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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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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 non-steroidal 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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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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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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TABLE OF CONTENTS

I Introduction Page 6 II Quality aspects Page 7 III Non-clinical aspects Page 9 IV Clinical aspects Page 9 V User consultation Page 12 VI Overall conclusion, benefit/risk assessment and

recommendation Page 13

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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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II 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: C13H18O2 Molecular mass: 206.3 g/mol Appearance: White or almost white, crystalline powder or colourless crystals. Solubility: 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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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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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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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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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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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: