Public Assessment Report Decentralised Procedure · Topotecan Mylan 1mg/ml Concentrate for Solution...

Public Assessment Report

Decentralised Procedure

TOPOTECAN MYLAN 1 MG/ML CONCNETRATE FOR

SOLUTION FOR INFUSION (Topotecan hydrochloride)

Procedure No: UK/H/3114/001/DC

UK Licence No: PL 04569/1104

Generics (UK) Limited t/a Mylan

PAR Topotecan Mylan 1mg/ml Concentrate for Solution for Infusion UK/H/3114/001/DC

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LAY SUMMARY Topotecan Mylan 1mg/ml Concentrate for Solution for Infusion

(topotecan hydrochloride)

This is a summary of the Public Assessment Report (PAR) for Topotecan Mylan 1mg/ml Concentrate

for Solution for Infusion (PL 04569/1104; UK/H/3114/001/DC). It explains how the application for

Topotecan Mylan 1mg/ml Concentrate for Solution for Infusion was assessed and its authorisation

recommended, as well as its conditions of use. It is not intended to provide practical advice on how to

use Topotecan Mylan 1mg/ml Concentrate for Solution for Infusion. For ease of reading, this product

will be referred to as Topotecan Solution for Infusion throughout this lay summary.

For practical information about using Topotecan Solution for Infusion, patients should read the package

leaflet or contact their doctor or pharmacist.

What is Topotecan Solution for Infusion and what is it used for?

The application for Topotecan Solution for Infusion was submitted as a hybrid application. Topotecan

Solution for Infusion is similar to a ‘reference medicine’ already authorised in the European Union (EU)

called Hycamtin 1mg/ml Powder for Solution for Infusion.

Topotecan Solution for Infusion is used to treat ovarian cancer or small cell lung cancer that has come

back after chemotherapy. It is also used to treat advanced cervical cancer if surgery or radiotherapy

treatment is not possible. When treating cervical cancer, Topotecan Solution for Infusion is combined

with another medicine called cisplatin.

How does Topotecan Solution for Infusion work?

This medicine contains the active ingredient topotecan hydrochloride. Topotecan is a type of

chemotherapy drug called a topoisomerase 1 inhibitor. It works by damaging the DNA of cancer cells

and a causing the cancer cells to die.

How is Topotecan Solution for Infusion used?

This medicine is only available on prescription.

The dose of Topotecan given will be worked out by a doctor, based on body size (surface area measured

in square metres), the results of blood tests carried out before treatment and the disease being treated.

A doctor or nurse will give the patient a suitable dose of Topotecan as an infusion (a drip). It is usually

dripped into the arm over about 30 minutes.

The recommended dose for ovarian and small cell lung cancer is 1.5 mg per square metre of body

surface area per day. Treatment will be given once a day for 5 days.

The recommended dose for cervical cancer is 0.75 mg per square metre of body surface area per day.

Treatment will be given once a day for 3 days. When treating cervical cancer, Topotecan is combined

with another medicine, called cisplatin.

This pattern of treatments will normally be repeated every three weeks, for all cancers. The treatment

may vary, depending on the results of regular blood tests.

What benefits of Topotecan Solution for Infusion have been shown in studies?

The company provided data from the published literature on topotecan hydrochloride. No additional

studies were needed as Topotecan Solution for Infusion is given as an infusion and contains the same

active substance, in the same concentration, as the reference medicine Hycamtin 1mg/ml Powder for

Solution for Infusion.


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What are the possible side effects of Topotecan Solution for Infusion?

Like all medicines, Topotecan Solution for Infusion can cause side effects, although not everybody gets

them.

For the full list of all side effects reported with Topotecan Solution for Infusion, see section 4 of the

package leaflet.

For the full list of restrictions, see the package leaflet.

Why was Topotecan Solution for Infusion approved?

It was concluded that, in accordance with EU requirements, Topotecan Solution for Infusion has been

shown to have comparable quality and to be comparable to Hycamtin 1mg/ml Powder for Solution for

Infusion. Therefore, the MHRA decided that the benefits outweigh the identified risks and

recommended that Topotecan Solution for Infusion can be approved for use.

What measures are being taken to ensure the safe and effective use of Topotecan Solution for

Infusion?

Safety information has been included in the Summary of Product Characteristics (SmPC) and the

package leaflet for Topotecan Solution for Infusion including the appropriate precautions to be followed

by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored and reviewed continuously.

Other information about Topotecan Solution for Infusion

Austria, Belgium, Czech Republic, Spain, France, Hungary, Italy, The Netherlands, Poland, Portugal,

Slovak Republic and the UK agreed to grant Marketing Authorisations for Topotecan Mylan 1mg/ml

Concentrate for Solution for Infusion on 30 November 2010. Marketing Authorisations were granted in

the UK on 11 January 2011.

In December 2015 the licence was withdrawn in the Czech Republic.

The full PAR for Topotecan Solution for Infusion follows this summary. For more information about

treatment with Topotecan Solution for Infusion read the package leaflet, or contact your doctor or

pharmacist.

