UK/H/5891/001/DC
PAR Ibupr ofen 100 mg/5 ml or al suspension
Public Assessment Report
Decentralised Procedure
Ibuprofen 100 mg/5 ml oral suspension
(Ibuprofen)
Procedure No: UK/H/5891/001/DC
UK Licence No: PL 34088/0042
Alkaloid-INT d.o.o.
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UK/H/5891/001/DC
PAR Ibupr ofen 100 mg/5 ml or al suspension
LAY SUMMARY
Ibuprofen 100 mg/5 ml oral suspension
(ibuprofen, oral suspension, 100 mg/5ml)
This is a summary of the Public Assessment Report (PAR) for Ibuprofen 100 mg/5 ml oral suspension
(PL 34088/0042; UK/H/5891/001/DC). It explains how Ibuprofen 100 mg/5 ml oral suspension was
assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide
practical advice on how to use Ibuprofen 100 mg/5 ml oral suspension.
The product will be referred to as Ibuprofen throughout the remainder of this PAR.
For practical information about using Ibuprofen, patients should read the package leaflet or contact their
doctor or pharmacist.
What is Ibuprofen and what is it used for?
Ibuprofen is a ‘generic medicine’. This means that Ibuprofen is similar to a ‘reference medicine’ already
authorised in the European Union (EU) called Brufen Syrup (Abbott Laboratories Ltd).
Ibuprofen is used in children, aged 3 months and older (weighing more than 5 kg) for short-term
symptomatic treatment of:
• Mild to moderate pain such as headache and toothache
• Fever
• Feverishness and symptoms of cold and flu
How does Ibuprofen work?
Ibuprofen (the active ingredient in this medicine) belongs to a group of medicines known as nonsteroidal anti-inflammatory drugs (NSAIDs) which relieve pain, reduce swelling and lower temperature
when the patient has a fever.
How is Ibuprofen used?
The pharmaceutical form of Ibuprofen is an oral suspension and the route of administration is via the
mouth (oral).
The patient must always take this medicine exactly as described in the package leaflet or as their doctor,
or pharmacist has told them. The patient should check with their doctor or pharmacist if they are not
sure.
It is recommended that patients with sensitive stomachs take Ibuprofen with food. Doses should be given
every 6-8 hours. Leave at least 4 hours between doses. The respective dosing interval should be chosen
in line with the symptoms.
The maximal daily dose should not be exceeded.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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The doses are:
There is a 5 ml plastic oral dosing syringe in the pack which should be used to administer the medicine.
Please read section 3 of the package leaflet for detailed information on dosing recommendations, the
route of administration, and the duration of treatment.
This medicine can be obtained without a prescription and is on the general sales list (GSL).
What benefits of Ibuprofen have been shown in studies?
Because Ibuprofen is a generic medicine, studies in patients have been limited to tests to determine that
this medicine is bioequivalent to the reference medicine Brufen Syrup (Abbott Laboratories Ltd). Two
medicines are bioequivalent when they produce the same levels of the active substance in the body.
What are the possible side effects of Ibuprofen?
Because Ibuprofen is a generic medicine, its benefits and possible side effects are taken as being the
same as the reference medicine.
For the full list of restrictions, see the package leaflet.
For the full list of all side effects reported with Ibuprofen, see section 4 of the package leaflet available
on the MHRA website.
Why was Ibuprofen approved?
It was concluded that, in accordance with EU requirements, Ibuprofen has been shown to have
comparable quality and to be bioequivalent to Brufen Syrup (Abbott Laboratories Ltd). Therefore, the
MHRA decided that, as for Brufen Syrup (Abbott Laboratories Ltd), the benefits are greater than their
risk and recommended that it can be approved for use.
What measures are being taken to ensure the safe and effective use of Ibuprofen?
