Public Assessment Report
Scientific discussion
RECOXA 7,5
RECOXA 15
Meloxicam
CZ/H/0103/001
CZ/H/0103/002
This module reflects the scientific discussion for the approval of Recoxa 7,5 and 15. The
procedure was finalised at 26 May 2005. For information on changes after this date please refer
to the module ‘Update’.
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I.
INTRODUCTION
This mutual recognition procedure application concerned a generic version of meloxicam
tablets under trade name Mobic or Movalis, 7.5/15 mg tablets.
The legal basis of this application is article 10.1 a)(iii) of Directive 2001/83/EC as amended,
“last paragraph” for for Recoxa 7.5 and “first paragraph” for 15 mg tablets with reference to
Movalis 15 mg tbl.
Original product authorised for non less than 6/10 years in the EEA is Mobic tablets by
Boehring Ingelheim Ltd. authorised in EU since 20.12.1995. The reference product is Movalis
15 mg tablets, Boehringer Ingelheim, Ltd., authorised since 1997 in the Czech Republic with
MA number /29/444/97-C.
Meloxicam is a nonsteroidal antirheumatic agent designed for the symptomatic treatment of
painful osteoarthrosis (arthrosis, a degenerative disease of joints), rheumatoid arthritis and the
symptomatic treatment of ankylozing spondylitis. The usual oral dose is 7.5 to 15 mg daily in
one dose.
With the Czech Republic as the Reference Member State in this mutual recognition
procedure, ZENTIVA, k.s., the Czech Republic is applying for the Marketing Authorisations
for Recoxa 7.5 mg and Recoxa 15 mg tablets in PL and SK. Recoxa 15 mg has been
authorised in the Czech Republic.
II.
QUALITY ASPECTS
II.1
Introduction
Recoxa 7.5 mg tablets are light yellow, round, biconvex tablets with bevel edges and with B
and 18 debossed on one side and plain on the reverse.
Recoxa 15 mg tablets are light yellow, round, biconvex tablets with bevel edges and with B
and 19 debossed on either side of break line and plain on the reverse.
The composition of Recoxa 7.5 mg tablets and Recoxa 15 mg tablets is proportional.
The product is packed into blisters (a white opaque PVC/PVDC//Al blister). Blisters are
inserted, together with a package leaflet, into a paper folding box. Each one packing is sized
10, 20 tablets.
II.2
2.2
Drug Substance
Meloxicam
(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3carboxamide-1,1-dioxide, ATC classification code M01AC06, CAS number 71125-38-7) is
non-steroidal anti-inflammatory drug used to relieve some symptoms of arthritis, such as
inflammation, swelling, stiffness and joint pain.
The active substance (API) is sourced from one source. The DMF procedure is used for the
API and the DMF was submitted by DMF holder. It has been experimentally proved that
meloxicam does not exist in polymorphic forms. The manufacture and the control of the
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quality of meloxicam were described sufficiently. The specifications are based on British
Pharmacopoiea monograph and comply with relevant ICH guideline. The stability data are in
line with ICH guideline and support the proposed re-test period.
II.3
Medicinal Product
For the development of generic Meloxicam 7.5 mg and 15 mg tablets the same or very similar
excipients as those contained in the original product were chosen. The generic product
contains lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide,
magnesium stearate, sodium citrate dihydrate and crospovidone, the originator product
contains povidone in addition.
All excipients are available worldwide and meet the pharmacopoeial (Ph.Eur.) standards.
The only excipient of animal origin is lactose. It is milk derivate which is sourced from
healthy animals under the same conditions as milk collected for human consumption,
therefore the TSE risk is negligible.
Magnesium stearate is manufactured from Stearic acid of vegetable base.
A bioequivalence study was only performed for Meloxicam 15 mg tablets because of
proportional composition of Meloxicam 7.5 mg tablets and Meloxicam 15 mg tablets.
Comparative dissolution profiles between Recoxa and original product have been provided;
the dissolution profiles are similar.
Comparative impurity profiles between Recoxa and original product have been provided and
are accepted.
Based on the above mentioned results, the generic product Recoxa developed by Zentiva can
be considered as essentially similar to the innovator product Mobic/Movalis.
