PL 04569/0927-8 - Medicines and Healthcare products Regulatory

Public Assessment Report

Decentralised Procedure

RABEPRAZOLE SODIUM 10 MG GASTRO-RESISTANT TABLETS

RABEPRAZOLE SODIUM 20 MG GASTRO-RESISTANT TABLETS

(Rabeprazole sodium)

Procedure No: UK/H/2090/001-2/DC

UK Licence No: PL 04569/0927-8

GENERICS (UK) LIMITED.

PAR Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets UK/H/2090/01-02/DC

LAY SUMMARY On 24 August 2012, Czech Republic Greece, Spain, France, Hungary, Ireland, Italy, Netherlands, Portugal and the UK agreed to grant Marketing Authorisations to Generics (UK) Limited (trading as Mylan) for the medicinal products Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets (PL 04569/0927-8/001-2/DC). The licences were granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After a subsequent national phase, Marketing Authorisations were granted in the UK on 06 November 2012. These are Prescription-Only Medicines (POM). Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets contain rabeprazole as the active ingredient. Rabeprazole belongs to a group of medicines called 'Proton Pump Inhibitors' (PPIs). They work by lowering the amount of acid that your stomach produces. This medicine can be used to treat the following conditions:

'Gastro-Oesophageal Reflux Disease' (GORD), which can include heartburn. GORD is caused when acid and food from your stomach escapes into your food pipe (oesophagus).

Ulcers in your stomach or the upper part of your gut (intestine). Zollinger-Ellison Syndrome where your stomach produces too much acid.

No new or unexpected safety concerns arose from these applications and it was judged that the benefits of taking Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets outweigh the risks and therefore Marketing Authorisations were granted.

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TABLE OF CONTENTS

Module 1: Information about 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 11 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 Conclusions and benefit-risk assessment Module 6 Steps taken after initial procedure Page 21

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Module 1

Product Name

Rabeprazole Sodium 10 mg Gastro-resistant Tablets Rabeprazole Sodium 20 mg Gastro-resistant Tablets

Type of Application

Generic, Article 10.1

Active Substances

Rabeprazole sodium

Form

Gastro-resistant tablets

Strength

10 mg and 20 mg..

MA Holder

Generics (UK) Limited, trading as Mylan, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

Reference Member State (RMS)

UK

Concerned Member States (CMS)

UK/H/2090/01-2/DC: Greece, Spain, France, Hungary, Ireland, Italy, Netherlands and Portugal UK/H/2090/02/DC: Czech Republic, Greece, Spain, France, Hungary, Ireland, Italy, Netherlands and Portuga.

Procedure Number

UK/H/2090/001-2/DC

Timetable

Day 208– 24 August 2012.

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Module 2 Summary of Product Characteristics

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.

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Module 3 Patient Information Leaflet

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.

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Module 4 Labelling

Carton:

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Blister:

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Carton:

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Blister:

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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 applications for Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets (PL 04569/0927-8/001-2/DC) could be approved. These applications were submitted via the decentralised procedure, with the UK as Reference Member State (RMS) and Czech Republic Greece, Spain, France, Hungary, Ireland, Italy, Netherlands and Portugal as Concerned Member States (CMS). These products are prescription-only medicines (POM). Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets are indicated for the treatment of:

Active duodenal ulcer Active benign gastric ulcer Symptomatic erosive or ulcerative Gastro-Oesophageal Reflux Disease (GORD). Gastro-Oesophageal Reflux Disease Long-term Management (GORD Maintenance) Symptomatic treatment of moderate to very severe Gastro-Oesophageal Reflux

Disease (symptomatic GORD) Zollinger-Ellison Syndrome

These are abridged applications submitted under Article 10(1) of Directive 2001/83/EC as amended, cross-referring to Pariet 10 mg and 20 mg Gastro-Resistant Tablets (Eisai Limited), which were first authorised in the EEA on 08 May 1998. The reference products have been registered in the EEA for more than 10 years, hence the period of data exclusivity has expired. Rabeprazole is a substituted benzimidazole which inhibits the function of the proton pump (H+/K+-ATPase) responsible for the terminal step in gastric acid secretion. Proton Pump Inhibitors (PPIs) reduce stomach acid by blocking the enzyme system responsible for active transport of acid into the gastrointestinal lumen of the gastric parietal cell, also known as the ‘proton pump’. Inactivation of proton pumps is accomplished by covalent binding of sulfenamides to the proton pumps’ cysteine residues. No new non-clinical studies were conducted, which is acceptable given that the products are intended to be generic versions of the originator products that have been licensed for over 10 years. Two bioequivalence studies (single dose; one in the fed state and the other in the fasted state) were submitted to support these applications, comparing the test product Rabeprazole Sodium 20 mg Gastro-resistant Tablets (Generics (UK) Limited) with the reference product Pariet 20 mg gastro-Resistant Tablets (Eisai Limited). With the exception of the bioequivalence studies, no new clinical studies were conducted, which is acceptable given that the applications were for products that are intended to be generic versions of the originator products that have been licensed for over 10 years. The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP).

