14 males
and 14 females between the ages 18 and 47 years (median 25 years) in the study.
24 subjects were non-smokers, 4 subjects were mild smokers (up to 10 cigarettes per day).
Plasma samples were analysed for the active metabolites (mono- and di-desmethylsibutramine
- M1 and M2) by an HPLC MS/MS method. Limits of quantification were 0.20 µg/L and 0.21
µg/L for M1 and M2, respectively. Stability of the samples was sufficiently documented.
Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out
on all AUC, Cmax, and tmax values in which subject, treatment, sequence, and period were
evaluated. Individual data are presented, logarithmic transformation was used (except for
tMAX).
Test and reference formulations showed similar adverse event profile.
A single dose, randomised, two-period, two-treatment, two-sequence, crossover
bioequivalence study on sibutramine preparations lindaxa 15 capsules versus Meridia 15 mg
capsules in healthy volunteers (cpa 278-06)
Subjects accepted for inclusion participated in a randomized, two-way, two sequence
crossover study. Following an overnight fasting period (at least 10 hours) healthy volunteers
received a single oral 15 mg sibutramine dose with 200 mL water on two separate occasion
with washout period of at least 12 days.
In each phase, a total 22 blood samples were taken at pre-dose and at 0.25, 0.50, 0.75, 1.00,
1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 16.0, 24.0, 32.0, 48.0, 72.0 and 96.0
hours after dosing. Plasma concentrations of SBA, N-mono-desmethyl-sibutramine (M1), and
N-di-desmethylsibutramine (M2) were determined and the pharmacokinetic parameters
Cmax, tmax, AUC0-last, AUC0-inf, residual area, and t1/2 were calculated. Primary
pharmacokinetic parameters were: AUC0-inf (or AUC0-last) and Cmax of SBA, secondary
parameters: AUC0-last, and tmax of SBA profiles, AUC0-inf, AUC0-last, Cmax and tmax of
N-di-desmethylsibutramine (M2)and N-mono-desmethylsibutramine (M1) profiles
Statement of compliance with GCP and GLP is presented.
72 subjects were enrolled. One subject was withdrawn from the study for an AE before the
second period.
They were healthy subjects of either sex, 18-55 years old, BMI within the normal range,
without alcohol or drug abuse, non-smokers or moderate smokers (less then 11 cigarettes),
screened for suitability.
In the group of 71 subjects employed for the bioequivalence assessment there were 33 males
and 38 females between the ages 18 and 49 years (median 30 years) in the study.
Fifty subjects were non-smokers, twenty-one subjects were mild smokers (up to 10 cigarettes
per day).
Plasma samples were analysed for sibutramine and its active metabolites (mono- and didesmethylsibutramine - M1 and M2) by an HPLC MS/MS method. Limit of quantification
was 0.09 µg/L, 0.09 µg/L and 0.20 µg/L for sibutramine, M1 and M2, respectively. Stability
of the samples was documented.
Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out
on all AUC, Cmax, and tmax values in which subject, treatment, sequence, and period were
evaluated. Individual data are presented, logarithmic transformation was used (except for
tMAX).
The bioequivalence has been sufficiently shown.
The Package leaflet for Lindaxa capsules has been shown to provide the tested consumer with
all required information in a clear and comprehensive form and the Readability testing was
performed according to the guidelines.