Public Assessment Report



Public Assessment Report

Scientific discussion

Lozap H

Losartanum 50 mg/Hydrochlorothiazidum 12,5 mg

CZ/H/0117/001/MR

Applicant: Zentiva a.s., Prague, Czech Republic

This module reflects the scientific discussion for the approval of Lozap H. The procedures were finalised at 15-02-2006.

QUALITY ASPECTS

Introduction

Lozap H is presented in the form of film-coated tablets containing 50 mg of losartan potassium and 12.5 of hydrochlorothiazide. The excipients are cellulose microcrystalline, mannitol, croscarmellose sodium, povidone and magnesii stearate, hypromellose, macrogolum, talc, simeticone emulsion and opaspray yellow.

The product is packed into blisters (a transparent PVC/PVDC foil//ALU foil). Outer package is a paper folding box together with a package leaflet.

Drug substance

Losartan Potassium

The active substance losartan potassium is not described in the European Pharmacopoeia. Losartan potassium is a white to off- white crystalline powder, freely soluble in water, soluble in ethanol and methanol; practically insoluble in chloroform, its melting range is 270°C- 276°C. At least two polymorphic forms exist (form I and form II), but only one polymorph is produced by the manufacturers and it is presented in Lozap H. There is a possible isomer at the imidazole ring. The level of the second isomer is limited in the final product.

Detailed information relating to the drug substance was submitted by DMF (Drug Master File) procedure.

The in house specification used is considered adequate to control the quality of the material.

Particle size, microbial purity, residual solvents are also tested.

Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the stated specification.

The drug substance is packed in double polyethylene bags, containing dessicant. Packaging materials conform to the European standards, compliance certificate of EC guidelines are provided.

Stability studies have been carried out on three batches in the proposed packaging under ICH conditions. The product was subjected to forced degradation and to photo stability testing. The re-test period is justified based on the stability results when substance is kept in the proposed packaging without specific storage conditions.

Hydrochlorothiazide

The active substance hydrochlorothiazide is described in the European Pharmacopoeia. Two sources of Hydrochlorothiazide were proposed.

Hydrochlorothiazide is a white or almost white crystalline powder, very slightly soluble in water, soluble in acetone, sparingly soluble in ethanol (96 per cent). It dissolves in diluted solutions of alkali hydroxides.

The drug substance hydrochlorothiazide does not show optical activity or different potential isomers.

The literature reports four different crystalline forms. Active substance was examined using IR spectroscopy, DSC and x-ray powder diffraction. One polymorph form (called form I) was confirmed.

One of the sources is the subject of a Certificate of Suitability for which a satisfactory copy was provided. The second manufacturer provided Applicant’s and Restricted Parts of DMF and a satisfactory Letter of Access. Additional tests on residual solvents and any other impurity were included in the specification. (This manufacturer was deleted after the authorization via Variation IA).

Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the stated specification.

The re-test period is justified based on the stability results.

Medicinal Product

Lozap H exists as film-coated tablets. The qualitative and quantitative composition is detailed for the core and the film-coating. All excipients are common pharmaceutical grade products covered by Ph.Eur. monography except simeticone emulsion SE 4 which is described in USP and Opaspray Yellow. Components of opaspray yellow are included in Ph.Eur. or BP and colouring agents comply with EC Directive 94/36/EC and 95/45/EC. Satisfactory Certificates of Analysis of all excipients have been provided.

No material of animal origin is used in composition.

The development of medicinal product has been sufficiently described; the essential similarity with brand leader product Hyzaar 50/12.5 has been documented.

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 on pilot scale batches have been submitted. It may be concluded that the manufacturing process has been shown to be reliable and capable of consistently producing a product that complies with pre-established quality and specifications.

Product specification

The proposed specification is acceptable. Satisfactory control tests are applied at the time of release and during shelf-life. Release and shelf life limits for the assay of losartan potassium and hydrochlorothiazide 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 with regulatory requirements.

Results of analysis for three production batches were given in documentation. All results complied with the specifications.

The inner packaging material is a blister made of a transparent PVC/PVDC foil//ALU foil. Satisfactory specifications for the blister 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

Stability studies of two pilot batches and five production batches have been provided in proposed blisters according to ICH conditions. All stability results meet the set specifications. Based on the data, the proposed shelf life of 2 years when stored up to 30°C is accepted.

