Naproksenas, 250mg, tabletės
Vartojimas: vartoti per burną
Registratorius: Proenzi s.r.o., Čekija
Sudedamosios medžiagos: Naproksenas
Public Assessment Report
Etrixenal 250 mg tablets
Applicant: Proenzi s.r.o
Reference Member State
Start of the procedure:
Date of this report:
Proposed name of the medicinal
Etrixenal 250 mg tablets
product in the RMS
Name of the drug substance (INN
Group: antiinflamatory and antirheumatic products, non-
ATC code: M01AE02
Pharmaceutical form(s) and
250 mg tablet
Reference Number(s) for the
Reference Member State:
Concerned Member States:
BG, CZ, EE, HU, LV, PL, RO, SK
Applicant (name and address)
Names and addresses of all proposed
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Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Etrixenal 250 mg tablets in the Short-term relief of acute mild or moderate pain (joints, muscles, tendons or menstruation) in adults is approvable.
II.1 Problem statement
For generic application this section is not applicable.
II.2 About the product
Naproxen is a non-steroidal anti-inflammatory analgesic compound with antipyretic properties as has been demonstrated in classical animal test systems. Naproxen exhibits its anti-inflammatory effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitary-adrenal axis.
Naproxen inhibits prostaglandin synthetase (as do other NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.
Short-term relief of acute mild or moderate pain (joints, muscles, tendons or menstruation) in adults.
500 mg initially followed by 250 mg at 6 - 8 hour intervals as needed, with a maximum daily dose after the first day of 750 mg.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for Etrixenal dosing is unknown. As with other drugs used in the elderly it is prudent to use the lowest effective dose and for the shortest duration possible as elderly patients are more prone to adverse events. The patient should be monitored regularly for GI bleeding during NSAID therapy.
Etrixenal is not recommended for use in children.
Patiens with renal/hepatic impairment
A lower dose should be considered in patients with renal or hepatic impairment. Etrixenal is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of naproxen metabolites has been seen in patients with severe renal failure or those on dialysis.
II.3 General comments on the submitted dossier
These decentralised applications for Etrixenal 250 mg tablets is a a so called “Generic Application” made according to Article 10(1) of Directive 2001/83/EC (as amended).
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With Lithuania as the Reference Member State in this Decentralized Procedure, Proenzi s.r.o. is applying for the Marketing Authorisations for Etrixenal 250 mg tablets in CMS: BG, CZ, EE, HU, LV, PL, RO, SK.
The active substance is not considered a new active substance.
Etrixenal is not recommended for use in children. Relevant information was included in SmPC and PL. There is no additional need for paediatric development and development in other special populations.
The applicant has submitted documentation to prove that Etrixenal 250 mg tablets is essentially similar to reference medicinal product Naprosyn 250 mg tablets by Roche Products Limited, UK. Naprosyn has been authorised since 1996 in UK. Etrixenal 250 mg tablets has the same qualitative composition in terms of active substance, the same pharmaceutical form, and is claimed to be bioequivalent to Naprosyn (the applicant has submitted as report bioequivalence study).
The submitted documentation is of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory quality, non-clinical and clinical overviews have been submitted. They represent an adequate summary of the dossier.
The applicant submitted a Risk Management Plan, version 1.0, dated 19 July 2013.
Detailed description of the Pharmacovigilance system has been provided (see Day 70 non-clinical and clinical AR).
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
The Qualified Person declaration, that the active substance naproxen is manufactured on the manufacturing site in compliance with the detailed guidelines on good manufacturing practice for starting materials, has been provided.
The bioequivalence study was signed for compliance with GLP and GCP.
III SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
The active substance naproxen is described in the European Pharmacopoeia. The CEP procedure is applied. The submitted updated CEP is the current version according to the EDQM certification database.
The drug product manufacturer´s specification for naproxen is based on European Pharmacopoeia and based on the specifications of drug substance manufacturer. Additional tests for particle size and microbiological quality are included. Test for particle size is proposed by the drug product manufacturer taking into consideration the formulation characteristics and requirements. The limits for above additional test were finalized based on the product development studies. The reference standards are suitable for use as reference materials. The container closure system is described in sufficient detail. The compliance of the packaging material with Commission Regulation 10/2011 is stated.
