Public Assessment Report. Scientific discussion. Rabeprazolnatrium Torrent Pharma. 10 mg and 20 mg gastro-resistant tablets. Rabeprazole sodium

Transcription

1 Public Assessment Report Scientific discussion Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets Rabeprazole sodium DK/H/1819/ /DC This module reflects the scientific discussion for the approval of Rabeprazolnatrium Torrent Pharma. The procedure was finalised on 9 March For information on changes after this date please refer to the module Update. 1/10

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets, from Torrent Pharma GmbH. The product was authorised in Denmark on 29 April The product is 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 - In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori in patients with peptic ulcer disease. Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump) The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Pariet 10 mg and 20 mg gastro-resistant tablets which has been registered in the United Kingdom by Eisai since The marketing authorisation is granted based on article 10.1/10.3 of Directive 2001/83/EC. II. II.1 QUALITY ASPECTS Introduction Each gastro-resistant tablet contains 10 mg or 20 mg rabeprazole sodium, equivalent to 9.42 mg or mg rabeprazole, respectively. The 10 mg gastro-resistant tablets are pink, round biconvex, coated tablets, plain on both sides. The 20 mg gastro-resistant tablets are yellow, round biconvex, coated tablets, plain on both sides. The tablets are available in OPA/Alu/PVC/Alu blister packs in pack sizes of 7, 14, 28, 56 and 98 gastro-resistant tablets. However, not all pack sizes may be marketed. The tablet core contains: Magnesium oxide; Mannitol; Sodium starch glycolate (Type A); Povidone (K-30) and Magnesium stearate. The intermediate layer consists of: Ethyl cellulose; Magnesium oxide and Diethyl phthalate. The coating is composed of: Hypromellose phthalate; Titanium dioxide (E 171); Talc; Diethyl phthalate; Iron oxide red (E 172) (10 mg only) and Iron oxide yellow (E 172) (20 mg only). Compliance with Good Manufacturing Practice 2/10

3 The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance INN: Rabeprazole sodium Chemical name(s): a) 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole Sodium b) 2-({[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)-1H-benzimidazole Sodium Molecular formula: C 18 H 20 N 3 NaO 3 S Molecular mass: Molecular structure: Rabeprazole sodium is a white to off - white powder, very soluble in water. The product contains one active substance, rabeprazole sodium, documentation on which is presented as a European Drug Master File (DMF) in CTD format. Both Applicant s Part and Restricted Part have been presented together with a suitable letter of access. The drug substance specification is compliant with general ICH requirements for specifications. An appropriate retest period when stored in the proposed packaging has been set based on the presented stability data. II.3 Medicinal Product The composition of the product is adequately described. The choice of excipients is justified and their functions explained. The container is well known and applicability demonstrated in stability studies. The manufacturing is a standard wet granulation and compression for manufacture of core tablets which are coated by a seal coating and enteric coating. Satisfactory validation of the manufacturing process is provided. The product specification covers appropriate parameters for this dosage form and includes relevant physicochemical, identification, assay and purity tests. Validations of the analytical methods have been presented. Batch analysis has been performed on three production scale batches of each strength and complies with the release requirements and confirms the consistency of the product manufacture. The conditions used in the stability studies are according to the ICH stability guideline. Stability data are provided for the proposed strength in the packaging materials intended for marketing. Results at long term storage are available for 12 months and within specification limits; however storage at accelerated conditions show significant changes after three months. 3/10

4 A shelf-life of 18 months with the conditions Do not store above 30 C. Store in the original package in order to protect from moisture is acceptable based on the presented data. III. NON-CLINICAL ASPECTS This product is a generic formulation of Pariet, which is available on the European market. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. This is acceptable for this type of application Environmental risk assessment The product is intended as a substitute for other identical products on the market. The approval of this product will not result in an increase in the total quantity of rabeprazole sodium released into the environment. It does not contain any component, which results in an additional hazard to the environment during storage, distribution, use and disposal. IV. CLINICAL ASPECTS IV.1 Introduction Rabeprazole sodium is a well-known active substance with established efficacy and tolerability. For this generic application, the MAH has submitted as report four bioequivalence studies under fasting and fed conditions in which the pharmacokinetic profile of the test product Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets is compared with the pharmacokinetic profile of the reference product Pariet 10 mg and 20 mg gastro-resistant tablets, Eisai GmbH, from the German market. Pharmacokinetic study 10 mg rabeprazole under fasting conditions The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way crossover, single-dose bioavailability study conducted under fasting conditions in 70 healthy Asian male subjects (mean age years) with a wash out period of 5 days between the two administrations. 10 mg rabeprazole sodium was administered in each period. 70 subjects completed the study. Blood samples were collected pre-dosing and at various time-points up to hours post administration of a single-dose 10 mg rabeprazole sodium delayed release tablet with 200 ml of water for the analyses of rabeprazole in plasma. The pharmacokinetic variables calculated were AUC 0-t, AUC 0-, C max, t max, K el and t ½. Data of 69 subjects were analysed. Bioequivalence was to be concluded if the 90%CI for primary parameters AUC 0-t and C max were within 80%-125%. Results 4/10

