Decentralised Procedure

Public Assessment Report

Ziloxicum 60 mg Hartkapseln

Acemetacin

DE/H/3936-3937/001/DC

Applicant: Drossapharm GmbH, Germany

Reference Member State DE

 TABLE OF CONTENTS
I. INTRODUCTION ............................................................... 4
II. EXECUTIVE SUMMARY ............................................................... 4
II.1 Problem statement ......................................................................................................... 4
II.2 About the product .......................................................................................................... 4
II.3 General comments on the submitted dossier................................................................... 4
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.5
III. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................... 5
III.1 Quality aspects ............................................................................................................... 5
III.2 Non-clinical aspects ........................................................................................................ 5
III.3 Clinical aspects............................................................................................................... 6
IV. BENEFIT RISK ASSESSMENT ............................................................... 7

Ziloxicum, DE/H/3936-3937/001/DC Public AR Page 2/7

ADMINISTRATIVE INFORMATION
Proposed name of the medicinal
product(s) in the RMS
Name of the drug substance (INN
name):
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and
strength(s):
Reference Number(s) for the
Decentralised Procedure
Reference Member State:
Member States concerned:
Applicant (name and address)
Ziloxicum, DE/H/3936-3937/001/DC
Ziloxicum 60 mg Hartkapseln
Acemetacin
M01AB11
Capsules, hard ; 60 mg
DE/H/3936-3937/001/DC
DE
DE/H/3936/001/DC: EL, HU, LU, MT
DE/H/3937/001/DC: LU
Drossapharm Arzneimittel Handelsgesellschaft mbH
Wallbrunnstr. 24, D-79539 Lrrach, Germany
Public AR Page 3/7
I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the application for Ziloxicum 60 mg
Hartkapseln, in the indications:
Symptomatic treatment of pain and inflammation in
acute arthritis (including gout)
chronic arthritis, particularly in rheumatoid arthritis (chronic polyarthritis)
ankylosing spondylitis (Bechterews Disease) and other inflammatory rheumatic spinal
disorders
osteoarthritis
soft tissue inflammatory rheumatic disorders
painful inflammation and swelling due to trauma,
is approved.

II. EXECUTIVE SUMMARY

II.1 Problem statement
N/A

II.2 About the product

Acemetacin is a glycolic acid ester, and acts as a prodrug. It is metabolized to the nonsteroidal anti-
inflammatory drug (NSAID) indometacin, which then acts as an inhibitor of cyclooxygenase,
producing the anti-inflammatory effects.
Observations from animal and clinical pharmacological studies as well as controlled clinical studies
indicate an advantage of acemetacin regarding gastric damage when compared to indometacin.
Acemetacin (as well as indometacin) are indicated in
symptomatic treatment of
acute arthritis (including gout)
chronic arthritis, particularly in rheumatoid arthritis (chronic polyarthritis)
ankylosing spondylitis (Bechterews Disease) and other inflammatory rheumatic spinal
disorders
irritation due to osteoarthritis and spondyloarthritis
soft tissue inflammatory rheumatic disorders
painful inflammation and swelling due to trauma

Acemetacin is well known product containing a widely used, well-known active substance. No
further clinical trials are provided by the applicant.
Drossapharm AG has developed a new Acemetacin forte 60 mg capsule in order to provide more
predictable absorption. The new (Drossapharm) formulation has a slightly different composition
which serves to reduce variability. Therefore, due to formulation changes, differences between Test
and Reference product were expected regarding pharmacokinetic values.

II.3 General comments on the submitted dossier

This application is a hybrid application submitted in accordance with Article 10.3 of Directive
2001/83/EC. This decentralised application concerns a generic version of Acemetacin, under the
trade name Ziloxicum 60 mg capsules, hard. In this Assessment Report, the name Acemetacin is
used.
The originator product, used as reference product in the supported Bioequivalence Study, is
Rantudil forte 60 mg capsules by MEDA Pharma GmbH, Germany.
With Germany acting as RMS in this procedure, the applicant applies for a marketing authorisation in
EL, HU, LU, MT (DE/H/3936/001/DC) and LU (DE/H/3937/001/DC), respectively.

Ziloxicum, DE/H/3936-3937/001/DC Public AR Page 4/7

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.
Additionally, GMP certificates of manufacturing facility of the drug product manufacturers issued by
the competent local authority following an inspection have been provided.
A qualified person declaration that the active substance is manufactured in compliance with the
detailed guidelines on good manufacturing practice for starting materials has been provided.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects
Drug substance
The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Ziloxicum
60 mg Hartkapseln are of sufficient quality in view of the present European regulatory requirements.
The drug substance of the present drug product is Acemetacin, which is described in the European
Pharmacopoeia. The suitability of the monograph to test the drug substance has been verified and is
documented with help of a certificate of suitability of the European pharmacopoeia: R0-CEP 2012-
211-Rev 01. According to the CEP, the re-test period of the drug substance is 60 months if stored in
double polyethylene bags placed in a cardboard drum with desiccant.

