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°C276°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.