Decentralised Procedure

Public Assessment Report

Burana

Ibuprofen

DE/H/5281/001/DC

Applicant: Orion Corporation

Date: 08.02.2019

This module reflects the scientific discussion for the approval of Burana 50 mg/g Gel. The
procedure was finalised on 26.03.2018.
 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 . 4
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 ............................................................................................ 8

Burana, DE/H/5281/001/DC Public AR 2/8

 ADMINISTRATIVE INFORMATION

Name of the medicinal product in the

Burana
RMS:

Name of the drug substance (INN

Ibuprofen
name):

Pharmaco-therapeutic group
M02AA13
(ATC Code):

Pharmaceutical form(s) and

50 mg/g Gel
strength(s):

Reference Number(s) for the

DE/H/5281/001/DC
Decentralised Procedure:

Reference Member State: DE

Concerned Member States: FI

Legal basis of application: Art. 10a - Well established use

Orion Corporation (Orion Pharma)
Applicant (name and address):
Orionintie 1
FIN-02200 ESPOO
Orion Corporation (Orion Pharma)
Names and addresses of all proposed
Orionintie 1
manufacturer(s) responsible for
FIN-02200 ESPOO
batch release in the EEA:
Orion Corporation Orion Pharma (BS 3)
Joensuunkatu 7
FIN-24100 SALO

Burana, DE/H/5281/001/DC Public AR 3/8

I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the application for Burana, in the
short-term treatment of local pain in acute strains, sprains or contusions of the upper or lower limb
resulting from benign traumas, e.g. sports injuries, is approved.

II. EXECUTIVE SUMMARY

II.1 Problem statement
Not applicable.

II.2 About the product

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that in conventional animal-inflammation
models has proven to be effective via prostaglandin-synthesis inhibition. In humans, ibuprofen reduces
inflammation-related pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits ADP- and
collagen-induced platelet aggregation.
For Burana 50 mg/g gel the claimed indication is the short-term symptomatic treatment of local pain in
acute strains, sprains or contusions of the upper or lower limb resulting from benign traumas, e.g.
sports injuries. The proposed user group are adults and adolescents aged from 14 years.

II.3 General comments on the submitted dossier

This is a decentralised application for Burana, submitted under article 10a (well-established use). On
25th Jan 2017 the applicant sought scientific advice in DE for Burana concerning a comparative
approach in respect with Nurofen 5% gel.
With Germany as the Reference Member State in this decentralised procedure, Orion Corporation is
also applying for the Marketing Authorisations for Burana in FI.
This application refers to published scientific literature. Besides, supportive comparative data
regarding the in vitro drug release (IVR) are provided to justify a bridging to the marketed Nurofen
5% gel.
As the active ingredient, Burana contains 50 mg racemic ibuprofen in one g of the gel. Burana has the
same composition as Extrapan 5% gel (Qualiphar, Belgium). The qualitative composition is:

Ibuprofen
Isopropyl alcohol
Hydroxyethyl cellulose
Sodium hydroxide
Benzyl alcohol
Water q.s.

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 prior to granting its National
authorisation.
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 Eudra GMP certificates are available for the manufacturing sites of the drug product
manufacturers.

GMP active substance

Qualified Person declarations that the active substance Ibuprofen is manufactured in compliance with
the detailed guidelines on good manufacturing practice for starting materials have been provided for
both drug product manufacturers.

Burana, DE/H/5281/001/DC Public AR 4/8

GLP
There is no information given about the GLP compliance of the cited studies. Usually, only GLP-
conform studies should be taken into consideration as relevant for the bibliographic application.

GCP
The application is based on published literature. There is no information given about the GCP
compliance of the cited studies. Usually, only studies with GCP compliance should be taken into
consideration as relevant for the bibliographic application.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects
Drug substance
The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Burana are
of sufficient quality in view of the present European regulatory requirements. No major objections
have been identified.
The drug substance of the present drug product is Ibuprofen, 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.
The control tests and specifications for drug substance product are adequately drawn up.
For the active substance a re-test period of 5 years is confirmed on the current CEP, when stored in
lock-rim fibre drums.

Drug Product
The development of the product Burana has been described, the choice of excipients is justified and
their functions explained.
The applicant provided an in vitro drug release study showing similar in vitro release rates of the test
and reference product. Additionally characteristics of the test and reference products affecting the
release i.e. viscosity and pH, were tested showing also similarity between test and reference product.
The provided data showing the equivalence of the test and reference product as justification for a
biowaiver are acceptable.
The product specifications cover appropriate parameters for this dosage form. Validations of the
analytical methods have been presented. Batch analysis has been performed on three 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.
The proposed shelf-life of 2 years without storage restriction for the drug product is accepted

III.2 Non clinical aspects

Pharmacology, Pharmacokinetics, Toxicology
The general pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well
known. The Applicant has provided a nonclinical overview which, overall, adequately summarises the
nonclinical data available for general pharmacology, pharmacokinetics and toxicology of systemically
applied ibuprofen.
However, for topically applied ibuprofen, the rate and extent of absorption and, related to this, the
therapeutic efficacy, local tolerance and systemic safety depends substantially on the specific
formulation used and the specific way of administration.
The Applicant has not provided any specific nonclinical data for the topical product currently
submitted for marketing authorisation. Therefore, from a nonclinical point of view, efficacy and safety
of the product has not been established. However, it is acknowledged that these nonclinical
deficiencies can be superseded by adequate clinical data and/or in vitro release data. In this respect,
reference is made to the Quality and the Clinical Assessment.