The manufacturing process can be considered as standard. The manufacture and in-process
controls are fully described in the dossier. All physical and chemical properties which are
critical for quality of the product were monitored. 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 preestablished quality and specifications.
The validation of production batches will be performed for three standard batches and then
evaluated in the validation report. The process validation scheme for the drug product is
provided and 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 meloxicam are in line with batch and stability data. Limits for
related substances are in line with ICH guidelines and stability data. Analytical methods have
been satisfactorily described and validated in accordance with regulatory requirements.
Satisfactory batch analysis data have been provided for three batches of each of strength. The
batch results comply with the specification and demonstrate consistent manufacture.
Suitability of chosen formulation and manufacturing process was also proven by stability
testing.
Stability trials were performed on the drug product according to the stability protocols and
ICH guidelines. Based on the data shelf-life of 3 years with no special conditions of storage
can be granted.
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The chemical-pharmaceutical documentation is well-arranged and of sufficient quality. Based
on the assessment, the product is approvable from the quality point.
Update: List of approved variations:
No.
CZ/H/0103/001/IB/001
CZ/H/0103/002/IB/001
No. of
change
IB
Nature of change
Status/date
Approved
14.3.2006
II
Change in pack size of the finished
product – extension of pack sizes to
10, 20, 30, 60 and 100 tablets
Correction of SPC and PIL +
harmonisation
Change in the specification of the
finished product
Change in test procedure of the
finished product
Change to batch release arrangements
and quality control testing of the
finished product – replacement of a
site where batch control/testing takes
place
Change of the manufacturer of the
active substance – addition of a new
manufacturer of active substance
Addition of a manufacturing site of
the finished dosage form
Addition of a primary and secondary
packaging site
Additional of Risk Management Plan
II
Change in SPC and PIL - NSAIDs
IA
Addition of primary and secondary
packaging site of the finished dosage
form
Change in the name and/or address of
the marketing authorisation holder
from Zentiva a.s., Prague to Zentiva
k.s., Prague
Change in the name and/or address of
a manufacturer of the finished product
from Zentiva a.s., Prague to Zentiva
k.s., Prague
Change to batch release arrangements
and quality control testing of the
finished product – addition of a
manufacturer responsible for batch
release
• change in batch size of active
substance
• change of specification of the active
CZ/H/0103/001/II/002
CZ/H/0103/002/II/002
CZ/H/0103/001/II/003
CZ/H/0103/002/II/003
CZ/H/0103/001/IB/004
CZ/H/0103/002/IB/004
CZ/H/0103/001/IA/005
CZ/H/0103/002/IA/005
II
CZ/H/0103/001/II/006
CZ/H/0103/002/II/006
II
CZ/H/0103/001/IB/007
CZ/H/0103/002/IB/007
CZ/H/0103/001/IA/008
CZ/H/0103/002/IA/008
CZ/H/0103/001/II/009
CZ/H/0103/002/II/009
CZ/H/0103/001/II/010
CZ/H/0103/002/II/010
CZ/H/0103/001/IA/011
CZ/H/0103/002/IA/011
IB
CZ/H/0103/001/IA/012
CZ/H/0103/002/IA/012
IA
CZ/H/0103/001/IA/013
CZ/H/0103/002/IA/013
IA
CZ/H/0103/002/IA/014
IA
II
IB
IA
IA
CZ/H/0103/001/IA/015/G IA
CZ/H/0103/002/IA/015/G
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Approved
14.3.2006
Approved
12.4.2006
Approved
12.4.2006
Positive
12.4.2006
Approved
10.11.2006
Approved
10.11.2006
Positive
10.11.2006
Approved
5.4.2007
Approved
5.4.2007
Positive
3.4.2007
Positive
27.3.2009
Positive
27.3.2009
Positive
1.4.2009
Approved
28.4.2010
CZ/H/0103/001/1A/017
CZ/H/0103/002/1A/017
IA
substance - change of specification of
a former non Pharmacopoeial
substance to comply with the Ph. Eur.
• change of specification of the active
substance - change of specification of
a former non Pharmacopoeial
substance to comply with the Ph. Eur.