A risk management plan (RMP) has been developed to ensure that Ibuprofen is used as safely as
possible. Based on this plan, safety information has been included in the Summary of Product
Characteristics and the package leaflet for Ibuprofen including the appropriate precautions to be
followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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Other information about Ibuprofen
Bulgaria, the Czech Republic, Spain, Croatia, Hungary, Poland, Romania, Slovenia and the UK agreed
to grant a Marketing Authorisation for Ibuprofen on 27 January 2016. A Marketing Authorisation was
granted in the UK on 23 February 2016.
The full PAR for Ibuprofen follows this summary.
For more information about treatment with Ibuprofen read the package leaflet, or contact your doctor or
pharmacist.
This summary was last updated in April 2016.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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TABLE OF CONTENTS
I
II
III
IV
V
VI
Introduction
Quality aspects
Non-clinical aspects
Clinical aspects
User consultation
Overall conclusion, benefit/risk assessment and
recommendation
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Page 7
Page 9
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Member States considered that the
application for Ibuprofen 100 mg/5 ml oral suspension (PL 34088/0042; UK/H/5891/001/DC) could be
approved. The product is a General Sales List (GSL) medicine indicated for use in children, aged 3
months (weighing more than 5 kg) and upwards for:
• Short term symptomatic treatment of mild to moderate pain and fever.
• Short-term symptomatic treatment of pain and feverishness associated with common cold and
influenza.
The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference
Member State (RMS) and Bulgaria, the Czech Republic, Spain, Croatia, Hungary, Poland, Romania and
Slovenia as Concerned Member States (CMS). The application was submitted under Article 10(1) of
Directive 2001/83/EC, as amended, as a generic application. The reference medicinal product for this
application is Brufen Syrup which was originally granted in the UK to Knoll Pharma Limited (PL
13530/0004) on 01 April 1993 and underwent change of ownership procedures to the current marketing
authorisation holder (MAH), Abbott Laboratories Ltd (PL 00037/0339), on 15 February 2002.
Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and anti-pyretic activity. The
drug's therapeutic effects as an NSAID are thought to result from its inhibitory effect on the enzyme
cyclo-oxygenase, which results in a marked reduction in prostaglandin synthesis.
One bioequivalence study was submitted to support this application (conducted under fasting
conditions). The applicant has stated that the bioequivalence study was conducted in accordance with
Good Clinical Practices (GCP), Good Laboratory Practices (GLP), The Declaration of Helsinki (Seoul,
2008) and the requirements of Directive 2001/83/ EC Annex I, as amended by Directive 2003/63/ EC
and Directive 2001/20/EC.
With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted,
which is acceptable given that this application was based on being a generic medicinal product of an
originator product that has been in clinical use for over 10 years.
The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in
place at all sites responsible for the manufacture, assembly and batch release 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.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP
certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’
issued by the inspection services of the competent authorities (or those countries with which the EEA
has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards
of GMP are in place at those non-Community sites.
The RMS and CMS considered that the application could be approved at the end of procedure on 27
January 2016. After a subsequent national phase, a licence was granted in the UK on 23 February 2016.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
II
UK/H/5891/001/DC
QUALITY ASPECTS
II.1 Introduction
Each 5 ml of oral suspension contains 100 mg of ibuprofen. Other ingredients consist of the following
pharmaceutical excipients glycerol, 70% liquid non-crystallising sorbitol (E420), xanthan gum,
microcrystalline cellulose and carmellose sodium, polysorbate grade 80, disodium edetate, saccharin
sodium, citric acid monohydrate, sodium citrate dihydrate, sodium benzoate (E211), apricot flavour
(containing propylene glycol, flavouring substance, natural flavouring substance, orange oil and lemon
oil), taste masking flavour [containing potato maltodextrin, flavouring components, aspartame
(E951)and acesulfame-K (E950)], simethicone emulsion 30%, sodium chloride and purified water. 100
ml of the finished product oral suspension is packed into 125 ml brown neutral glass bottles supplied
with a polypropylene screw cap with a polyethylene sealing or alternative polypropylene screw cap
child-resistant tamper evident ring with embossing and liner and placed into a cardboard box. Each
cardboard box also contains one plastic 5 ml graduated oral syringe for dosing, and an instruction leaflet.