Three commercial scale batches have been included in the stability studies. The tested parameters are considered to indicate stability sufficiently. The proposed retest date for naproxen drug substance, used by the drug product manufacturer is acceptable.
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The development of the product has been described, the choice of excipients is justified and their functions explained.
The product specifications cover appropriate parameters for this dosage form. The control tests and specifications for drug product are adequately drawn up.
Validations of the analytical methods have been presented. Batch analysis has been performed on several batches. The batch analysis results show that the finished products meet the specifications proposed.
The conditions used in the stability studies are according to the ICH stability guideline.
The proposed shelf-life of four years with storage statement “This medicinal product does not require any special storage conditions” for the drug product is considered acceptable
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of naproxen are well known. As naproxen is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
Environmental Risk Assessment (ERA)
Since Etrixenal is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
There are no objections to approval of Etrixenal from a non-clinical point of view.
III.3 Clinical aspects
The clinical overview on the clinical pharmacology, efficacy and safety is adequate.
The European Reference Product Naprosyn 250 mg tablets (Roche Products Limited, UK) is used because Reference Medicinal Product have been never authorised in the chosen Reference Member State (RMS) Lithuania.
One bioequivalence study has been submitted for the 250 mg strength. Naproxen has a elimination half-life of approximately 12–15 hours.
Pharmacokinetic study (366-09)
An open-label, single-dose, randomized, two-period, two-sequence, two-treatment cross-over study under fed conditions in healthy male subjects (Study No.: 366-09) has been conducted.
The reference product: Naprosyn 250 mg tablets (Roche Products Limited, UK) from the UK market.
Design of the study is acceptable wash-out long (8 days) is enough, sampling period long is enough, sampling scheme is adequate to estimate PK parameters.
The analytical method is acceptable, correctly validated, handling of samples is adequate. Pharmacokinetic variables are adequate.
Both the test and reference dosage forms have essentially similar pharmacokinetic parameters in terms of AUC and Cmax for naproxen. The log transformed 90% CI ranges for Cmax was 91.43 – 100.06%, AUC (0-t) was 100.16 – 104.53% and AUC(0-∞) was 99.70 – 104.57%.
Study subjects received non high-fat meal. It is stated that naproxen should be taken preferably with or after food in the originator SmPC. Therefore the study under fed conditions is acceptable. Whereas no specific recommendation is given in the originator SmPC, the meal in BE study should be a high-fat meal. However study subjects received non high-fat meal. It does not meet Guideline on the
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Investigation of Bioequivalence (Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr, 2010). Bioequivalence study of naproxen on 250 mg strength was conducted in year-2009 as per the recommendations in force at that point in time and hence the selection of meal was non-high fat in nature. Concomitant administration of food can delay the absorption of naproxen, but does not affect its extent. Therefore the use of low-fat meal instead of standard high-fat meal in the bioequivalence study conducted on 250 mg strength is not likely to have any impact on the outcome of the bioequivalence study.
Pharmacokinetic study (NAPR-1677-13)
The applicant present report from another BE study conducted recently in 2013 using 500 mg strength of naproxen tablets wherein high-fat meal was used as per the current recommendations. This BE study was carried out as an open label, balanced, randomized, single dose, two treatment, two period, two-sequence, two-way cross-over, comparative oral bioavailability study of the test product Naproxen 500 mg tablets with the reference product Naprosyn 500 mg Tablets of Roche products Limited, UK] in healthy adult human subjects under fed conditions. The results were satisfactory thus demonstrating that the proposed product is bio-equivalent to the reference product. The results of presented BE study (Study No. NAPR-1677-13) for 500 mg strength were satisfactory thus demonstrating that the proposed product is bioequivalent to the reference product. Both the test and reference dosage forms have essentially similar pharmacokinetic parameters in terms of AUC(0-t), AUC(0-∞) and Cmax for naproxen. The log transformed 90% CI ranges were for: Cmax 94.76 – 101.17%, AUC (0-t): 100,84 – 108,06%, AUC(0-∞): 100.83 – 106.26%.