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The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture, assembly and batch release of these products. The RMS and CMS considered that the applications could be approved with the end of procedure (Day 208) on 24 August 2012. After the subsequent national phase, the licences were granted in the UK on 06 November 2012.

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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Rabeprazole Sodium 10 mg Gastro-resistant Tablets Rabeprazole Sodium 20 mg Gastro-resistant Tablets

Name(s) of the active substance(s) (INN) Rabeprazole sodium Pharmacotherapeutic classification (ATC code) Alimentary tract and metabolism, Drugs for peptic

ulcer and Gastro-Oesophageal Reflux Disease (GORD), proton pump inhibitors (A02 BC04).

Pharmaceutical form and strength(s) 10 mg and 20 mg gastro-resistant tablets.

Reference numbers for the Mutual Recognition Procedure

UK/H/2090/001-2/DC

Reference Member State United Kingdom

Concerned Member State UK/H/2090/01-2/DC: Greece, Spain, France, Hungary, Ireland, Italy, Netherlands, Portugal UK/H/2090/02/DC: Czech Republic, Greece, Spain, France, Hungary, Ireland, Italy, Netherlands and Portuga

Marketing Authorisation Number(s) PL 04569/0927-8 Name and address of the authorisation holder Mylan, Potters Bar, Hertfordshire, EN6 1TL, United

Kingdom.

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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN: Rabeprazole sodium Chemical names: (±)-2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]-

methyl]sulfinyl]-1H-benzimidazole sodium salt 2-[{[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl]-1H-

benzimidazole sodium Structure:

Molecular formula: C18H20N3NaO3S Molecular mass: 381.43 Appearance: Rabeprazole sodium is a white to yellowish powder. Solubility: Rabeprazole sodium is very soluble in water and slightly soluble in

methanol. Rabeprazole sodium is not the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the active substance. All potential known impurities have been identified and characterised. Satisfactory Certificates of Analysis have been provided for all working standards. Batch analysis data are provided and comply with the proposed specification. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been generated to support a suitable retest period when stored in the proposed packaging.

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P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients mannitol, magnesium oxide, heavy, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium stearate, ethylcellulose, hypromellose phthalate, acetylated mono and di-glycerides, talc, titanium dioxide (E 171) and opacode black S-1-17823 [consisting of shellac~45% (20% Esterified), iron oxide black (E172), propylene glycol and ammonium hydroxide (28%)]. In addition:

the 10 mg strength also contains iron oxide red (E172) and opadry pink 03A540019 [consisting of HPMC 2910/hypromellose 6 Cp, titanium dioxide (E171), acetylated monoglycerides and iron oxide red (E172)].

the 20 mg strength also contains iron oxide yellow (E172) and opadry yellow 03A520021 [consisting of HMPC 2910/hypromellose 6 Cp, titanium dioxide (E171), acetylated monoglycerides and iron oxide yellow (E172)].

All excipients comply with their respective European Pharmacopoeia monographs with the exception of low substituted hydroxypropyl cellulose, iron oxide red (E 172) and yellow (E172) which are controlled to United States Pharmacopoeia (USP)/National Formulary (NF) specifications and acetylated monoglycerides, opadry pink 03A540019, opadry yellow 03A520021 and opacode black S-1-17823 which are controlled to suitable in-house specifications. 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 these products. Pharmaceutical Development The objective of the development programme was to formulate stable, robust,gastro-resistant tablets containing 10 mg and 20 mg rabeprazole sodium, which could be considered generic medicinal products of Pariet 10 mg and 20 mg Gastro-Resistant Tablets (Eisai Limited). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for the proposed and originator products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at commercial scale and has shown satisfactory results. Finished Product Specification The proposed finished product specifications are acceptable. Test methods have been described and have been adequately validated. Batch data have been provided, which comply with the release specifications. Certificates of Analysis have been provided for all working standards used.

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Container-Closure System All strengths of the finished product are packaged in:

desiccant embedded cold form blisters comprised of form pack laminate with desiccant layer (calcium oxide) on one side and hard tempered aluminium foil (dull side lacquered and bright side polyethylene (PE) extrusion coated) on the other side in pack sizes of 7, 14, 28, 30, 50, 56, 98 and 100 tablets..

cold form perforated unit dose blisters comprising of form pack laminate with desiccant layer one side and hard tempered aluminium foil on the other side in pack sizes of 14 x 1 tablets, 28 x 1 tablets and 50 x 1 tablets.

white opaque high density polyethylene (HDPE) bottles with white opaque polypropylene (PP) screw cap and desiccant (calcium oxide) in pack sizes of 30 and 100 tablets

It has been stated that not all pack sizes may be marketed. However, the Marketing Authorisation Holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability of the product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 18 months for all presentation types which reduces to 60 days after first opening for the bottle presentation only with the storage conditions ‘Do not store above 25°C. Store in the original container in order to protect from moisture.’ Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence study. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PIL and labels are acceptable. 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 it contains. Marketing Authorisation Application (MAA) form The MAA forms are satisfactory. Quality Overall Summary The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion There are no objections to the approval of these products from a pharmaceutical view-point.