This summary was last updated in September 2016.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 5

III Non-clinical aspects Page 8

IV Clinical aspects Page 8

V User consultation Page 9

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 9


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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and

Concerned Member States (CMSs) consider that the application for Topotecan Mylan 1mg/ml

concentrate for solution for infusion, in the treatment of metastatic ovarian cancer after failure of first or

subsequent therapy, and relapsed small cell lung cancer where retreatment with first line regimen is not

appropriate, could be approved.

This application was submitted under Article 10.3, hybrid application, claiming to be essentially similar

to Hycamtin 1mg/ml Powder for Solution for Infusion (EM 10592/0201), which was first licensed in the

UK to GlaxoSmithKline UK (formerly by SmithKline Beecham Plc.), authorised in the EU via a

centralised procedure on 12th November 1996.

With UK as the RMS in this Decentralised Procedure (UK/H/3114/001/DC), Generics UK Limited

applied for the Marketing Authorisation for Topotecan Mylan 1mg/ml Concentrate for Solution for

Infusion in Austria, Belgium, Czech Republic, Spain, France, Hungary, Italy, The Netherlands, Poland,

Portugal and Slovak Republic.

Topotecan is a camptothecin analogue and topo-I targeting agent, synthesized by the introduction of a

basic side chain at the 9 position of the 10-hydroxycamptothecin ring. Topotecan prevents DNA

replication in cancer cells by inhibiting the enzyme topoisomerase I.

No new non-clinical or clinical studies were conducted, which is acceptable given that the application

was based on being a medicinal product essentially similar to the originator product that has been

licensed for over 10 years.

The RMS has been assured that acceptable standards of GMP are in place for this product type at all

sites responsible for the manufacture and assembly 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 considers that 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 non-submission of a Risk Management Plan.

All member states agreed to grant a licence for the above product at the end of procedure (Day 210 –

30th November 2010). After a subsequent national phase, the UK granted a licence for this product on

11th January 2011 (PL 04569/1104). In December 2015 the licence was withdrawn in the Czech

Republic.

II QUALITY ASPECTS

II.1 Introduction

Topotecan Mylan 1 mg/ml concentrate for solution for infusion is a clear, yellowish solution. One ml

concentrate for solution for infusion contains 1 mg of the active ingredient topotecan (as hydrochloride).

Other ingredients consist of the pharmaceutical excipients, namely sodium hydroxide, hydrochloric acid

and water for injections.

The finished product is supplied in the following containers.


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- 1mg/1ml of Topotecan Mylan in 2R (2ml) colourless type I glass vials, together with bromobutyl

rubber fluoropolymer film-coated stopper and aluminium flip-off cap.

- 2mg/2ml of Topotecan Mylan in 6R-short (6ml) colourless type I glass vials, together with bromobutyl


- 4mg/4ml of Topotecan Mylan in 6R (6ml) colourless type I glass vials, together with bromobutyl


Topotecan Mylan is available in cartons containing 1, 5 and 10 vials.

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.

II.2 Drug substance INN: Topotecan hydrochloride

Chemical name: (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1Hpyrano[

3’,4’:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride

Structure:

Molecular formula: C23H23N3O5•xHCl (x=1.0-1.5)

Molecular weight: 457.9

Physical form: Yellow to orange powder. It has one chiral centre that originates from the starting

material, 10-hydroxy-camptothecin

Synthesis of the drug substance from the designated starting material 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 drug substance. Analytical methods have been

appropriately validated and are satisfactory for ensuring compliance with the relevant specifications.

Certificates of Analysis for all working standards have been provided.

Batch analysis data are provided and comply with the proposed specification.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging used to

store the drug substance. Confirmation has been provided that the primary packaging complies with

current guidelines concerning materials in contact with food.


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Appropriate stability data have been generated, supporting a suitable retest period for active topotecan

hydrochloride when stored in the proposed packaging.

II.3 Medicinal Product

Pharmaceutical Development

The objective of the pharmaceutical development programme was to obtain stable product containing

topotecan hydrochloride that could be considered essentially similar to Hycamtin 1mg/ml Powder for

Solution for Infusion.

Suitable pharmaceutical development data have been provided for this application.

All excipients comply with their respective European Pharmacopoeia (Ph. Eur.) monographs. None of

the excipients are sourced from animal or human origin. No genetically modified organisms (GMO)

have been used in the preparation of this product.

Manufacturing Process

A description and flow-chart of the manufacturing method have been provided. In-process controls are

satisfactory based on process validation data and controls on the finished products. Process validation

has been carried out on batches of the product. The results are satisfactory.

Finished Product Specification

The finished product specification is satisfactory. Test methods have been described and adequately

validated, as appropriate. Batch data have been provided and comply with the release specifications.

Certificates of Analysis have been provided for any working standards used.

Stability of the product

Stability studies were performed, in accordance with current guidelines, on batches of finished product

in the packaging proposed for marketing.

