Public Assessment Report Scientific Discussion Irinotecan “BMM Pharma”

Public Assessment Report

Scientific discussion

Irinotecan “BMM Pharma” 20 mg/ml concentrate for solution for infusion

Irinotecan hydrochloride trihydrate

DK/H/1065/001/DC

This module reflects the scientific discussion for the approval of Irinotecan “BMM Pharma”. The procedure was finalised on 8 November 2007. For information on changes after this date please refer to the module ‘Update’.

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Irinotecan “BMM Pharma” 20 mg/ml concentrate for solution for infusion, from BMM Pharma AB. The product was authorised in Denmark on 3 January 2008. The product is indicated for the treatment of advanced colorectal cancer:  In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced cancer.  As a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Irinotecan in combination with cetuximab is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of irinotecan- including cytotoxic therapy.

Irinotecan is a well-known antineoplastic agent for parenteral use (ATC code L 01 XX 19). It is a specific inhibitor of DNA topoisomerase I and thus cytotoxic.

This decentralised procedure concerns a generic application claiming essential similarity with the reference product Campto which has been registered in Denmark since 16 July 1998 by Pfizer ApS.

The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

Each ml contains 20 mg irinotecan hydrochloride trihydrate, equivalent to 17.33 mg irinotecan.

Irinotecan “BMM Pharma” 2 ml contains 40 mg irinotecan hydrochloride trihydrate. Irinotecan “BMM Pharma” 5 ml contains 100 mg irinotecan hydrochloride trihydrate.

The product is a clear, colourless to pale yellow solution.

The product is packed in 5 ml Type 1 amber glass vials with rubber closures and flip off tear off aluminium seals. Each pack contains 1 vial. However, not all pack sizes may be marketed.

The product must be diluted before use and is for single use only.

The product contains: Sorbitol; Lactic acid; Sodium hydroxide (to adjust to pH 3.5) and Water for injections.

Compliance with Good Manufacturing Practice 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: Irinotecan hydrochloride trihydrate Chemical name(s): [1,4’-Bipiperidine]-1’-carboxylic acid (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4- hydroxy-3,14-dioxo-1H-pyrano [3’,4’ : 6,7] indolizino [1,2-b]quinolin-9-yl ester.

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Molecular formula: C33H38N4O6 * HCl * 3 H2O Molecular mass: 677.20

Molecular structure:

Irinotecan hydrochloride trihydrate is a pale yellow to yellow coloured powder soluble in dimethyl sulphoxide. The Irinotecan molecule is optically active, with one chiral centre. Irinotecan hydrochloride trihydrate does not exhibit polymorphism.

Irinotecan hydrochloride trihydrate is not described in the European Pharmacopoeia (Ph.Eur.) and information on this substance has been provided in the form of an EDMF. Information on the 3 step synthesis of irinotecan hydrochloride trihydrate from starting materials is provided. Specifications for both starting materials and intermediate products are provided and are acceptable. The drug substance specification is compliant with general ICH and Ph.Eur. requirements for drug substances.

Stability data are presented supporting a retest period of two years when stored at 2 – 8 C. Irinotecan hydrochloride trihydrate is photostable.

II.3 Medicinal Product

The product composition has been properly presented. Product development has been described, the choice of excipients justified and their functions explained. Although stable to heating in an autoclave, the product is prepared by aseptic processing. Sterilisation procedures are satisfactorily validated.

The manufacturing site is currently being expanded to include terminal sterilisation processing and is expected to be operational within a year. Irinotecan 20mg/ml solution will be manufactured using terminal sterilisation once this processing is implemented.

Compatibility studies with 5% dextrose solution and 0.9 % sodium chloride solution have been performed with satisfactory results.

The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on 3 batches. The batch analysis results show that the finished product meets the proposed specifications.

Satisfactory stability data are presented to support a proposed shelf-life of 2 years with the storage precaution “Keep the vial in the outer carton in order to protect from light. Do not freeze”.

Chemical and physical in-use stability has been demonstrated in glucose 5% and sodium chloride 0.9% for 24 hours at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2 to 8°C.

A commitment has been made to perform temperature cycling studies to ensure that product may be transported satisfactorily from the manufacturing site to the batch release site by different transport means.

3/5 III. NON-CLINICAL ASPECTS

This product is a generic formulation of Campto, 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 irinotecan 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

Irinotecan is a well-known active substance with established efficacy and tolerability.

The product is to be administered as an aqueous intravenous solution containing the same active substance in the same concentration as the reference product. Thus in accordance with the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), bioequivalence studies are not requested.

IV.2 Risk management plan & Pharmacovigilance system

Irinotecan was first approved in 1995, and there is now more than 10 years post-authorisation experience with the active substance. The safety profile of irinotecan 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 Campto marketed by Pfizer ApS.

Readability test 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 Swedish. 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.

4/5 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

Irinotecan “BMM Pharma” 20 mg/ml concentrate for solution for infusion has a proven chemical- pharmaceutical quality and is a generic form of Campto. Campto is a well-known medicinal product with an established favourable efficacy and safety profile.

The product is to be administered as an aqueous intravenous solution containing the same active substance in the same concentration as the Brand Leader. Thus in accordance with the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), no bioequivalence studies are not requested.

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 irinotecan 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 Irinotecan “BMM Pharma” with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 8 November 2007. Irinotecan “BMM Pharma” was authorised in Denmark on 3 January 2008.

A European harmonised birth date has been allocated (1995-05-05) and subsequently the next data lock point for irinotecan is 2008-05, after which the PSUR submission cycle is 3 years.

The date for the first renewal will be: 8 November 2012.

The following post-approval commitments have been made during the procedure:

 Temperature cycling studies will be performed on commercial batches of finished product (as the current regulatory batches are close to expiry). The results will be submitted for review.

 Results of analytical method transfer to the new proposed batch control testing site will be reported before the marketing of the first batch. Certificates of Analysis of the finished product will be presented.

 Process validation data will be submitted on batches greater than 20L in size prior to marketing of these batches.

 The product will not be marketed in Sweden until a variation for sterilisation of the drug product in its final container has been submitted and approved.

 All batches for the starting material will be released with a total impurities limit of NMT 0.5%. The total impurities limit may be further adjusted upwards at a later date, if necessary, when justified by appropriate batch data.

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