Public Assessment Report

(1)

Public Assessment Report

Decentralised Procedure

Ibuprofen and phenylephrine hydrochloride 200mg/5mg

film-coated tablets

Procedure No: UK/H/4930/001/DC

UK Licence No: PL 17780/0563

(2)

LAY SUMMARY

On 30 May 2013, the Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation to Winthrop Pharmaceuticals UK Limited (trading as Zentiva) for the medicinal product Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets

(PL 17780/0563; UK/H/4930/001/DC). This medicine is a pharmacy (P) medicine, available only from pharmacies under the supervision of a pharmacist. Ibuprofen and phenylephrine hydrochloride

200mg/5mg film-coated tablets are effective in relieving the symptoms of influenza and cold, including fever, headache, painful sinuses, sore throat and muscle and joint pain. Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets also help with runny nose, relieve stuffy nose and nasal sinuses, which facilitates breathing.

Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets contain the active substances ibuprofen and phenylephrine hydrochloride. Ibuprofen belongs to a group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) and is effective against aches and pains (including headache), swelling and can also reduce a fever. Phenylephrine hydrochloride (nasal

decongestant) reduces swelling in the passages of the nose, relieving nasal congestion and reducing the pressure which may cause a headache.

No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets outweigh the risks and a Marketing Authorisation was granted.

(3)

3

Module 1

Information about the initial procedure

Product Name Ibuprofen and phenylephrine hydrochloride 200mg/5mg

film-coated tablets

Type of Application Well-established use, Article 10a

Active Substances Ibuprofen and phenylephrine hydrochloride

Forms Film-coated tablets

Strengths 200 mg ibuprofen + 5 mg phenylephrine hydrochloride

MA Holder Winthrop Pharmaceuticals UK Limited

One Onslow Street Guildford

Surrey

GU1 4YS, UK

(Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS)

Reference Member State (RMS) UK

Concerned Member States (CMS) Czech Republic, Luxembourg, Poland, Romania and Slovak

Republic

Procedure Number UK/H/4930/001/DC

(5)

5

Module 2

Summary of Product Characteristics

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.

(6)

Module 3

Patient Information Leaflet

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.

(7)

7

Module 4

Labelling

The MAH has submitted a text version only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed.

(8)

(9)

9

Module 5

Scientific discussion during initial procedure

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the member states considered that the application for Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets

(PL 17780/0563; UK/H/4930/001/DC) could be approved. The product is a pharmacy (P) medicine available from pharmacies and is designed for the relief of symptoms of cold and influenza with associated congestion including aches and pain, headache, fever, sore throat, blocked nose and sinuses. The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Czech Republic, Luxembourg, Poland, Romania and Slovak Republic as Concerned Member States (CMS) The application was submitted under Article 10a of Directive 2001/83/EC, as amended, claiming to be an application for a product containing active substances of well-established use.

Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets contain the active

ingredients ibuprofen and phenyephrine hydrochloride. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) and has anti-inflammatory, analgesic and antipyretic properties. Phenylephrine

hydrochloride is an alpha1-adrenoceptor agonist. Its action on the peripheral alpha1 receptors induces

vasoconstriction, which in the nasal mucosa, results in a decongestant effect.

One single-dose, fasting, bioequivalence study was submitted to support the application, comparing the applicant’s test product Ibuprofen/phenylephrine hydrochloride film-coated tablet 200mg/5mg and the reference product Lemsip Max All Night Cold and Flu 200mg/5mg film-coated tablets (Reckitt

Benckiser Healthcare, UK). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP).

With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted, which is acceptable given that the application is a bibliographic application for a product containing active ingredients of well-established use.

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.

The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 02 May 2013. After a subsequent national phase, a licence was granted in the UK on 30 May 2013.

(10)

II. ABOUT THE PRODUCT

Name of the product in the Reference Member State Ibuprofen and phenylephrine hydrochloride

200mg/5mg film-coated tablets

Name(s) of the active substance(s) (INN) Ibuprofen and phenylephrine hydrochloride

Pharmacotherapeutic classification (ATC code) Anti-inflammatory and anti-rheumatic products,

non-steroids (ATC code: M01AE51 - ibuprofen, combinations)

Pharmaceutical form(s) and strength(s) Film-coated tablet; 200 mg ibuprofen + 5 mg

phenylephrine hydrochloride

Reference number(s) for the Decentralised Procedure UK/H/4930/001/DC

Reference Member State (RMS) _{United Kingdom}

Concerned Member States (CMS) Czech Republic, Luxembourg, Poland, Romania

and Slovak Republic

Marketing Authorisation Number(s) PL 17780/0563

Name and address of the authorisation holder Winthrop Pharmaceuticals UK Limited,

One Onslow Street, Guildford,

Surrey,

GU1 4YS, UK.

