PANTOPRAZOLE 20 MG GASTRO-RESISTANT TABLETS PANTOPRAZOLE … · · 2013-02-25MHRA PAR – Pantoprazole 20 mg and 40 mg gastro-resistant tablets (PL 20092/0070-1) 4 - INTRODUCTION

MHRA PAR – Pantoprazole 20 mg and 40 mg gastro-resistant tablets (PL 20092/0070-1) 1 -

PANTOPRAZOLE 20 MG GASTRO-RESISTANT TABLETS PANTOPRAZOLE 40 MG GASTRO-RESISTANT TABLETS

(Pantoprazole sodium sesquihydrate)

PL 20092/0070-1

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 14

Steps taken after authorisation – summary

Page 15

Summary of Product Characteristics

Page 16

Patient Information Leaflet

Page 17

Labelling Page 18



PL 20092/0070-1

LAY SUMMARY The MHRA granted Lupin (UK) Ltd Marketing Authorisations (licences) for the medicinal products Pantoprazole 20 mg and 40 mg gastro-resistant tablets on 03 December 2012. These products are prescription-only medicines (POM) used for treating acid related diseases of the stomach and intestine. Pantoprazole 20 mg gastro-resistant tablets are used for: Adults and adolescents 12 years of age and above:

Treating symptoms (e.g. heartburn, acid regurgitation, pain on swallowing) associated to gastro-oesophageal reflux disease caused by reflux of acid from the stomach.

Long term management of reflux oesophagitis (inflammation of the oesophagus accompanied by the regurgitation of stomach acid) and preventing its return.

Pantoprazole 40 mg gastro-resistant tablets are used for: Adults and adolescents 12 years of age and above:

Reflux oesophagitis. An inflammation of your oesophagus (the tube which connects your throat to your stomach) accompanied by the regurgitation of stomach acid.

Adults:

An infection with a bacterium called Helicobacter pylori in patients with duodenal ulcers and stomach ulcers in combination with two antibiotics (Eradication therapy). The aim is to get rid of the bacteria and so reduce the likelihood of these ulcers returning.

Stomach and duodenal ulcers Zollinger-Ellison Syndrome and other conditions producing too much acid in the

stomach. Pantoprazole belongs to a group of medicines called proton pump inhibitors. Proton pump inhibitors reduce the amount of acid that your stomach makes. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Pantoprazole 20 mg and 40 mg gastro-resistant tablets outweigh the risks; hence Marketing Authorisations have been granted.



PL 20092/0070-1

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 6

Non-clinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusions and risk benefit assessment Page 13


INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted Lupin (UK) Ltd, Marketing Authorisations for the medicinal products Pantoprazole 20 mg and 40 mg gastro-resistant tablets (PL 20092/0070-1) on 03 December 2012. These products are prescription-only medicines (POM). Pantoprazole 20 mg gastro-resistant tablets are indicated for Adults and adolescents 12 years of age and above:

Symptomatic gastro-oesophageal disease. Long term management and prevention of relapse in reflux oesophagitis.

Adults:

Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4 of SmPC).

Pantoprazole 40 mg gastro-resistant tablets are indicated for: Adults and adolescents 12 years of age and above:

Reflux oesophagitis. Adults:

Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

Gastric and duodenal ulcer. Zollinger-Ellison syndrome and other pathological hypersecretory conditions.

These are abridged applications submitted under Article 10(1) of Directive 2001/83/EC as amended, cross-referring to Protium 20 mg and 40mg Tablets (Altana Pharma AG), which have been authorised in the EEA since 07 January 1999 and 04 June 1996 respectively. The reference products have been registered in the EEA for more than 10 years, hence the period of data exclusivity has expired. The reference products used in the bioequivalence studies were Eupantol 20mg, comprimé gastro-résistant (Nycomed France) and Eupantol 40mg Tablet (Altana Pharma, France) taken from the French market. It has been confirmed that these products are identical to the equivalent products in the UK (Protium 20 mg and 40mg Tablets). Pantoprazole belongs to a group of medicines called proton pump inhibitors. It is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific action on the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic channel in the parietal cells, where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent, and affects both basal and stimulated acid secretion. No new non-clinical data have been submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. Three single-dose, bioequivalence studies under fasting (20 mg and 40 mg) and fed conditions (40 mg only) were submitted to support these applications, comparing the test