• change in specification of the active
substance
Change from DMF for the active
substance to the European
Pharmacopoeia certificate of
suitability
II.4
Discussion on chemical, pharmaceutical and biological aspects
III.
NON-CLINICAL ASPECTS
III.1
Introduction
Positive
19.8.2010
As meloxicam is a widely used, well-known active substance, no further studies are required.
Overview based on literature review is, thus, appropriate.
The non-clinical overview has been written by a relevant expert.
III.2
Pharmacology
III.3
Pharmacokinetics
III.4
Toxicology
III.5
Ecotoxicity/environmental risk assessment
III.6
Discussion on the non-clinical aspects
No objections to the approval of meloxicam tablets were raised by the RMS or CMSs from a
non-clinical point of view.
IV.
CLINICAL ASPECTS
IV.1
Introduction
This assessment report represents an evaluation of the key elements of the information
provided by the company in the dossier.
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As meloxicam is a widely used, well-known active substance, no further studies are required.
Overview based on literature review is, thus, appropriate.
IV.2
Pharmacokinetics
The to-be marketed RECOXA 7.5 mg and RECOXA 15 mg tablets (producer Zentiva, k.s.,
Prague, Czech Republic) is claimed to be essentially similar to the product MOBIC  15 mg
tablets (Boehringer Ingelheim, United Kingdom), authorized for more than 6 years in the EU.
The marketing authorisation holder for the reference product is Boehringer Ingelheim, the
company which developed meloxicam and which holds patent rights for this drug substance.
To prove bioequivalence of the RECOXA tablets, a study was submitted in which the
formulation MELOXICAM 15 mg tablets (Bioglan Generics Ltd., Ireland), which is identical
to the assessed tablet (RECOXA, Zentiva, Czech Republic), is compared with MOBIC 15
mg tablets (Boehringer Ingelheim, United Kingdom), which is identical to MOVALIS 15 mg
tablets (Boehringer Ingelheim).
These abridged applications concern Mutual Recognition Procedures for marketing
authorisations according to the EEC-Directive 2001/83/EC article 10.1 (a) (iii), first paragraph
– so called ‘generic application’.
Results from one bioequivalence study of the 15 mg tablets have been submitted in support of
the application. The study was audited by an experienced auditor of sponsor and declared to
be performed according to ICH GCP standards: Randomised, Two-period, Cross-over
Comparative Bioavailability study on MELOXICAM 15 mg Tablets (Bioglan Generics Ltd.,
Ireland) versus MOBIC 15 mg Tablets (Boehringer Ingelheim Ltd. U.K.) in Healthy
Volunteers. Study director: Miroslav Ryska, Ph.D., site of the study: QUINTA-ANALYTICA
s.r.o., Prague, Czech Republic. Clinical investigator: Ivan Ulc, M.D.,Ph.D., site of the clinical
part: CEPHA, s.r.o., Pilsen, CZ; October/November 2001; Study number 033/121/00.
The objective of the study was to compare bioavailability of two meloxicam formulations on
the request of Bioglan Generics Ltd., Clonmel, Tipperary, Ireland. This was an open
(laboratory blind), single-dose, randomised, two-way cross-over study. The study was
conducted in compliance with the Declaration of Helsinki (Edinburgh, Scotland, October
2000), current GCP and GLP guidelines, and other applicable international and national
regulatory requirements. No unexpected adverse drug reaction occurred.
The total twenty-six (24+2 alternates for substitution of dropouts) healthy male and female
volunteers initiated the study. One dropout not related to the study medication occurred
during washout period, another dropout not related to the study medication occurred during
study period 2. Consequently, 24 subjects completed the entire study procedures: 12 males
and 12 females. According to the study protocol, twenty-four (24) subjects were analyzed and
statistically evaluated in non-balanced study design (11 times sequence TR, 13 times
sequence RT). Their median age of them was 23 years (range 19 and 44 years) and median
weight 68.2 kg (range 53.8 and 93.1 kg).
Test product: MELOXICAM 15 mg tablets (Bioglan Generics Ltd., Ireland, batch number
PTD/1048E/20)
Reference product: MOBIC® 15 mg tablets (Boehringer Ingelheim Ltd. U.K., batch number
009621)
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The test batch No. PTD/1048E/20 was manufactured under GMP conditions and of an
appropriate size of 100.000 tablets. The test product is considered representative of the
product to be marketed.