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS

III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS

ACTIVE SUBSTANCE – IBUPROFEN

INN: Ibuprofen

Chemical name: ((2RS)-2-[4-(2-methylpropyl)phenyl] propanoic acid

Structure:

Molecular formula: C13H18O2

Molecular weight: 206.3

Appearance: A 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

(11)

11 ACTIVE SUBSTANCE – PHENYEPHRINE HYDROCHLORIDE

INN: Phenylephrine hydrochloride

Chemical name: (1R)-1-(3-hydroxyphenyl)-2-(methylamino) ethanol hydrochloride

Structure:

Molecular Formula: C9H13NO2,HCl

Molecular weight: 203.7 g/mol

Appearance: A white or almost white crystalline powder

Solubility Freely soluble in water and alcohol.

Phenylephrine hydrochloride is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance phenylephrine hydrochloride are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.

MEDICINAL PRODUCT Other Ingredients

Other ingredients consist of the pharmaceutical excipients namely maize starch, pregelatinised maize starch, sodium starch glycolate (type A), talc, Povidone 30, colloidal anhydrous silica, Stearic acid 50, Hypromellose 2910/5, Macrogol 6000 and titanium dioxide (E171). Appropriate justification for the inclusion of each excipient has been provided.

All excipients comply with their respective European Pharmacopoeia monographs. Certificates of Analysis have been provided for all excipients, showing compliance with the proposed specification. None of the excipients contain materials of animal or human origin.

No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development

The objective of the development programme was to formulate a safe, efficacious, stable immediate-release tablet formulation containing the active ingredient ibuprofen 200mg and phenylephrine hydrochloride 5 mg.

A satisfactory account of the pharmaceutical development has been provided.

Satisfactory comparative in-vitro dissolution and impurity profiles have been provided for the applicant’s proposed product and an existing product (Ibalgin, Zentiva CZ, Czech Republic). Manufacturing Process

A 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 with production-scale batches and has shown satisfactory results.

Control of Finished Product

The finished product specification is acceptable. Test methods have been described that have been validated adequately. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for all working standards used.

(12)

Container-Closure System

The product is packaged in transparent polvinylchloride/aluminium foil blisters. These are packed into in paper folding boxes with Patient Information Leaflets in pack sizes of 12 and 24 film-coated tablets. Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations (Directive 2002/72/EC, as amended) concerning materials in contact with foodstuff.

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 2 years, with the storage conditions “Store below 25C. Store in the original package in order to protect from light.”

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. The bioequivalence study is discussed in Section III.3, Clinical Aspects. Summary of Product Characteristics (SmPC), Product Information Leaflet (PIL) and Labels The SmPC, PIL and label texts are satisfactory from a pharmaceutical perspective. The Marketing Authorisation Holder (MAH) has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed.

A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups (‘user testing’), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to

understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that the leaflet contains.

Marketing Authorisation Application (MAA) Form

The MAA form is satisfactory from a pharmaceutical perspective. Expert Report (Quality Overall Summary)

The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier.

Conclusion

(13)

13 III.3 CLINICAL ASPECTS

Clinical Pharmacololgy

The clinical pharmacology of ibuprofen and phenylephrine hydrochloride are well-known, which is adequately summarised in the clinical overview. However to allow bridging to the literature data, clinical data demonstrating bioequivalence was required for this application. In support of the application, the Marketing Authorisation Holder submitted a report for the following bioequivalence study.

An open label, four period, two sequence, controlled, block randomised replicate design single-dose study comparing the extent and rate of absorption of Ibuprofen/phenylephrine hydrochloride film-coated tablet 200mg/5mg (Zentiva k.s, Czech Republic) with Lemsip Max All Night Cold and Flu 200mg/5mg film-coated tablet (Reckitt Benckiser Healthcare, UK) in healthy male and female subjects under fasting conditions.