Drug Product
The development of the product Ziloxicum 60 mg Hartkapseln has been described, the choice of
excipients is justified and their functions explained. The active ingredient and excipients used are
well known and of pharmacopoeial quality. The product specifications cover appropriate parameters
for this dosage form. Validations of the analytical methods have been presented. Batch analysis has
been performed on four production 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 control tests and specifications for drug product are adequately
drawn up. A shelf-life of 60 months with a storage restriction of Do not store above 30C. for the
drug product is accepted.

III.2 Non-clinical aspects

Pharmacology, pharmacokine tics, toxicology
Pharmacodynamic, pharmacokinetic and toxicological properties of acemetacin are well known. As
acemetacin is a widely used, well-known active substance, the applicant has not provided additional
non-clinical studies and further non-clinical studies are not required. Overview based on literature
review is, thus, appropriate. The submitted non-clinical overview on the non-clinical pharmacology,
pharmacokinetics and toxicology of acemetacin is considered adequate.

Environmental Risk Assessment (ERA)

The presented Log Kow is below 3 therefore no further screening for persistence, bioaccumulation
and toxicity is necessary. The PECsurfacewater value exceeds the action limit of 0.01 g/L.
Therefore, a Phase II assessment is required.
An updated ERA will be presented as post approval commitment within 2 years after the start of
marketing of each European country which acemetacin actually marketed by Drossapharm GmbH.
The assessment of the ERA will be concluded when ERA data have been submitted by the applicant.

Ziloxicum, DE/H/3936-3937/001/DC Public AR Page 5/7

III.3 Clinical aspects
The application refers to Article 10.3 of Directive 2001/83/EC (hybrid application). This is
appropriate in the case where bioequivalence cannot be demonstrated through bioavailibility studies
with the reference product. Acemetacin as well as the main active metabolite Indometacin are well
known, and in case of a synonym product containing a widely used, well-known active substance, no
further clinical trials are required and none are provided by the applicant. The applicant has
submitted a single oral dose, open label, randomized, four-period, replicate designed, comparative
bioavailability study of acemetacin 60 mg following administration after light continental breakfast
(Study no. SC02408 / EudraCT NO: 2009-01459040).

Clinical efficacy / safety

Analgesic efficacy cannot simply be predicted from plasma concentrations but varies individually as
a function of the individual patients sensitivity, clinical status and analgesics pre-treatment. Due to
the particularities of the newly developed formulation bioequivalence with the originator tablets
cannot be shown in terms of Cmax due to flatter, however more stable, plasma concentrations over the
12 hour dosing interval. A similar efficacy and safety profile (as compared to the reference product)
can be assumed for the newly developed formulation without providing additional phase III data in
the proposed indications.

User Testing
Overall, the test methodology follows the guidelines of the European Commission (Guideline on the
readability of the label and package leaflet of medicinal products for human use, Revision January
2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning
consultations with target patient groups for the packet leaflet, May 2006).
Both the first and the second test round met the success criteria of 90% of the subjects being able to
locate the requested information, and of those, 90% being able to give the correct answer, to indicate
that they understood the information presented. The general impression of the PL (Content, language
and layout) was mostly positive. In conclusion, the user test is considered acceptable.

Summary Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed
Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File
fully complies with the new legal requirements as set out in the Commission Implementing
Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

Summary of safety concerns
Important identified risks Gastrointestinal disorders (ulcer,
perforation and bleeding)
Cardiovascular and cerebrovascular
events
Severe skin reactions
Hepatic disorders
Important potential risks Renal disorders
Missing information Use during pregnancy and lactation
Use in patients less than 18 years of age
Use in patients with Renal Insufficiency
Use in patients with Hepatic Impairment
No additional pharmacovigilance or risk minimisation activities have been proposed.

Ziloxicum, DE/H/3936-3937/001/DC Public AR Page 6/7

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

PSURs shall be submitted in accordance with the requirements set out in the list of Union
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and
published on the European medicines web-portal. Marketing authorisation holders shall
continuously check the European medicines web-portal for the DLP and frequency of
submission of the next PSUR.
For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of
Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in
the EURD list.
For medicinal products that do not fall within the categories waived of the obligation to
submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow
the DLP according to the EURD list.

IV. BENEFIT RISK ASSESSMENT

The application contains an adequate documentation of the safety, quality and pharmaceutical
development program. The discussed literature and additional pharmacokinetic data presented are
sufficient to demonstrate comparability of the applied generic and originator product with regard to
safety and efficacy. Analgesic efficacy cannot simply be predicted from plasma concentrations but
varies individually as a function of the individual patients sensitivity, clinical status and analgesics
pre-treatment. Due to the particularities of the newly developed formulation bioequivalence with the
originator tablets cannot be shown in terms of Cmax due to flatter, however more stable, plasma
concentrations over the 12 hour dosing interval. A similar efficacy and safety profile (as compared to
the reference product) can be assumed for the newly developed formulation without providing
additional phase III data in the proposed indications.
The application is approved.
For intermediate amendments see current product information.

Ziloxicum, DE/H/3936-3937/001/DC Public AR Page 7/7