STEPS TAKEN AFTER AUTHORIZATION – SUMMARY

|Application type and scope |

|Variation IA: |

|Deletion of any manufacturing site |

|Variation IB: |

|Change in the name of the medicinal product (for PL only) |

|Variation II: |

|Addition of Risk Management Plan |

|Renewal |

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

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Lozap H Zentiva tablets, in the treatment of hypertension in patients in whom a combined therapy is suitable, could be approved. The applicant claims essential similarity, under article 10.1(a)(iii) of Directive 2001/83 (as amended) to Hyzaar tablets, Merck Sharp & Dohme B.V., Netherlands which contains the same active substances in the same strength.

To support the application, the applicant has submitted as report one bioequivalence study.

This study was a single centre, bioequivalence, open-label, balanced, single-dose, randomized, 2-way crossover study, performed under fasting conditions. Prior to study commencement, subjects were randomly assigned to a treatment in accordance with the randomization scheme and the randomisation code was broken when the clinical and laboratory portion was completed for statistical and reporting purposes.

The study evaluated the comparative bioavailability of Léčiva’s Lozap H coated tablets with the Hyzaar 50/12,5 coated tablets (Merck, Sharp and Dohme, The Netherlands) when administered as a single dose to twenty-four normal, healthy, male volunteers. Following each drug administration, 15 blood samples were taken at 0 (pre-drug), 20 minutes, 40 minutes, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 15, 24 and 30 hours. Plasma was harvested from each sample and the losartan and hydrochlorothiazide concentrations were determined. Losartan concentrations were determined only in plasma samples collected up to 10 hours following administration due to its short elimination half-life.

Subjects received a single dose of two tablets of losartan (100 mg) and hydrochlorothiazide (25 mg) with 250 ml of water. The administered dose was set with respect to the sensitivity of the analytical method for hydrochlorothiazide. The used dose is within usually prescribed therapeutic dose.

The comparative bioavailability between formulations was evaluated based on the statistical comparisons of the areas under the plasma losartan and hydrochlorothiazide concentrations versus time curves (AUC’s) and peak losartan and hydrochlorothiazide concentrations (cmax) as the primary endpoints and the time to reach maximal plasma concentrations (Tmax) as the secondary endpoint.

There was no scheduled prior or concomitant therapy during this study. The treatment phases were separated by a washout period of minimum 7 days. All clinical work was conducted in compliance with Good Clinical Practice Rules (GCP).

Twenty-four (24) normal, healthy male volunteers aged between 18 and 45 years were selected for the study and four (4) substitutes. An inclusion/exclusion check-list was completed for each subject on the day of medical examination to assess suitability for inclusion.

A validated and sufficiently sensitive HPLC assay method was employed for the analysis of losartan and hydrochlorothiazide in plasma samples. The method for losartan determination was capable to analyse samples with at least 20-1800 ng/ml content. The method for hydrochlorothiazide analysis has range at least 5-250 ng/ml. Blood samples were obtained and stored using standardized procedure.

All statistical analyses were carried out using standard statistical procedures. Cmax and tmax were determined directly from the observed values. T1/2 was calculated by least squares regression analysis of log-transformed data. AUC0-t was calculated by linear trapezoidal rule and AUC0-∞ was determined by extrapolation to infinity.

The primary pharmacokinetic parameters were AUC0-∞ and cmax and secondary parameters were AUC0-t, tmax and T1/2 for both losartan and hydrochlorothiazide. With regard to the pharmacokinetic profile of losartan and hydrochlorothiazide the chosen parameters are acceptable.

Two-way analysis of variance (ANOVA) was carried out on all AUCs, cmax, tmax values in which subject, treatment, sequence and period was evaluated, along with standard or geometric confidence intervals. For all analyses, effects were considered statistically significant if the probability associated with F was less than 0.050. Cmax and tmax was determined directly from the observed values, T1/2 was calculated by least squares regression analysis of log-transformed data and AUC0-t was calculated by linear trapezoidal rule and AUC0-∞ was determined by extrapolation to infinity.

ANOVAs performed on the pharmacokinetic indices did not detect any statistically significant difference between the two formulations for any of the parameters AUC0-t, AUC0-∞, Cmax. The 90 % geometric confidence intervals were within the bioequivalence range 80 – 125 % for AUC and 75-133 % for Cmax. .

Based on the presented bioequivalence study Lozap H is considered bioequivalent with Hyzaar.

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download