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III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of rabeprazole sodium are well-known, no new non-clinical studies are required and none have been provided. The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant pharmacology and toxicology. Since Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant Tablets are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment (ERA) is therefore not deemed necessary. There are no objections to the approval of these products from a non-clinical view-point. III.3 CLINICAL ASPECTS Pharmacokinetics In support of these applications, the marketing authorisation holder has submitted the following bioequivalence studies: STUDY 1 A pivotal, replicate, balanced, randomised four-period crossover study to compare the pharmacokinetics of the test product Rabeprazole Sodium 20 mg Gastro-resistant Tablets (Generics (UK) Limited) versus the reference product Pariet 20 mg gastro-Resistant Tablets (Eisai Limited) in healthy adult volunteers under fasted conditions. All volunteers received a single oral dose of either the test or reference product as a 1 x 20 mg tablet administered with 240 ml of water after an overnight fast. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 24 hours post dose. The washout period between treatment periods was at least 7 days. The pharmacokinetic results for rabeprazole (fasted conditions) are presented below [mean value, standard deviation (±SD) and 90% confidence intervals]: Treatment AUC0-t

ng/ml/h AUC0-∞

ng/ml/h Cmax

ng/ml Test

1558.422 ± 748.8417 1589.802 ± 768.3107 667.173 ± 243.1417

Reference

1491.208 ± 804.9826 1521.185 ± 821.0836 632.614 ± 265.7392

*Ratio (90% CI)

107.23 (101.64 – 113.14) 107.01 (101.60 – 112.69) 110.40 (100.11 - 121.76)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration * ln-transformed values

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STUDY 2 A pivotal, replicate, balanced, randomised four-period crossover study to compare the pharmacokinetics of the test product Rabeprazole Sodium 20 mg Gastro-resistant Tablets (Generics (UK) Limited) versus the reference product Pariet 20 mg gastro-Resistant Tablets (Eisai Limited) in healthy adult volunteers under fed conditions. All volunteers were fasted overnight and were then given a high fat breakfast prior to receiving a single oral dose of either the test or reference product as a 1 x 20 mg tablet. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 24 hours post dose. The washout period between treatment periods was at least 7 days. The pharmacokinetic results for rabeprazole (fed conditions) are presented below [mean value, standard deviation (±SD) and 90% confidence intervals]: Treatment AUC0-t

ng/ml/h AUC0-∞

ng/ml/h Cmax

ng/ml Test

1543.978 ± 663.39177 1572.781 ±680.5504 689.298 ± 241.3384

Reference

1506.421 ± 667.1631 1532.114 ± 677.0997 688.964± 266.8994

*Ratio (90% CI)

104.01 (98.75 – 109.55) 103.62 (98.64 – 108.85) 103.58 (93.70 - 114.49)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration * ln-transformed values

The 90% confidence intervals for AUC and Cmax for test versus reference product for rabeprazole in the fed and fasting state are within predefined acceptance criteria specified in ”Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr) in both the fed and fasting states. Thus, the data support the claim that the test product is bioequivalent to the reference product. As the 10 mg and 20 mg strengths of the product meet the criteria specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions of the bioequivalence study on the 20 mg strength can be extrapolated to the 10 mg strength. Pharmacodynamics No new pharmacodynamic data were submitted and none were required for these applications. Efficacy No new efficacy data were submitted and none were required for these applications. Safety With the exception of the data generated during the bioequivalence studies, no new safety data were submitted and none were required for these applications. No new or unexpected safety issues were highlighted by the bioequivalence data.

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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels The SmPCs, PIL and labels are acceptable. The SmPCs are consistent with that for the originator products. The PIL is consistent with the SmPCs and in line with current guidelines. The labelling is in-line with current guidelines. MAA Forms The MAA forms are satisfactory. 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 these products. Conclusion There are no objections to the approval of these products from a clinical view-point. IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The quality characteristics of Rabeprazole Sodium 10 mg and 20 mg Gastro-resistant 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 and none are required for applications of this type. The pharmacodynamic, pharmacokinetic and toxicological properties of rabeprazole are well-known. EFFICACY With the exception of the bioequivalence studies, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s Rabeprazole Sodium 20 mg Gastro-resistant Tablets (Generics (UK) Limited) and its respective reference product Pariet 20 mg gastro-Resistant Tablets (Eisai Limited). As the 10 mg and 20 mg, strengths of the product meet the biowaiver criteria specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions of the bioequivalence studies on the 20 mg strength can be extrapolated to the 10 mg strength.

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SAFETY With the exception of the bioequivalence studies, no new data were submitted and none are required for applications of this type. As the safety profile of rabeprazole is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the bioequivalence studies. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with that for the reference products, and in line with current guidelines. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence studies support the claim that the applicant’s products and the originator products are interchangeable. Extensive clinical experience with rabeprazole is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.

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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

PL 04569/0927-8 - Medicines and Healthcare products Regulatory

Documents

Transcript of PL 04569/0927-8 - Medicines and Healthcare products Regulatory