Both formulations were declared to contain 15 mg of meloxicam.
After a 10 h fasting period, each subject was administered orally a single dose (one tablet, i.e.
15 mg of meloxicam) of one of the two meloxicam formulations with 200 ml water and with a
standard breakfast immediately after drug administration. The second period of the cross-over
study was carried out after 14 days washout period. Blood samples were taken predose and at
0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96, and 120 hours after dosing. The
subjects were confined at the study centre from –11.5 hour until collection of the 24-hour
blood sample
Plasma samples for meloxicam content were analysed by means of validated HPLC method
with limit of quantification as low as 30 ng/ml of plasma. The calibration curve ranged from
30 to 3000 ng/ml.
The individual plasma levels as well as the calibration and quality control data were tabulated
together with the descriptive statistics data for 24 subjects. The pharmacokinetic parameters,
characterizing the rate and extent of the absorption of meloxicam and the rate of its
elimination, were calculated and statistically evaluated using both parametric and nonparametric approach, whichever appropriate. The following parameters derived from the
plasma concentration versus time profiles were extracted:
AUC(0-inf.), AUC(0-t), Cmax (both linear and ln-transformed), (Cmax/AUC(0-inf.) ) (lntransformed), (AUC(0-t)/AUC(0-inf.) ), tmax, kel and t½ (all linear). Parallel to the determination of
90% confidence intervals for the individual test/reference geometric mean ratios of all main
parameters, they were subjected to analysis of variance using general linear models procedure
of SAS software. Two one-sided t-tests on each parameter were performed, too. Nonparametric tests were performed for tmax, kel and t½ . Statistical evaluation was performed for
Cmax, AUC(0-t), and AUC(0-inf) using SPSS 11.01 for Windows and the 90% confidence
intervals for the test/reference ratio were calculated.
The tolerance of the study products was good. Except six adverse effects in 3 subjects
(nausea, vomiting, headache), no serious or unexpected adverse drug reaction occurred.
The primary objective was to establish bioequivalence for meloxicam after administration of
one 15 mg tablet of test and reference products, respectively. The mean T/R ratios (log normal
distribution) for the main parameters AUC0- were 96.66% (90% C.I.: 93.06%, 100.41%),
AUC(0-t) 97.20% (93.75%, 100.78%), Cmax, 98.75% (93.86%, 103.89%), and (Cmax/AUC(0-inf.)
) 102.16% (97.66%, 106.86%). Similar elimination half-life (t1/2e) of meloxicam was assessed
after the administration of the studied products: the Test/Reference ratio (linear distribution)
was 98.04% (90% C.I. 91.07%, 105.01%).
The null hypothesis of bioinequivalence was rejected with respect of pharmacokinetic
parameters characterising the rate and the extent of absorption, i.e. AUC(0-inf.), AUC(0-t), Cmax,
and (Cmax/AUC(0-inf.)).
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The statistical power calculated for all the main pharmacokinetic parameters was higher than
99%.
Based on the pharmacokinetic parameters of meloxicam, the reference and test 15 mg tablet
formulations are bioequivalent with respect to the extent and rate of absorption, although the
study design was non-balanced (11 times sequence TR, 13 times sequence RT). The 90%
confidence intervals calculated for AUC(0-t), AUC(0-inf), Cmax, and (Cmax/AUC(0-inf.) ) were
within the range of acceptability, and the power of the statistical tests was sufficient, too.
Therefore, the test formulation MELOXICAM 15 mg tablets (Bioglan Generics Ltd., Ireland)
could be judged to be bioequivalent to the reference formulation MOBIC® 15 mg tablets
(Boehringer Ingelheim Ltd. U.K.).
IV.3
Pharmacodynamics
IV.4
Clinical efficacy
IV.5
Clinical safety
IV.6
Discussion on the clinical aspects
No other clinical studies were conducted to support this application.
V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The current products have shown to be bioequivalent with the innovator, and, therefore, the
benefit/risk balance of these products can be considered similar to the innovator product.
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