Public Assessment Report
Scientific discussion
Coxtral
nimesulide
CZ/H/0116/001/MR
Applicant: Zentiva, a.s., Prague, Czech Republic
This module reflects the scientific discussion for the approval of Coxtral 100 mg, Tablet.
The procedures were finalised at 13-02-2006.
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INTRODUCTION
This generic application for a marketing authorisation concerns Coxtral tablets in the strength
100 mg of nimesulide. Coxtral tablets has been approved in the Mutual Recognition Procedure on
February 13, 2006. The Concerned Member States were EE, LT, PL. Originally this medicinal
product was approved nationally in the Czech Republic on March 6, 2002.
The tablets are claimed to be essentially similar to Aulin, manufactured by Roche, authorised in
the Czech Republic since 1997, marketing authorisation number 29/179/97-C. The reference
medicinal product has therefore been authorised in the EU for more than 6 years.
Coxtral is indicated for the treatment of rheumatoid arthritis, osteoarthritis, fever, dysmenorrhea,
postoperative pain, and other inflammatory conditions.
The reference product used in the bioequivalence study was Aulin, one bioequivalence study
was carried out to compare product Coxtral to reference product Aulin after a single dose at fasting
state. No new pre-clinical and clinical studies, besides the bioequivalence studies, were
conducted. This is acceptable for this abridged application.
QUALITY ASPECTS
Introduction
Coxtral is presented in the form of tablets containing 100 mg of nimesulide. The excipients
are lactose monohydrate, cellulose microcrystalline, sodium starch glycollate (type A),
hydroxypropylcellulose, docusate sodium and magnesii stearate.
The product is packed into blisters (a white opaque PVC/PVDC foil/Al foil) or transparent, brown
glass bottles closed with a screw HDPE cap with a snap ring or opaque, white HDPE bottles closed
wiht a screw HDPE cap with a snap ring.
Outer package is a paper folding box together with a package leaflet.
Drug substance
The active substance nimesulide is described in the European Pharmacopoeia. Nimesulide is a
yellowish crystalline powder, practically insoluble in water, freely soluble in acetone, slightly soluble
in ethanol, melting point is about 149 °C. Nimesulide has no asymmetric carbons and is not optically
active. There is no potential for chirality or isomerism. Nimesulide shows two polymorphic forms but
only one polymorph is produced by the manufacturers and it is presented in Coxtral.
Two manufacturers of the active substance are involved, one of them is holder of a Certificate of
Suitability, a copy of which is presented in the documentation, the other has submitted DMF.
In addition to the PhEur. specification, the following tests are added – particle size, microbial
purity, residual solvents.
Satisfactory Certificates of Analysis have been provided which demonstrate compliance with the
stated specification.
Medicinal Product
The development of medicinal product has been sufficiently described; the essential similarity
with brand leader product Aulin has been documented.
Tablets are formulated using excipients described in the current Ph Eur. Lactose monohydrate is
the only material of animal origin used in manufacture of the tablets. TSE risk is minimised in line
with EMEA/CPMP/571/02.
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The manufacturing process has been presented with its critical steps and with in-process
controls. The validation of manufacturing process confirms that the process is reproducible,
and demonstrates compliance with the specification. The tests and limits are considered
appropriate to justified the quality of the medicinal product. The analytical methods have been
sufficiently described and validated.
Batch analysis data have demonstrated compliance with the proposed release specification.
The safety of proposed packaging material has been documented.
Stability studies under ICH conditions have been performed and data presented. The data
support the shelf life proposed in the SPC, 2 years when stored at temperatures not exceeding
25 °C in all proposed containers.
CLINICAL ASPECTS
It’s acceptable that specific studies have not been performed, as the application is submitted in
accordance with Article 10.1 of Directive 2001/83/EC.
Nimesulid is authorised for more than 10 years in Europe and therefore it is a well-known active
substance.
Nimesulide is well absorbed after ingestion by mouth. Peak plasma level occurs 2-3 hours after a
single dose of 100mg nimesulide tablet. When given with meal the Cmax is reduced by approximately
20%. Neither the total bioavailability measured by AUC nor tmax are affected by food.
Up to 99% of the drug binds to proteins in plasma. The distribution to other tissues is rapid. A single
dose of 100mg tablet induces maximal concentrations in the uterus, oviduct, ovaries at 3 hours postdose, while reaching about 50% of respective plasma levels. Apparent volume of distribution is
reported between 0.18-0.39 l/kg.
Nimesulide is metabolized in liver by several pathways including cytochrome p450 2C9. Both parent
compound and its main para-hydroxy- metabolite are pharmacologically active. The lag time before
appearance of the main metabolite in plasma is 0.8 hours, its production is constant over time and
substantially slower than the speed of nimesulide absorption. Hydroxynimesulide in plasma is almost
completely conjugated.
Half-lives of nimesulide and hydroxynimesulide are reported between 1.8-5.22, and 3.2-6 hours,
respectively.
Totally 1-3% of administered dose are eliminated unchanged. Nimesulide is excreted mainly in urine.
Approximately 29% of the dose is found as metabolites in faeces.
Bioequivalence
One study was conducted to prove bio-equivalence of Coxtral 100 mg tablets with the
reference product Aulin 100mg.
A two-way, randomized, single-dose, cross-over, fasted study of Coxtral in healthy male
subjects has been conducted.
Twenty six subjects have regularly completed both study periods. Their samples were
analysed using a validated HPLC method and statistically evaluated. There were no reported
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deviations from protocol, no adverse events, and no subject was excluded throughout the
study.
Subjects were selected by appropriate inclusion criteria, the factors influencing food-drug and
other interactions with the pharmacokinetics have been excluded and regime standardized.
Wash-out as well as sampling intervals were long enough.
Pharmacokinetic parameters Cmax and tmax were determined directly from concentration-time profiles
of individual subjects, t1/2 was estimated by least squares regression analysis, and AUCt by linear
trapezoidal rule with extrapolation to infinity for AUCinf. Geometric means of Cmax, and AUCinf. were
considered as primary parameters to test the bioequivalence as pre-specified in the protocol, 90%
confidence intervals were estimated. Pre-defined acceptance range of bioequivalence was 0.80-1.25
for AUCinf. and 0.70-1.43 for Cmax. Primary parameters were AUCt, AUCinf., and Cmax.
Descriptive statistics was used to summarize the results. Two-way ANOVA was carried out on all
AUCs, Cmax, and tmax values in which factors of subject, treatment, sequence, and period were
evaluated.
The results show generally low intra-individual variation after administration of both
products. The individual AUCt/AUCinf. ratios ranged from 92.6% to 98.8%, and 93.7%-98.9%
for Coxtral, and Aulin, respectively.
ANOVA performed on the PK parameters did not detect any significant difference between the test
and reference products for any of the parameters AUCt, AUCinf., Cmax. Further, there were no
statistically significant differences between analysed factors of subjects, treatments, periods, and
sequences in case of the pharmacokinetic parameters of AUCt, AUCinf., and Cmax.
Bioequivalence has been satisfactorily demonstrated.
Since this product has been shown to be essentially similar and refer to a product approved based on a
full application with regard to clinical efficacy/safety data, no further such data have been submitted or
are considered necessary.
The risk/benefit ratio is considered positive and Coxtral is recommended for approval.
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