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Public Assessment Report

Scientific discussion

Lozap H

Losartanum 50 mg/Hydrochlorothiazidum 1!5 mg

CZ/H/0117/001/MR

Applicant" #enti$a a%s%! Prague! &zech Republic

'his module reflects the scientific discussion for the appro$al of Lozap H% 'he procedures (ere

finalised at 15)0)00*%

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+,AL-'. ASP&'S

-ntroduction

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 po!idone and magnesii stearate hypromellose

macrogolum talc simeticone emulsion and opaspray yello".

The product is pac#ed into blisters $a transparent %&'(%&)' foil((*L+ foil,. uter pac#age

is a paper folding box together "ith a pac#age leaflet.

rug substance

Losartan %otassium

The acti!e substance losartan potassium is not described in the uropean %harmacopoeia.

Losartan potassium is a "hite to off- "hite crystalline po"der freely soluble in "ater soluble

in ethanol and methanol/ practically insoluble in chloroform its melting range is 20'-2'. *t least t"o polymorphic forms exist $form 3 and form 33, 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 le!el of the second isomer is limited in the final product.

)etailed information relating to the drug substance "as submitted by )4 $)rug 4aster

ile, procedure.

The in house specification used is considered ade6uate to control the 6uality of the material.

%article size microbial purity residual sol!ents are also tested.

7atisfactory 'ertificates of *nalysis ha!e been pro!ided "hich demonstrate compliance "ith

the stated specification.

The drug substance is pac#ed in double polyethylene bags containing dessicant. %ac#agingmaterials conform to the uropean standards compliance certificate of ' guidelines are

pro!ided.

7tability studies ha!e been carried out on three batches in the proposed pac#aging under 3'H

conditions. The product "as sub8ected to forced degradation and to photo stability testing.

The re-test period is 8ustified based on the stability results "hen substance is #ept in the

proposed pac#aging "ithout specific storage conditions.

Hydrochlorothiazide

The acti!e substance hydrochlorothiazide is described in the uropean %harmacopoeia. T"o

sources of Hydrochlorothiazide "ere proposed.

Hydrochlorothiazide is a "hite or almost "hite crystalline po"der !ery slightly soluble in

"ater , soluble in acetone, sparingly soluble in ethanol (9 per cent). 3t dissol!es in diluted solutions

of al#ali hydroxides.

The drug substance hydrochlorothiazide does not sho" optical acti!ity or different potential

isomers.

The literature reports four different crystalline forms. *cti!e substance "as examined using

3: spectroscopy )7' and x-ray po"der diffraction. ne polymorph form $called form 3, "as

confirmed.ne of the sources is the sub8ect of a 'ertificate of 7uitability for "hich a satisfactory copy "as

pro!ided. The second manufacturer pro!ided *pplicant;s and :estricted %arts of )4 and a

satisfactory Letter of *ccess. *dditional tests on residual sol!ents and any other impurity "ere

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included in the specification. (This manufacturer was deleted after the authorization via Variation

IA).

7atisfactory 'ertificates of *nalysis ha!e been pro!ided "hich demonstrate compliance "ith

the stated specification.

The re-test period is 8ustified based on the stability results.

edicinal Product

Lozap H exists as film-coated tablets. The 6ualitati!e and 6uantitati!e composition is detailed

for the core and the film-coating. *ll excipients are common pharmaceutical grade products

co!ered by %h.ur. monography except simeticone emulsion 7 < "hich is described in +7%

and paspray =ello". 'omponents of opaspray yello" are included in %h.ur. or >% and

colouring agents comply "ith ' )irecti!e 9<(?(' and 95(<5('. 7atisfactory 'ertificates

of *nalysis of all excipients ha!e been pro!ided.

@o material of animal origin is used in composition.

The de!elopment of medicinal product has been sufficiently described/ the essential similarity

"ith brand leader product Hyzaar 50(12.5 has been documented.

4anufacturing of the product

The manufacturing process can be considered as standard. The manufacture and in-process

controls are fully described in the dossier. :esults of process !alidation on pilot scale batches

ha!e been submitted. 3t may be concluded that the manufacturing process has been sho"n to

be reliable and capable of consistently producing a product that complies "ith pre-established

6uality and specifications.

%roduct specification

The proposed specification is acceptable. 7atisfactory control tests are applied at the time of

release and during shelf-life. :elease and shelf life limits for the assay of losartan potassium

and hydrochlorothiazide are in line "ith batch and stability data. Limits for related substances

comply "ith 3'H guidelines.

*nalytical methods ha!e been satisfactorily described and !alidated in accordance "ith

regulatory re6uirements.

:esults of analysis for three production batches "ere gi!en in documentation. *ll results

complied "ith the specifications.

The inner pac#aging material is a blister made of a transparent %&'(%&)' foil((*L+ foil.7atisfactory specifications for the blister ha!e been pro!ided as "ell as 3: identification and

certificates of analysis. The pac#aging material complies "ith %h.ur. and + directi!es.

7tability of the product

7tability studies of t"o pilot batches and fi!e production batches ha!e been pro!ided in

proposed blisters according to 3'H conditions. *ll stability results meet the set specifications.

>ased on the data the proposed shelf life of 2 years "hen stored up to ?0' is accepted.