products Pantoprazole 20 mg and 40 mg gastro-resistant tablets (Lupin (UK) Ltd) and the reference products Eupantol 20mg, comprimé gastro-résistant (Nycomed France) and Eupantol 40mg Tablet (Altana Pharma, France). The bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence studies, no new clinical studies were performed, which is acceptable given that the applications were based on being a generic medicinal products of originator products that have been in clinical use for over 10 years. No new or unexpected safety concerns were raised during the assessment of these applications and it was, therefore, judged that the benefits of taking Pantoprazole 20 mg and 40 mg gastro-resistant tablets outweigh the risks; hence Marketing Authorisations have been granted.


PHARMACEUTICAL ASSESSMENT

ACTIVE SUBSTANCE INN: Pantoprazole sodium sesquihydrate Chemical name: Sodium 5-Difluoromethoxy-2-[[( 3,4-dimethoxy-2-

pyridinyl)methyl]sulfinyl]-1H-benzimidazole sesquihydrate Structural formula:

Molecular formula: C16H14F2N3NaO4S . 1.5.H2O. Molecular mass: 432.38 Appearance: White or almost white, crystalline powder. Solubility: Freely soluble in water and methanol. Pantoprazole sodium sesquihydrate is 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 supporting a suitable retest period when stored in the proposed packaging. MEDICINAL PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients, mannitol, sodium carbonate ( anhydrous), sodium starch glycolate, hydroxypropyl cellulose, calcium stearate, luster clear (consisiting of carrageenan, microcrystalline cellulose and macrogol), magnesium oxide, methacrylic acid ethyl acrylate copolymer dispersion (1:1) 30 percent, triethyl citrate,


polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E171), lecithin, yellow iron oxide (E172), shellac, black iron oxide (E172) and propylene glycol. All excipients used comply with their respective European Pharmacopoeia monograph with the exception of the top coat and imprinting ink which are controlled to suitable in-house specifications. In addition, the in-house specifications are in compliance with current EEC directives concerning the use of colouring agents. Satisfactory Certificates of Analysis have been provided for all excipients. 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 robust, stable tablets containing 20 mg and 40 mg pantoprazole (as sodium sesquihydrate) which could be considered as generic medicinal products of Protium 20 mg and 40mg Tablets (Altana Pharma AG). 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. Manufacture A description and flow-chart of the manufacturing method has been provided. Satisfactory batch formula have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated at pilot scale and has shown satisfactory results. In addition the marketing authorisation holder (MAH) has committed to perform process validation on future commercial scale batches. Finished product specification The finished product specification is satisfactory. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container Closure System All strengths of the finished product are packaged in:

Aluminium/aluminium blisters with aluminium lidding foil and are available in pack sizes of 2 (40 mg only), 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98 and 100 tablets. In addition the 20 mg strength is also available in pack sizes of 112, 120, 140 and 500 tablets.

High density polyethylene (HDPE) bottles and are available in pack sizes of 2 (40 mg only), 7, 14, 15, 28, 30, 50, 56, 60, 84, 90, 98 and 100 tablets. In addition the 20 mg strength is also available in pack sizes of 112, 120, 140 and 500 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 Stability studies were performed in accordance with current guidelines on batches of the finished product packed 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 moisture.’ for the blister packs and ‘Store below 25°C. Keep the container tightly closed in order to protect from moisture.’ for the HDPE bottles. 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 Leaflets (PIL) and Labelling The SmPCs, PILs and labelling are satisfactory. 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 leaflet conforms to the requirements. The test shows that the patients/users are able to act upon the information that the leaflet contains. MAA Form The MAA forms are satisfactory. Expert Report (Quality Overall Summary) A quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion It is recommended that marketing authorisations are granted for these applications.


NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY No new non-clinical data were submitted, which is acceptable given that the proposed products are generic medicinal products of originator products that have been licensed for over 10 years. NON-CLINICAL EXPERT REPORT The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products’ pharmacology and toxicology. ENVIRONMENTAL RISK ASSESSMENT Since Pantoprazole 20 mg and 40 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. CONCLUSION It is recommended that marketing authorisations are granted for these applications.


CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of pantoprazole is well-known. With the exception of the bioequivalence study, no pharmacokinetic or pharmacodynamic data were submitted for these applications, and none were required for applications of this type. The following bioequivalence studies were submitted: Study 1: An open label, balanced, randomised, two-treatment, two-sequence, two-period, single dose, two-way crossover study to compare the pharmacokinetics of the test product Pantoprazole 20 mg gastro-resistant tablets (Lupin (UK) Ltd) versus the reference product Eupantol 20mg, comprimé gastro-résistant (Nycomed France) in healthy adult male 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 after an overnight fast of at least 8 hours. 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 14 days. The pharmacokinetic results for pantoprazole, for the test product versus the reference product for the 20 mg strength are presented below non-transformed values; arithmetic and geometric mean, standard deviation, ratios and 90% confidence intervals):

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


Study 2: An open label, balanced, randomised, two-treatment, two-sequence, two-period, single dose, two-way crossover study to compare the pharmacokinetics of the test product Pantoprazole 40 mg gastro-resistant tablets (Lupin (UK) Ltd) versus the reference product Eupantol 40mg Tablet (Altana Pharma, France) in healthy adult male volunteers under fasted conditions. All volunteers received a single oral dose of either the test or reference product as a 1 x 40 mg tablet administered with 240 ml of water after an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 36 hours post dose. The washout period between treatment periods was at least 14 days. The pharmacokinetic results for pantoprazole, for the test product versus the reference product for the 40 mg strength under fasted conditions are presented below (antilog of least square mean, ratios and 90% confidence intervals):

*Ratio and confidence intervals in percentage.

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 Cmax maximum plasma concentration

Study 3: An open label, balanced, randomised, two-treatment, two-sequence, two-period, single dose, two-way crossover study to compare the pharmacokinetics of the test product Pantoprazole 40 mg gastro-resistant tablets (Lupin (UK) Ltd) versus the reference product Eupantol 40mg Tablet (Altana Pharma, France) in healthy adult male volunteers under fed conditions. All volunteers received a single oral dose of either the test or reference product as a 1 x 40 mg tablet with 240 ml of water administered 30 minutes after commencing a high fat breakfast (approximately 1000 calories) following an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 30 hours post dose. The washout period between treatment periods was at least 14 days. The pharmacokinetic results for pantoprazole, for the test product versus the reference product for the 40 mg strength in the fed state are presented below (antilog of least square mean, ratios and 90% confidence intervals):


*Ratio and confidence intervals in percentage.

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 Cmax maximum plasma concentration

For all studies, the 90% confidence intervals for AUC and Cmax were within the predefined acceptance range for pantoprazole. Bioequivalence was therefore demonstrated between all strengths of test product and its respective reference product in fasting and non-fasting conditions. 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 raised by the bioequivalence data. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), 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. Clinical Expert Report 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. A 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 viewpoint.


IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Pantoprazole 20 mg and 40 mg gastro-resistant 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. 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 Pantoprazole 20 mg and 40 mg gastro-resistant tablets and their respective reference products. 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 pantoprazole 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, PILs and labelling are satisfactory and consistent with that for the reference product, where appropriate. 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 pantoprazole is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.



PL 20092/0070-1

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation applications on 03 December

2008.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 07 January 2009.

3 Following assessment of the applications the MHRA requested further information relating to the quality dossier: For PL 20092/0070: on 17 June 2009, 18 March 2010, 30 September 2010 and 25 July 2012. For PL 20092/0071: on 05 November 2010. and the clinical dossier for both applications on 30 March 2009 and for PL 20092/0071 only on 05 August 2011.

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier: For PL 20092/0070: on 03 August 2009, 29 March 2010, 25 August 2011 and 05 November 2012. For PL 20092/0071: on 03 August 2011. And the clinical dossier on: For PL 20092/0070: 03 August 2009. For PL 20092/0071: 31 July 2009 and 25 August 2011.

5 The applications were determined on 03 December 2012.



PL 20092/0070-1

STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome


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.


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.


LABELLING Blister carton:


Blister:

Bottle label:


Blister carton:


Blister label:

Bottle label:

Documents

PANTOPRAZOLE 20 MG GASTRO-RESISTANT TABLETS PANTOPRAZOLE … · · 2013-02-25MHRA PAR – Pantoprazole 20 mg and 40 mg gastro-resistant tablets (PL 20092/0070-1) 4 - INTRODUCTION