A detailed discussion justifying biowaiver for bioequivalence study on 250 mg strength based on satisfactory study conducted on 500 mg strength is presented.
According to Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr, 2010) the general biowaiver criteria (linear pharmacokinetics, the same manufacturing process, the same qualitative composition of the different strengths, the composition of the strengths are quantitatively proportional, dissolution) are met. Biowaiver for 250 mg strength based on bioequivalence study conducted on 500 mg strength is acceptable.
No new data have been submitted. No data are required for this application (bioequivalence has been shown by pharmacokinetic studies).
To support the application, the applicant has submitted as report bioequivalence study with 250 mg and 500 mg naproxen. Provided that bioequivalence with the originator product is demonstrated, additional data is not necessary.
The SmPC of Etrixenal has some differences from that of the reference product.
Whereas Etrixenal is proposed as OTC product this medicinal product has less indications for short-term use than the reference product Naprosyn. Moreover Etrixenal is not used for paediatric population (see Table 1).
Table 1. Therapeutic indications of Etrixenal and Naprosyn.
Etrixenal 250 mg tablets
Naprosyn 250 mg tablets
Short-term relief of acute mild or moderate pain
Treatment of rheumatoid arthritis, osteoarthrosis
(joints, muscles, tendons or menstruation) in
(degenerative arthritis), ankylosing spondylitis,
acute gout, acute musculoskeletal disorders and
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Juvenile rheumatoid arthritis
To support the application, the applicant has submitted as report bioequivalence study with 250 mg naproxen:
- Both (test and reference) treatments were tolerated very well.
- No serious adverse events were reported.
Therefore, it is judged that the study drugs were safe and well tolerated by the healthy adult subjects enrolled in this study.
If the bioequivalence with the originator product was proved, additional data would not be necessary.
Risk Management Plan
The Applicant states that there is no need for additional risk minimization activities because this is generic application and the product has a well-known safety profile. Applicant will perform routine pharmacovigilance activities. As Etrixenal is proposed to be OTC medicinal product adequate information in the Package Leaflet (PL) is very important for the patients. The applicant has presented updated (Day 106) RMP and correct the part V ”Risk minimisation measures” by adding information for patients.
RMS agrees that this is acceptable.
Periodic Safety Update Report (PSUR)
According to the EURD list (March 2013) no PSURs are currently required for monocomponent naproxen containing products referred to in Art. 10(1) of Directive 2001/83/EC, as amended. The applicant should monitor the EURD list for any changes to the requirements for PSUR submission and changes in periodicity and Data Lock Point.
Common renewal date
The RMS proposes a common renewal date five years after the finalisation/approval of this DCP. The applicant agrees with this proposal.
IVBENEFIT RISK ASSESSMENT
The use of naproxen is well established. It has recognised efficacy and acceptable safety.
From a quality point of view, there are no objections against granting MA for the product at issue.
From a non-clinical point of view, the pharmacodynamic, pharmacokinetic and toxicological properties of naproxen are well known. There are no objections to approval of Etrixenal from a non-clinical point of view.
From a clinical point of view, the application contains an adequate review of published clinical data and the submitted bioequivalence studies (366-09 and NAPR-1677-13). Both the test and reference dosage forms have essentially similar pharmacokinetic parameters of AUC and Cmax for naproxen. The bioequivalence studies were signed for compliance with GLP, GCP.
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AUTHORISATION AND PRODUCT INFORMATION
V.1Conditions for the marketing authorisation
Not subject to medical prescription (OTC).
V.2Summary of Product Characteristics (SmPC)
The SmPC of Etrixenal has some differences from that of the reference product.
Whereas Etrixenal is proposed as OTC product this medicinal product has less indications for short-term use than the reference product Naprosyn. Moreover Etrixenal is not used for paediatric population (see Section III.3, Table 1 of this Overview AR).
The other sections of SmPC mainly is in accordance with the innovator’s SmPC.
The SmPC is acceptable.
V.3Package Leaflet (PL) and User Testing
The PL mainly is in accordance with the SmPC.
User testing covered the key safety messages. Participants were able to locate, understand and use the information, at least 90% of the time, for every question. The general comments were mainly positive. The User Testing is considered positive and no changes are recommended to the PL based on the results.