The 5 ml plastic oral syringe for dosing is graduated at 2.5 ml and 5 ml for measuring of the doses.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components.
II.2. Drug Substance
INN:
Ibuprofen
Chemical names:
(2RS)-2-[4-(2-Methylpropyl)phenyl]propanoic acid.
Structural formula:
Molecular formula:
Molecular mass:
Appearance:
Solubility:
C13H18O2
206.3 g/mol
White or almost white, crystalline powder or colourless crystals.
Practically insoluble in water, freely soluble in acetone, in methanol and in
methylene chloride. It dissolves in dilute solutions of alkali hydroxides and
carbonates.
Ibuprofen is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, ibuprofen, are covered by the
European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability.
II.3. Medicinal Product
Pharmaceutical Development
The objective of the development programme was to formulate a safe, efficacious, oral suspension
containing 100 mg of ibuprofen per 5 ml of oral suspension that was comparable in performance to the
originator product Brufen Syrup (Abbott Laboratories Ltd). A satisfactory account of the pharmaceutical
development has been provided.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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All excipients comply with their respective European Pharmacopoeia monographs with the exception of
the apricot flavour, taste masking flavour and simethicone emulsion 30% which are controlled to
suitable in-house specifications. In addition, confirmation has been provided that the apricot and taste
masking flavours comply with current EU directives for flavourings suitable for use in foodstuffs.
Satisfactory Certificates of Analysis have been provided for all excipients. Suitable batch analysis data
have been provided for each excipient.
None of the excipients contain materials of animal or human origin.
No genetically modified organisms (GMO) have been used in the preparation of this product.
Manufacture of the product
Satisfactory batch formula has been provided for the manufacture of the product, along with an
appropriate account of the manufacturing process. The manufacturing process has been validated at
commercial-scale batch size and has shown satisfactory results.
Finished Product Specification
The finished product specification proposed is acceptable. Test methods have been described that have
been adequately validated. Batch data have been provided which comply with the release specification.
Certificates of Analysis have been provided for all working standards used.
Stability of the Product
Finished product stability studies were performed in accordance with current guidelines on batches of
finished product in the packaging proposed for marketing. The data from these studies support a
shelf-life of 3 years for the unopened bottle with no special storage conditions. The in-use shelf life of
the product is 3 months after first opening.
Suitable post approval stability commitments have been provided to continue stability testing on batches
of finished product.
II.4 Discussion on chemical, pharmaceutical and biological aspects
There are no objections to the approval of these applications from a pharmaceutical viewpoint.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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III
NON-CLINICAL ASPECTS
III.1 Introduction
As the pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well-known, no
new non-clinical studies are required and none have been provided. An overview based on the literature
review is, thus, appropriate.
The MAH’s non-clinical expert report has been written by an appropriately qualified person and is
satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,
pharmacokinetics and toxicology.
III.2 Pharmacology
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.3 Pharmacokinetics
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.4 Toxicology
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.5 Ecotoxicity/environmental risk assessment (ERA)
A detailed literature based ERA has been provided, and the expert has described that adsorption studies
indicate that further study of the terrestrial compartment is unnecessary, and that ibuprofen can be
considered to be readily biodegradable. This is agreed. The use of aquatic effect data from the Han et al
(2010) study to determine Environmental Quality Standard (EQS) for ibuprofen is of some debate. The
ERA concludes that there is a potential risk to aquatic organisms although this seems to rely on the
findings from this study. The Scientific Committee on Health and Environmental Risks (SCHER),
convened by the European Commission, concluded in 2011 that the Han et al. (2010) study was not
reliable and should not be used as the key study for setting an environmental quality standard for
ibuprofen in water. Another study in the same species indicates that there was limited impairment in
reproduction or other adverse effects at the maximum concentration tested (100 μg/L), a factor of 4
higher than that determined in Han et al. As a result there is equivocal evidence to suggest the effect on
aquatic organisms. The RMS considers that the approach to the ERA should be consistent with other
ibuprofen containing products and text in the product literature to warn the patient to dispose of the
product responsibly is recommended.