The results from these studies support a shelf-life of 3 years with the special storage conditions of “Store

in a refrigerator (2°C – 8°C)” and “Keep the vial in the outer carton in order to protect from light”.

Shelf life after opening the container

Chemical and physical in-use stability has been demonstrated for 48 hours at 2 °C – 8 °C or at room

temperature. From a microbiological point of view, unless the method of opening precludes the risk of

microbiological contamination, the product should be used immediately. If not used immediately, in-use

storage times and conditions are the responsibility of the user.

Shelf life after preparing the solution for infusion ready for use

Chemical and physical in-use stability has been demonstrated for 96 hours at 2 °C – 8 °C and for 48

hours at room temperature. 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 normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution

has taken place in controlled and validated aseptic conditions.

II.4 Discussion on chemical, pharmaceutical and biological aspects

It is recommended that a Marketing Authorisation is granted for Topotecan Mylan 1mg/ml concentrate

for solution for infusion.

II.5 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

Labels

The SmPCs, PIL and labels are satisfactory and, where appropriate, in line with current guidance.


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III NON-CLINICAL ASPECTS

III.1 Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of topotecan hydrochloride are

well-known. No new non-clinical data have been submitted for this application and none are required.

The applicant has provided an overview based on published literature. The non-clinical overview has

been written by an appropriately qualified person and is satisfactory, providing an appropriate review of

the product’s pharmacology and toxicology.

III.2 Pharmacology

No new pharmacology data are required for this application and none have been submitted.

III.3 Pharmacokinetics No new pharmacokinetic data are required for this application and none have been submitted.

III.4 Toxicology

No new toxicology data are required for this application and none have been submitted.

III.5 Ecotoxicity/Environmental risk Assessment (ERA)

A suitable justification has been provided for non-submission of the environmental risk assessment.

III.6 Discussion of the non-clinical aspects



IV. CLINICAL ASPECTS

IV.1 Introduction

No new clinical studies have been performed and none are required for this type of application. The

applicant’s clinical overview has been written by an appropriately qualified person and is considered

acceptable.

IV.2 Pharmacokinetics

No new data have been submitted and none are required for applications of this type.

According to the Committee for Proprietary Medicinal Products “Guideline on the Investigation of

Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev.1 Corr**), there is no requirement for a

bioequivalence study for products where the active ingredient is present in solution.

IV.3 Pharmacodynamics

No new pharmacodynamic data were submitted and none are required for applications of this type.

IV.4 Clinical efficacy

No new data on efficacy have been submitted and none are required for applications of this type.

IV.5 Clinical Safety

Topotecan hydrochloride has an acceptable adverse events profile. No new safety data are supplied or

required for this application. Topotecan hydrochloride has a well-established side-effect profile and is

generally well-tolerated.

IV.6 Pharmacovigilance System

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.


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IV.7 Discussion of the clinical aspects



V. USER CONSULTATION The package leaflet has been evaluated in accordance with the requirements of Articles 59(3) and 61(1)

of Directive 2001/83/EC, as amended. User testing of the package leaflet has been accepted, based on a

bridging report provided by the applicant making reference to the user-testing of the PIL for Irinotecan

medac as the parent PIL. The products are from the same therapeutic class and have similar indications.

A critical analysis demonstrated that the key messages for safe and effective use for both leaflets were

similar. The justification on the rationale for bridging is accepted.

VI OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. The data supplied supports the claim that the applicant’s product and the innovator product

are interchangeable. Extensive clinical experience with topotecan hydrochloride is considered to have

demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be

positive.

In accordance with Directive 2010/84/EU, the current version of the SmPCs and PIL are available on the

MHRA website.

The approved labels are shown below:


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Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

Scope Procedure

number

Product

Information

affected

Date of

start of the

procedure

Date of end

of procedure

Approval/

non

approval

Assessment

report

attached Type IB variation to

update the Summary of

Product Characteristics

(SmPC) in line with

the text of the

reference medicinal

product. Consequently

the patient information

leaflet (PIL) has been

updated

PL

04569/1104

- 0016

UK/H/3114/

001/IB/007

SmPC and

PIL

18/07/16 24/08/16 Approval Y

(Annex 1)


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Annex 1

Reference: PL 04569/1104 - 0016

Product: Topotecan Mylan 1 mg/ml concentrate for solution for infusion

Marketing Authorisation Holder: Generics (UK) Limited

Active Ingredient(s): Topotecan hydrochloride

Reason:

Type IB variation to update sections 2, 4.2, 4.3, 4.4, 4.8, 4.9, 5.1, 5.2, 6.4 and 6.6 of the Summary of

Product Characteristics (SmPC) in line with the text of the reference medicinal product Hycamtin

powder for concentrate for solution for infusion (Novartis Europharm Limited). Consequently the

patient information leaflet (PIL) has been updated.

Supporting Evidence

Revised SmPC fragments and an updated PIL have been provided.

Evaluation

The amended sections of the SmPC and PIL are satisfactory.

The current SmPC and PIL are available on the MHRA website.

Decision

Approved on 24 August 2016.

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