Public Assessment Report

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1 Public Assessment Report Decentralised Procedure Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets Procedure No: UK Licence No: PL 17780/0563 Winthrop Pharmaceuticals UK Limited

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; ). 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. 2

3 TABLE OF CONTENTS Module 1: Information about the initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Patient Information Leaflet Page 6 Module 4: Labelling Page 7 Module 5: Scientific discussion during initial procedure Page 9 I Introduction II About the product III Scientific overview and discussion III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall conclusion and benefit/risk assessment Module 6: Steps taken after initial procedure Page 17 3

4 Module 1 Product Name Type of Application Active Substances Forms Strengths MA Holder Information about the initial procedure Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets Well-established use, Article 10a Ibuprofen and phenylephrine hydrochloride Film-coated tablets 200 mg ibuprofen + 5 mg phenylephrine hydrochloride 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 Timetable Day May

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. 5

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. 6

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. 7

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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; ) 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 alpha 1 -adrenoceptor agonist. Its action on the peripheral alpha 1 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 After a subsequent national phase, a licence was granted in the UK on 30 May

10 II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form(s) and strength(s) Reference number(s) for the Decentralised Procedure Reference Member State (RMS) Concerned Member States (CMS) Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets Ibuprofen and phenylephrine hydrochloride Anti-inflammatory and anti-rheumatic products, non-steroids (ATC code: M01AE51 - ibuprofen, combinations) Film-coated tablet; 200 mg ibuprofen + 5 mg phenylephrine hydrochloride United Kingdom 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: C 13 H 18 O 2 Molecular weight: 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 Ibuprofen is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance ibuprofen are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. 10

11 ACTIVE SUBSTANCE PHENYEPHRINE HYDROCHLORIDE INN: Phenylephrine hydrochloride Chemical name: (1R)-1-(3-hydroxyphenyl)-2-(methylamino) ethanol hydrochloride Structure: Molecular Formula: C 9 H 13 NO 2,HCl Molecular weight: 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. 11

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 The grant of a Marketing Authorisation is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen and phenylephrine hydrochloride are well-known, no new non-clinical data have been submitted and none were required. The non-clinical overview was written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. Suitable justification has been provided for the non-submission of an Environmental Risk Assessment. The grant of a Marketing Authorisation is recommended. 12

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 singledose 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 C max (ng/ml) AUC 0-t (ng/ml*hours) AUC 0-inf (ng/ml*hours) Mean SD CV C max maximum plasma concentration AUC 0-t area under the plasma concentration-time curve from time zero to t hours AUC 0-inf area under the plasma concentration-time curve from time zero to infinity SD standard deviation CV coefficient of variation Test treatment C max (ng/ml) AUC 0-t (ng/ml*hours) AUC 0-inf (ng/ml*hours) Mean SD CV C max maximum plasma concentration AUC 0-t area under the plasma concentration-time curve from time zero to t hours AUC 0-inf area under the plasma concentration-time curve from time zero to infinity SD standard deviation CV coefficient of variation Pharmacokinetic parameters (geometric means ratios and confidence intervals [CI]) of ibuprofen Test Name Parameter Geo Mean Ratio Lower 90% CL Upper 90% CL (test/reference) Classic 90% CI C max Classic 90% CI AUC 0-t C max AUC 0-t CI CL maximum plasma concentration area under the plasma concentration-time curve from time zero to t hours confidence interval confidence limit. 13

14 Phenylephrine Reference treatment C max (pg/ml) AUC 0-t (pg/ml*hours) AUC 0-inf (pg/ml*hours) Mean SD CV C max maximum plasma concentration AUC 0-t area under the plasma concentration-time curve from time zero to t hours AUC 0-inf area under the plasma concentration-time curve from time zero to infinity SD standard deviation CV coefficient of variation Test treatment C max (pg/ml) AUC 0-t (pg/ml*hours) AUC 0-inf (pg/ml*hours) Mean SD CV C max maximum plasma concentration AUC 0-t area under the plasma concentration-time curve from time zero to t hours AUC 0-inf area under the plasma concentration-time curve from time zero to infinity SD standard deviation CV coefficient of variation Pharmacokinetic parameters (geometric means ratios and confidence intervals [CI]) of phenylephrine Test Name Parameter Geo Mean Ratio Lower 90% CL Upper 90% CL (test/reference) Classic 90% CI C max Classic 90% CI AUC 0-t C max AUC 0-t CI CL maximum plasma concentration area under the plasma concentration-time curve from time zero to t hours confidence interval confidence limit. The 90 % confidence intervals of the test/reference ratio of geometric means for AUC 0-t and C nax for ibuprofen and phenylephrine hydrochloride lie within the acceptable limits of % to %. 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). Efficacy The efficacy of ibuprofen and phenylephrine hydrochloride is well-known. No new efficacy data have been submitted and none are required for this type of application. Safety The safety profiles of ibuprofen and phenylephrine hydrochloride, both separately and in varying combinations is well established. With the exception of the safety data generated during the bioequivalence study, no new safety data were submitted and none are required for this type of application. No new or unexpected safety issues were raised during the bioequivalence study. 14

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 The grant of a Marketing Authorisation is recommended. 15

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 benefit/risk balance is therefore considered to be positive. 16

17 Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 17