Subjects were administered one tablet of either the test or the reference product twice (on two different occasions according to a 4 period crossover replicate design) with 240 ml of water, after at least an 8-hour fast. Blood sampling was performed pre-dose and up to 24 hours post dose in each treatment period. The washout period between the two treatment arms was 7 days. The pharmacokinetic results are presented below: Ibuprofen Reference treatment Cmax (ng/mL) AUC0-t (ng/mL*Hours) AUC0-inf (ng/mL*Hours) Mean 19809.290 75289.231 77372.723 SD 4646.142 19057.370 19489.732 CV 23.454 25.312 25.189

Cmax maximum plasma concentration

AUC0-t area under the plasma concentration-time curve from time zero to t hours

AUC0-inf area under the plasma concentration-time curve from time zero to infinity

SD standard deviation CV coefficient of variation Test treatment Cmax (ng/mL) AUC0-t (ng/mL*Hours) AUC0-inf (ng/mL*Hours) Mean 19348.994 75145.830 76986.627 SD 3564.594 19439.075 19572.578 CV 18.423 25.868 25.423

SD standard deviation CV coefficient of variation

Pharmacokinetic parameters (geometric means ratios and confidence intervals [CI]) of ibuprofen

Test Name Parameter Geo Mean Ratio

(test/reference)

Lower 90% CL Upper 90% CL

Classic 90% CI Cmax 98.29 94.52 102.21

Classic 90% CI AUC0-t 99.526 97.472 101.622

CI confidence interval CL confidence limit.

(14)

Phenylephrine Reference treatment Cmax (pg/mL) AUC0-t (pg/mL*Hours) AUC0-inf (pg/mL*Hours) Mean 628.324 641.811 699.477 SD 224.263 163.181 192.770 CV 35.692 25.425 27.559

SD standard deviation CV coefficient of variation Test treatment Cmax (pg/mL) AUC0-t (pg/mL*Hours) AUC0-inf (pg/mL*Hours) Mean 639.539 654.951 710.421 SD 319.051 205.294 214.516 CV 49.888 31.345 30.196

SD standard deviation CV coefficient of variation

Pharmacokinetic parameters (geometric means ratios and confidence intervals [CI]) of phenylephrine

Test Name Parameter Geo Mean Ratio

(test/reference)

Lower 90% CL Upper 90% CL

Classic 90% CI Cmax 99.40 93.38 105.81

Classic 90% CI AUC0-t 100.954 97.108 104.953

CI confidence interval CL confidence limit.

The 90 % confidence intervals of the test/reference ratio of geometric means for AUC0-t and Cnax for

ibuprofen and phenylephrine hydrochloride lie within the acceptable limits of 80.00 % to 125.00 %. Thus, the data support the claim that the actives in the applicant’s test product are bioequivalent to the actives in the reference product Lemsip Max All Night Cold and Flu 200mg/5mg film-coated tablets (Reckitt Benckiser healthcare, UK).

(15)

15 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPC, PIL and labels are acceptable from a clinical perspective. The PIL is consistent with the details in the SmPC and in line with the current guidance. The labelling is also in line with the current guidance.

Clinical Expert Report (Clinical Overview)

The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier.

Pharmacovigilance System and Risk Management Plan

The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for

pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

Suitable justification has been provided for not submitting a Risk Management Plan for this product. Conclusion

(16)

IV OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY

The important quality characteristics of Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance.

NON-CLINICAL

No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology of ibuprofen and phenylephrine hydrochloride are well-known, no additional data were required. EFFICACY

With the exception of the bioequivalence study, no new data were submitted.

Bioequivalence has been demonstrated between the applicant’s product and the reference product Lemsip Max All Night Cold and Flu 200mg/5mg film-coated tablets (Reckitt Benckiser Healthcare, UK).

SAFETY

The safety profiles of ibuprofen and phenylephrine hydrochloride, both separately and in varying combinations are well established.

With the exception of the safety data from the bioequivalence study, no new data were submitted. No new or unexpected safety concerns arose from the bioequivalence study.

PRODUCT LITERATURE

The SmPC, PIL and labelling are satisfactory and in line with current guidance. BENEFIT/RISK ASSESSMENT

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with ibuprofen and phenylephrine hydrochloride, separately and in combination is considered to have demonstrated the therapeutic value of the compounds. The

(17)

17

Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted Application type Scope Outcome

Public Assessment Report