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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.

Drug substance Losartan Potassium The active substance losartan potassium is not described in the European Pharmacopoeia. talc. The excipients are cellulose microcrystalline. containing dessicant. povidone and magnesii stearate. macrogolum. At least two polymorphic forms exist (form I and form II). sparingly soluble in ethanol (96 per cent). One polymorph form (called form I) was confirmed. The product is packed into blisters (a transparent PVC/PVDC foil//ALU foil). Two sources of Hydrochlorothiazide were proposed. The level of the second isomer is limited in the final product. but only one polymorph is produced by the manufacturers and it is presented in Lozap H. its melting range is 270°C276°C. Packaging materials conform to the European standards. It dissolves in diluted solutions of alkali hydroxides. soluble in ethanol and methanol. microbial purity. The in house specification used is considered adequate to control the quality of the material. The product was subjected to forced degradation and to photo stability testing. There is a possible isomer at the imidazole ring. Losartan potassium is a white to off. Hydrochlorothiazide The active substance hydrochlorothiazide is described in the European Pharmacopoeia. Stability studies have been carried out on three batches in the proposed packaging under ICH conditions. freely soluble in water. The re-test period is justified based on the stability results when substance is kept in the proposed packaging without specific storage conditions. The literature reports four different crystalline forms. One of the sources is the subject of a Certificate of Suitability for which a satisfactory copy was provided. Hydrochlorothiazide is a white or almost white crystalline powder. hypromellose.5 of hydrochlorothiazide. Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the stated specification. practically insoluble in chloroform. The drug substance is packed in double polyethylene bags. The drug substance hydrochlorothiazide does not show optical activity or different potential isomers. soluble in acetone. mannitol. compliance certificate of EC guidelines are provided. Outer package is a paper folding box together with a package leaflet.QUALITY ASPECTS Introduction Lozap H is presented in the form of film-coated tablets containing 50 mg of losartan potassium and 12. Particle size. simeticone emulsion and opaspray yellow. croscarmellose sodium. Detailed information relating to the drug substance was submitted by DMF (Drug Master File) procedure. very slightly soluble in water. Additional tests on residual solvents and any other impurity were . The second manufacturer provided Applicant’s and Restricted Parts of DMF and a satisfactory Letter of Access.white crystalline powder. residual solvents are also tested. Active substance was examined using IR spectroscopy. DSC and x-ray powder diffraction.

included in the specification. Manufacturing of the product The manufacturing process can be considered as standard. STEPS TAKEN AFTER AUTHORIZATION – SUMMARY Application type and scope Variation IA: .Eur. Based on the data. Release and shelf life limits for the assay of losartan potassium and hydrochlorothiazide are in line with batch and stability data.Eur. 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. Results of analysis for three production batches were given in documentation. Stability of the product Stability studies of two pilot batches and five production batches have been provided in proposed blisters according to ICH conditions. Components of opaspray yellow are included in Ph. monography except simeticone emulsion SE 4 which is described in USP and Opaspray Yellow.Eur. The development of medicinal product has been sufficiently described. (This manufacturer was deleted after the authorization via Variation IA). Limits for related substances comply with ICH guidelines. All results complied with the specifications. All excipients are common pharmaceutical grade products covered by Ph. Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the stated specification. Analytical methods have been satisfactorily described and validated in accordance with regulatory requirements. The packaging material complies with Ph. Satisfactory control tests are applied at the time of release and during shelf-life. The inner packaging material is a blister made of a transparent PVC/PVDC foil//ALU foil. and EU directives. Medicinal Product Lozap H exists as film-coated tablets. the proposed shelf life of 2 years when stored up to 30°C is accepted. The re-test period is justified based on the stability results. the essential similarity with brand leader product Hyzaar 50/12. Product specification The proposed specification is acceptable. Satisfactory specifications for the blister have been provided as well as IR identification and certificates of analysis. 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. The manufacture and in-process controls are fully described in the dossier.5 has been documented. All stability results meet the set specifications. No material of animal origin is used in composition. Results of process validation on pilot scale batches have been submitted. The qualitative and quantitative composition is detailed for the core and the film-coating.

CLINICAL ASPECTS Based on the review of the data on quality.V. 15. The administered dose was set with respect to the sensitivity of the analytical method for hydrochlorothiazide. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. 2-way crossover study. Prior to study commencement. bioequivalence. 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. This study was a single centre. 2. The Netherlands) when administered as a single dose to twenty-four normal. randomized. The study evaluated the comparative bioavailability of Léčiva’s Lozap H coated tablets with the Hyzaar 50/12. balanced. manufacture and control of the drug substance and drug product has been presented in a satisfactory manner. The used dose is within usually prescribed therapeutic dose.1(a)(iii) of Directive 2001/83 (as amended) to Hyzaar tablets. 3. could be approved. Subjects received a single dose of two tablets of losartan (100 mg) and hydrochlorothiazide (25 mg) with 250 ml of water. The applicant claims essential similarity. in the treatment of hypertension in patients in whom a combined therapy is suitable. single-dose. healthy. 6. To support the application. male volunteers. 4. performed under fasting conditions.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. Merck Sharp & Dohme B. safety and efficacy.. 2. 8. 40 minutes. 1. Losartan concentrations were determined only in plasma samples collected up to 10 hours following administration due to its short elimination half-life. 10. 15 blood samples were taken at 0 (pre-drug). the RMS considers that the application for Lozap H Zentiva tablets. Plasma was harvested from each sample and the losartan and hydrochlorothiazide concentrations were determined. Sharp and Dohme.5.5 coated tablets (Merck. under article 10. Netherlands which contains the same active substances in the same strength. and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in the clinic. Following each drug administration.5. 1. 20 minutes. open-label. . the applicant has submitted as report one bioequivalence study. 24 and 30 hours.

The 90 % geometric confidence intervals were within the bioequivalence range 80 – 125 % for AUC and 75-133 % for Cmax. AUC0-t was calculated by linear trapezoidal rule and AUC0-∞ was determined by extrapolation to infinity. tmax values in which subject. AUC0-∞. A validated and sufficiently sensitive HPLC assay method was employed for the analysis of losartan and hydrochlorothiazide in plasma samples. ANOVAs performed on the pharmacokinetic indices did not detect any statistically significant difference between the two formulations for any of the parameters AUC0-t. Based on the presented bioequivalence study Lozap H is considered bioequivalent with Hyzaar.050. The treatment phases were separated by a washout period of minimum 7 days. Twenty-four (24) normal. For all analyses. . An inclusion/exclusion check-list was completed for each subject on the day of medical examination to assess suitability for inclusion. sequence and period was evaluated. Two-way analysis of variance (ANOVA) was carried out on all AUCs. T1/2 was calculated by least squares regression analysis of log-transformed data. tmax and T1/2 for both losartan and hydrochlorothiazide. All statistical analyses were carried out using standard statistical procedures. Cmax. effects were considered statistically significant if the probability associated with F was less than 0. C max and tmax was determined directly from the observed values. healthy male volunteers aged between 18 and 45 years were selected for the study and four (4) substitutes. The method for losartan determination was capable to analyse samples with at least 20-1800 ng/ml content. c max. 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. With regard to the pharmacokinetic profile of losartan and hydrochlorothiazide the chosen parameters are acceptable. The primary pharmacokinetic parameters were AUC0-∞ and cmax and secondary parameters were AUC0-t. along with standard or geometric confidence intervals. . There was no scheduled prior or concomitant therapy during this study. treatment. C max and tmax were determined directly from the observed values.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 (c max) as the primary endpoints and the time to reach maximal plasma concentrations (T max) as the secondary endpoint. Blood samples were obtained and stored using standardized procedure. All clinical work was conducted in compliance with Good Clinical Practice Rules (GCP). The method for hydrochlorothiazide analysis has range at least 5-250 ng/ml.