S'PS 'A23 A4'R A,'HR-#A'-3 6 S,AR.

*pplication type and scope&ariation 3*A

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)eletion of any manufacturing site

&ariation 3>A

'hange in the name of the medicinal product $for %L only,

&ariation 33A

*ddition of :is# 4anagement %lan

:ene"al

iscussion on chemical and pharmaceutical aspects

3nformation on de!elopment 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 6uality characteristics and these

in turn lead to the conclusion that the product should ha!e a satisfactory and uniform

performance in the clinic.

&L-3-&AL ASP&'S

>ased on the re!ie" of the data on 6uality safety and efficacy the :47 considers that the

application for Lozap H Benti!a tablets in the treatment of hypertension in patients in "hom

a combined therapy is suitable could be appro!ed. The applicant claims essential similarity

under article 10.1$a,$iii, of )irecti!e 2001(C? $as amended, to Hyzaar tablets 4erc# 7harp D

)ohme >.&. @etherlands "hich contains the same acti!e substances in the same strength.

To support the application the applicant has submitted as report one bioe6ui!alence study.

This study "as a single centre bioe6ui!alence open-label balanced single-dose

randomized 2-"ay crosso!er study performed under fasting conditions. %rior to study

commencement sub8ects "ere randomly assigned to a treatment in accordance "ith the

randomization scheme and the randomisation code "as bro#en "hen the clinical and

laboratory portion "as completed for statistical and reporting purposes.

The study e!aluated the comparati!e bioa!ailability of LEFi!a;s Lozap H coated tablets "ith

the Hyzaar 50(125 coated tablets $4erc# 7harp and )ohme The @etherlands, "hen

administered as a single dose to t"enty-four normal healthy male !olunteers. ollo"ing eachdrug administration 15 blood samples "ere ta#en at 0 $pre-drug, 20 minutes <0 minutes 1

1.5 2 2.5 ? < C 10 15 2< and ?0 hours. %lasma "as har!ested from each sample and the

losartan and hydrochlorothiazide concentrations "ere determined. Losartan concentrations

"ere determined only in plasma samples collected up to 10 hours follo"ing administration

due to its short elimination half-life.

7ub8ects recei!ed a single dose of t"o tablets of losartan $100 mg, and hydrochlorothiazide

$25 mg, "ith 250 ml of "ater. The administered dose "as set "ith respect to the sensiti!ity of

the analytical method for hydrochlorothiazide. The used dose is "ithin usually prescribed

therapeutic dose.

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The comparati!e bioa!ailability bet"een formulations "as e!aluated based on the statistical

comparisons of the areas under the plasma losartan and hydrochlorothiazide concentrations

!ersus time cur!es $*+';s, and pea# losartan and hydrochlorothiazide concentrations $c max,

as the primary endpoints and the time to reach maximal plasma concentrations $T max, as the

secondary endpoint.

There "as no scheduled prior or concomitant therapy during this study. The treatment phases

"ere separated by a "ashout period of minimum days. *ll clinical "or# "as conducted in

compliance "ith Good 'linical %ractice :ules $G'%,.

T"enty-four $2<, normal healthy male !olunteers aged bet"een 1C and <5 years "ere

selected for the study and four $<, substitutes. *n inclusion(exclusion chec#-list "as

completed for each sub8ect on the day of medical examination to assess suitability for

inclusion.

* !alidated and sufficiently sensiti!e H%L' assay method "as employed for the analysis of losartan and hydrochlorothiazide in plasma samples. The method for losartan determination

"as capable to analyse samples "ith at least 20-1C00 ng(ml content. The method for

hydrochlorothiazide analysis has range at least 5-250 ng(ml. >lood samples "ere obtained and

stored using standardized procedure.

*ll statistical analyses "ere carried out using standard statistical procedures. 'max and tmax

"ere determined directly from the obser!ed !alues. T1(2 "as calculated by least s6uares

regression analysis of log-transformed data. *+'0-t "as calculated by linear trapezoidal rule

and *+'0- "as determined by extrapolation to infinity.

The primary pharmaco#inetic parameters "ere *+'0- and cmax and secondary parameters

"ere *+'0-t tmax and T1(2 for both losartan and hydrochlorothiazide. Iith regard to the

pharmaco#inetic profile of losartan and hydrochlorothiazide the chosen parameters are

acceptable.

T"o-"ay analysis of !ariance $*@&*, "as carried out on all *+'s cmax tmax !alues in

"hich sub8ect treatment se6uence and period "as e!aluated along "ith standard or

geometric confidence inter!als. or all analyses effects "ere considered statistically

significant if the probability associated "ith "as less than 0.050. 'max and tmax "as

determined directly from the obser!ed !alues T1(2 "as calculated by least s6uares regression

analysis of log-transformed data and *+'0-t "as calculated by linear trapezoidal rule and*+'0- "as determined by extrapolation to infinity.

*@&*s performed on the pharmaco#inetic indices did not detect any statistically significant

difference bet"een the t"o formulations for any of the parameters *+'0-t *+'0- 'max. The

90 J geometric confidence inter!als "ere "ithin the bioe6ui!alence range C0 K 125 J for

*+' and 5-1?? J for 'max. .

>ased on the presented bioe6ui!alence study Lozap H is considered bioe6ui!alent "ith

Hyzaar.

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