Environmental Risk Assessment (ERA)

The applicant provided a justification for waiving ERA studies. The provided justification is
acceptable since the product is not intended for the German markets, as stated in the cover letter of the
initial dossier. There is no increase of ibuprofen on the Finnish market.

Burana, DE/H/5281/001/DC Public AR 5/8

Conclusion
In this procedure an ERA is not required since there is no increase of ibuprofen on the Finnish market.
However, publically available data show a high toxicity of ibuprofen to fish and an environmental risk
cannot be excluded. Therefore, the applicant inserted an advice into section 5.3 (preclinical safety
data) and section 6.6 of the SmPC: The active substance ibuprofen shows an environmental risk to the
aquatic environment. This is in line with the proposal of the CHMP SmPC Advisory Group from May
2014.

III.3 Clinical aspects

The clinical overview is sufficient. In addition, the applicant has submitted a clinical expert statement
(CES) to support the use of Burana without a doctor’s prescription.

Pharmacokinetics
The pharmacokinetics of topically applied ibuprofen is known. The rate and extent of absorption
depends considerably on the formulation, way of administration and use of occlusion.

Pharmacodynamics
The pharmacodynamics of ibuprofen is well-known.

Clinical efficacy and clinical safety

For Burana the claimed indication is the short-term symptomatic treatment of local pain in acute
strains, sprains or contusions of the upper or lower limb resulting from benign traumas, e.g. sports
injuries. The proposed user group are adults and adolescents aged from 14 years. The applicant stated
that dermally applied ibuprofen is well suited for the treatment of patients with Osteoarthritis and
other forms of musculoskeletal pain because the formulations are able to penetrate muscle, synovium,
and joint tissues proximal to and below the site of application.
Burana is qualitatively identical and quantitatively very similar to Nurofen 5% gel (1.04% difference
in sodium hydroxide amount). Supportive results from in vitro comparative studies have been
provided to justify the bridge to the marketed Nurofen 5% gel. In this respect reference is made to the
Quality assessment. Pharmaceutical equivalence between Burana and Nurofen 5% gel has been
shown.

Selective review of submitted literature has shown that the usage of ibuprofen 5% gel was effective in
soft tissue injuries regarding two studies published in 2002 by the same group comparing ibuprofen
gel (Ibugel, Dermal Laboratories, UK). In the first study [Machen 2002], the efficacy of ibuprofen 5%
gel (Ibugel) was evaluated in a placebo-controlled study in patients with soft tissue injuries. Patients
received either active gel (n=40) or placebo gel (n=41) for a maximum of 7 days. Pain and interference
with physical activity were assessed daily using visual analogue scales. There was a significant
difference (p<0.001) in favour of active treatment for the time to achieve clinically meaningful
reduction in pain. By day 7, 75% of patients in the active gel group had a clinically meaningful
reduction of pain compared with 39% of patients who received placebo. Despite differences between
study centres, the data for interference with physical activity also showed an advantage for active
treatment. By day 7, 79% of patients in the active gel group had a clinically meaningful reduction in
interference with physical activity, compared with 44% of patients who received placebo.

In the second study [Whitefield 2002], the efficacy of ibuprofen 5% gel (Ibugel) and ibuprofen
400 mg tablets (1200 mg daily) was compared in a double-blind, double-dummy, parallel group study
in patients with acute soft tissue injuries. Patients received either active gel plus placebo tablets (n=50)
or active tablets plus placebo gel (n=50) for at least 7 days. The gel was applied and 1 tablet was taken
3 times daily. The 2 treatments showed similar efficacy. There were no significant differences between
the groups for either the primary efficacy endpoint, the median time for the injury to be rated as
“completely better” by the patients (>14 days active gel, 13.5 days active tablets, p=0.59), or for other
efficacy measures including the times to clinically significant relief from pain at rest or on movement
and swelling. The authors concluded that ibuprofen gel showed similar efficacy to oral ibuprofen
400 mg and may offer improved tolerability.

There is evidence that topical NSAIDs, including ibuprofen, do less harm than oral NSAIDs.

Burana, DE/H/5281/001/DC Public AR 6/8

Furthermore, Burana has been marketed by the brand name Extrapan Ibuprofenum 5% gel in Belgium
since March 2001. According to the Applicant no safety concerns have been raised in the meantime.
The safety of the product is thus considered well covered.

Legal Status
In DE the legal status of ibuprofen 5% gel is OTC in accordance with the
Arzneimittelverschreibungsverordnung (AMVV).

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 has submitted a signed Summary of the Applicant's and/or 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

The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to ibuprofen gel.

Safety specification

Important identified risks  Application site reactions

 Systemic adverse reactions typical of NSAIDs
Important potential risks  N/A

Missing information  Use in patients < 14 years of age

Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed
by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by
the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP and any agreed subsequent updates of the RMP.

Burana, DE/H/5281/001/DC Public AR 7/8

An updated RMP should be submitted:
- At the request of the RMS;
- Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time, but via different procedures.

Periodic Safety Update Report (PSUR)

The marketing authorisation holder shall submit periodic safety update reports for this product 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.

IV. BENEFIT RISK ASSESSMENT

Based on the review of the data on quality, safety and efficacy, the benefit-risk-balance for Burana, in
the short-term treatment of local pain in acute strains, sprains or contusions of the upper or lower limb
resulting from benign traumas, e.g. sports injuries, is positive. The application is approved. For
intermediate amendments see current product information.

Burana, DE/H/5281/001/DC Public AR 8/8