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-(4-Chlorophenyl)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 3-layer 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 Abbott GmbH Co.KG, authorised 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-di-desmethylsibutramine (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)

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.

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 di-desmethylsibutramine - 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.

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.