5 90% CI for primary parameters C max ( ) and AUC 0-t ( ) are within the acceptance criteria for bioequivalence under fasting conditions, when data of subject no. 59 is excluded. The product proposed for marketing was tolerated equally well as reference product. Pharmacokinetic study 10 mg rabeprazole under fed conditions The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way crossover, single-dose bioavailability study conducted under fed conditions in 70 healthy Asian male 5/10

6 subjects (mean values of age years) with a wash out period of 5 days between the two administrations. 10 mg rabeprazole sodium was administered in each period. 70 subjects completed the study. Blood samples were collected pre-dosing and at various time-points up to hours post administration of a single-dose 10 mg delayed release rabeprazole tablet with 200 ml of water for the analyses of parent compound rabeprazole in plasma. The pharmacokinetic variables calculated were AUC 0-t, AUC 0-, C max, t max, K el and t ½. Data of 69 subjects were analysed. Bioequivalence was to be concluded if the 90%CI for primary parameters AUC 0-t and C max were within 80%-125%. Results 6/10

7 90% CI for primary parameters C max (87.32 to ) and AUC 0-t (87.82 to ) are within the acceptance criteria for bioequivalence under fed conditions when data of subject no. 36 is excluded. The product proposed for marketing was tolerated equally well as reference product. Pharmacokinetic study 20 mg rabeprazole under fasting conditions The study was an open-label, randomized, balanced, two-treatment, two-sequence, two-period, twoway crossover, single-dose bioavailability study conducted under fasting conditions in 70 healthy, Asian male subjects (18-43 years) with a wash out period of 7 days between the administration of a single dose 20 mg rabeprazole sodium gastro-resistant tablet in each period. 68 subjects completed the study. Blood samples were collected pre-dosing and at various time-points up to 24.0 hours post administration of a single-dose 20 mg rabeprazole sodium tablet with 200 ml of water for the analyses of rabeprazole in plasma. The pharmacokinetic variables calculated were AUC 0-t, AUC 0-, C max, t max, K el and t ½. Data of 68 subjects were analysed. Bioequivalence was to be concluded if the 90%CI for primary parameters AUC 0-t, AUC 0- and C max were within 80%-125%. Results 7/10

8 The 90%CI for primary parameters AUC 0-t ( ), AUC 0- ( ) and C max ( ) were within the acceptance criteria. The product proposed for marketing was tolerated equally well as reference product. Pharmacokinetic study 20 mg rabeprazole under fed conditions The study was an open-label, randomized, balanced, two-treatment, two-sequence, two-period, twoway crossover, single-dose bioavailability study conducted under fed conditions in 70 healthy, Asian male subjects (18-44 years) with a wash out period of 7 days between the administration of a single dose 20 mg rabeprazole sodium gastro-resistant tablet in each period. 67 subjects completed the study for PK analysis. Blood samples were collected pre-dosing and at various time-points up to hours post administration of a single-dose 20 mg rabeprazole sodium delayed release tablet with 200 ml of water under fed conditions for the analyses of rabeprazole in plasma. The pharmacokinetic variables calculated were AUC 0-t, AUC 0-, C max, t max, K el and t ½. Data of 67 subjects were analysed. Bioequivalence was to be concluded if the 90%CI for primary parameters AUC 0-t, AUC 0- and C max were within 80%-125%. Results 8/10

9 The 90%CI for primary parameters AUC 0-t ( ), AUC 0- ( ) and C max ( ) were within the acceptance criteria. The product proposed for marketing was tolerated equally well as reference product. Based on the submitted bioequivalence studies under fasting and fed condition for the 10 mg and 20 mg formulations Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets is considered bioequivalent with Pariet 10 mg and 20 mg gastro-resistant tablets, Eisai. The RMS has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.2 Risk management plan & Pharmacovigilance system Rabeprazole sodium was first approved in 1998, and there is now more than 10 years postauthorisation experience with the active substance. The safety profile of rabeprazole sodium can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or postauthorisation which are not adequately covered by the current SPC. Additional risk minimisation activities have not been identified for the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. The Pharmacovigilance system described 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 identification and notification of any potential risks occurring either in the Community or in a third country. V. PRODUCT INFORMATION SmPC and Package leaflet The content of the SmPC and package leaflet approved during the decentralised procedure is in accordance with that accepted for the reference product Pariet marketed by Eisai. Readability test 9/10

10 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 test consisted of a pilot test with 2 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. 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. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets has a proven chemicalpharmaceutical quality and is a generic form of Pariet. Pariet is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with other rabeprazole containing products. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 9 March Rabeprazolnatrium Torrent Pharma 10 mg and 20 mg gastro-resistant tablets was authorised in Denmark on 29 April The PSUR submission cycle is 3 years. In case a Harmonised EU birth date for rabeprazole is published, the applicant has committed to adapt the DLP/HBD and to submit the PSUR 60 days from the harmonised DLP. The date for the first renewal will be: 9 March The following post-approval commitments have been made during the procedure: Certificate of analysis will be provided for the other proposed batch sizes and provided satisfactory process validation is submitted. The DLP/HBD will be adapted in case a Harmonised EU birth date for rabeprazole is published and the PSUR submitted 60 days from the harmonised DLP. 10/10