Trumpa kokybinės dalies apžvalga
Vaistinio preparato registravimo paraiška pateikta pagal direktyvos 2001/83/EB 10 str. 1d. “generinis”. Vaistinio preparato veiklioji medžiaga naproksenas aprašytas Europos farmakopėjoje. Veikliosios medžiagos gamintojas turi naprokseno kokybės atitikties Europos farmakopėjai sertifikatą. Galutinio produkto gamintojo veikliosios medžiagos naprokseno specifikacija yra tinkamos kokybės. Naprokseno specifikacijoje reglamentuojamų parametrų nustatymui naudojamos analizės procedūros yra tokios pačios, kaip ir reglamentuoja Europos farmakopėja straipsnyje naprokseno kokybei. Galutinio produkto sudėtyje esančios pagalbinės medžiagos yra saugios ir plačiai naudojamos farmacinių preparatų kūrimui. Pareiškėjas pateikė pakankamai duomenų paraiškai pagal direktyvos 2001/83/EB 10 str. 1d. “generinis” pagrįsti. Galutinio produkto specifikacijos kokybė yra tinkama ir atitinka pripažintų standartų reikalavimus. Galutinio produkto kokybei kontroliuoti analizės procedūros yra parinktos tinkamai, šiuolaikinės ir validuotos.
Reglamentuojamos vaistinio preparato tinkamumo laikas ir laikymo sąlygos yra patvirtintos stabilumo tyrimo duomenimis. Stabilumo tyrimų duomenimis siūlomas vaistinio preparato tinkamumo laikas yra 4 metai. Jokių specialių šio vaistinio preparato laikymo sąlygų nėra reglamentuojama.
Visus klausimus dėl vaistinio preparato kokybės pareiškėjas išsprendė todėl esminių prieštaravimų dėl vaistinio preparato kokybės nėra.
Trumpa ikiklinikinės ir klinikinės dalies apžvalga
Etrixenal 250 mg tabletės yra nereceptinis vaistinis preparatas, skirtas vartoti suaugusiems pacientams nurodytoms indikacijoms.
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Trumpalaikis ūminio silpno arba vidutinio stiprumo skausmo (sąnarių, raumenų, sausgyslių ar mėnesinių) malšinimas suaugusiesiems.
Vaistinio preparato paraiška rinkodaros teisei suteikti pateikta pagal direktyvos 2001/83/EB 10 str. 1d. “generinis”. Pareiškėjas klinikiniais tyrimais įrodė, kad vaistinis preparatas Etrixenal 250 mg tabletės yra iš esmės panašus į referencinį vaistinį preparatą Naprosyn 250 mg tablets (Roche Products Limited, Jungtinė Karalystė).
Naproksenas yra nesteroidinis priešuždegiminis skausmą malšinantis vaistinis preparatas. Jis (kaip ir kiti nesteroidiniai vaistai nuo uždegimo) slopina prostaglandinų sintezę.
Naprokseno farmakodinaminės, farmakokinetinės ir toksikologinės savybės yra gerai žinomos. Kadangi pateikta generinė paraiška, yra referuojama į referencinio vaistinio preparato tyrimų duomenis, todėl naujų ikiklinikinių tyrimų duomenų pareiškėjas nepateikė.
Kadangi pateikta generinė paraiška, pareiškėjas pateikė biologinio ekvivalentiškumo klinikinius tyrimus, kurie buvo atlikti laikantis geros klinikinės praktikos ir geros laboratorinės praktikos.
Remiantis pateiktais kokybės, saugumo ir veiksmingumo duomenimis, decentralizuotoje procedūroje dalyvaujančios referencinė šalis (Lietuva) ir pripažįstančios šalys (BG, CZ, EE, HU, LV, PL, RO, SK) nutarė, kad vaistiniam preparatui Etrixenal 250 mg tabletės rinkodaros teisę suteikti galima ir europinė fazė buvo sėkmingai baigta (204 dieną) 2014-08-14. Po nacionalinės fazės Lietuvoje rinkodaros teisė suteikta 2014-10-16.
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|Vartojimas||vartoti per burną|
|Registratorius||Proenzi s.r.o., Čekija|