The ERA submitted is acceptable and the additional text to the product literature is supported.
III.6 Discussion on the non-clinical aspects
There are no objections to the approval of these applications from a non-clinical viewpoint.
IV
CLINICAL ASPECTS
IV.1 Introduction
IV.1 Introduction
The clinical pharmacology of ibuprofen is well-known. With the exception of data from the
bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided
or are required for these applications.
No new efficacy or safety studies have been performed and none are required for this type of
application. A comprehensive review of the published literature has been provided by the applicant,
citing the well-established clinical pharmacology, efficacy and safety of ibuprofen.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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Based on the data provided, Ibuprofen can be considered bioequivalent to Brufen Syrup (Abbott
Laboratories Ltd).
IV.2 Pharmacokinetics
In support of this application, the applicant submitted the following bioequivalence study:
STUDY
An open label, randomised, single-dose, 2-way crossover study to compare the pharmacokinetics
of the applicant’s test product Ibuprofen (Alkaloid-INT d.o.o.) versus the reference product,
Brufen Syrup (Abbott Laboratories Ltd), in healthy adult subjects under fasting conditions.
The subjects were administered a single 10 ml dose (200 mg) of either the test or the reference product
following an overnight fast of at least 10 hours. Blood samples were collected for plasma levels before
dosing and up to and including 14 hours after each administration. The washout period between the
treatment phases was 7 days.
Ibuprofen is a racemic mixture of R-(-) ibuprofen and S-(+) ibuprofen; bioequivalence was based on
data from levels of the pharmacologically more active enantiomer S-(+) ibuprofen in the plasma.
The pharmacokinetic results are presented below:
Table: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median,
range) for Plasma S-(+) ibuprofen:
*ln-transformed values.
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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Table: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median,
range) for Plasma R-(+) ibuprofen:
Conclusion
The 90% confidence intervals of the test/reference ratio for AUC, and Cmax values for ibuprofen (for
both R-(-) ibuprofen and S-(+) ibuprofen enantiomer) lie within the acceptable limits of 80.00% to
125.00%, in line with the ‘Guideline on the Investigation of Bioequivalence
(CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the claim that the applicant’s test
product is bioequivalent to the reference product Brufen Syrup (Abbott Laboratories Ltd).
IV.3 Pharmacodynamics
No new pharmacodynamic data were submitted and none were required for an application of this type.
IV.4 Clinical efficacy
No new efficacy data were submitted and none were required for an application of this type.
IV.5 Clinical safety
No new safety data were submitted and none were required for this application.
IV.6 Risk Management Plan (RMP)
The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), 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.
A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is
listed below:
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PAR Ibupr ofen 100 mg/5 ml or al suspension
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Summary table of safety concerns:
Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.
IV.7 Discussion on the clinical aspects
With the exception of the bioequivalence study, no new clinical studies were conducted, which is
acceptable given that the application was based on being a generic medicinal product of an originator
product that has been licensed for over 10 years.
Bioequivalence has been demonstrated between the applicant’s test product Ibuprofen (Alkaloid-INT
d.o.o.) versus the reference product, Brufen Syrup (Abbott Laboratories Ltd).
The grant of a marketing authorisation is recommended for this application.
V
User consultation
The package leaflet has been evaluated via a user consultation study, in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of
user testing the PIL was English.
The results show that the package leaflet meets the criteria for readability, as set out in the Guideline on
the readability of the label and package leaflet of medicinal products for human use.
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VI
Overall conclusion, benefit/risk assessment and recommendation
The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been
identified. Extensive clinical experience with ibuprofen is considered to have demonstrated the
therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.
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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient
Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are
available on the MHRA website.
The approved labelling for Ibuprofen is presented below:
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