Procedure No. Product no · PDF file 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union

20 October 2011 EMA/1352/2012 Committee for Medicinal Products for Human Use (CHMP)

CHMP assessment report

Topotecan Eagle

International non-proprietary name: topotecan

Procedure No. EMEA/H/C/002261

Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted.

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CHMP assessment report EMA/1352/2012 Page 2/29

Table of contents

1. Background information on the procedure .............................................. 3 1.1. Submission of the dossier.................................................................................... 3 1.2. Manufacturers ........................................................ Error! Bookmark not defined. 1.3. Steps taken for the assessment of the product ....................................................... 4

2. Scientific discussion ................................................................................ 6 2.1. Introduction ...................................................................................................... 6 2.2. Quality aspects .................................................................................................. 6 2.2.1. Introduction ................................................................................................... 6 2.2.2. Active substance ............................................................................................ 7 2.2.3. Finished medicinal product................................................................................ 8 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 9 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ....................... 9 2.3. Non- clinical aspects ........................................................................................... 9 2.3.1. Introduction ................................................................................................... 9 2.3.2. Pharmacology ............................................................................................... 10 2.3.3. Pharmacokinetics .......................................................................................... 12 2.3.4. Toxicology.................................................................................................... 12 2.3.5. Ecotoxicity/environmental risk assessment........................................................ 15 2.3.6. Discussion on non-clinical aspects.................................................................... 15 2.3.7. Conclusion on the non-clinical aspects .............................................................. 16 2.4. Clinical aspects ................................................................................................ 16 2.4.1. Introduction ................................................................................................. 16 2.4.2. Pharmacokinetics .......................................................................................... 17 2.4.3. Pharmacodynamics........................................................................................ 18 2.4.4. Clinical efficacy ............................................................................................. 18 2.4.5. Clinical safety ............................................................................................... 20 2.4.6. Post marketing experience.............................................................................. 20 2.4.7. Discussion on clinical aspects .......................................................................... 20 2.4.8. Conclusions on clinical aspects ........................................................................ 21 2.5. Pharmacovigilance............................................................................................ 21

3. Benefit-risk balance .............................................................................. 27

4. ................................................................................. 27 Recommendation

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1. Background information on the procedure

1.1. Submission of the dossier

The applicant Eagle Laboratories Ltd submitted on 30 June 2010 an application for Marketing

Authorisation to the European Medicines Agency (EMA) for Topotecan Eagle, through the centralised

procedure under Article 3 (3) of Regulation (EC) No. 726/2004– ‘Generic of a Centrally authorised

product’. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on

21.12.2009.

The application concerns a hybrid medicinal product as defined in Article 10(2)(b) of Directive

2001/83/EC and refers to a reference product for which a Marketing Authorisation is or has been

granted in the Union on the basis of a complete dossier in accordance with Article 8(3) of Directive

2001/83/EC.

The applicant applied for the following indication:.

Treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-

line regimen is not considered appropriate.

In combination with Cisplatin for patients with carcinoma of the cervix recurrent after radiotherapy and

for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained

treatment free interval to justify treatment with the combination.

The legal basis for this application refers to:

Article 10(3) of Directive 2001/83/EC.

The application submitted is composed of administrative information, complete quality data and

appropriate non-clinical and clinical data.

Information on paediatric requirements

Not applicable-

Information relating to orphan market exclusivity

Similarity

Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No

847/2000, the applicant did not submit a critical report addressing the possible similarity with

authorised orphan medicinal products because there is no authorised orphan medicinal product for a

condition related to the proposed indication.

The chosen reference product is:

 Medicinal product which is or has been authorised in accordance with Community provisions in force for not less than 6/10 years in the EEA:

 Product name, strength, pharmaceutical form: Hycamtin 1mg and 4mg powder for concentrate for solution for infusion

 Marketing authorisation holder:SmithKline Beecham plc

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 Date of authorisation: 12-11-1996

 Marketing authorisation granted by:

 Community

 Community Marketing authorisation number: EU/1/96/027/004, EU/1/96/027/005, EU/1/96/027/001, EU 1/96/027/003.

 Medicinal product authorised in the Community/Members State where the application is made or European reference medicinal product:

 Product name, strength, pharmaceutical form: Hycamtin 1mg and 4mg powder for concentrate for solution for infusion

 Marketing authorisation holder: SmithKline Beecham plc

 Date of authorisation: 12-11-1996

 Marketing authorisation granted by:

 Community

 Community Marketing authorisation number: EU/1/96/027/004, EU/1/96/027/005, EU/1/96/027/001, EU 1/96/027/003.

Scientific advice

The applicant did not seek scientific advice at the CHMP.

Licensing status

The product was not licensed in any country at the time of submission of the application.

1.2. Steps taken for the assessment of the product

The Rapporteur appointed by the CHMP was:

Rapporteur: Dr.Andrea Laslop

 The application was received by the EMA on 30 June 2010.

 The procedure started on 21 July 2010.

 The Rapporteur's first Assessment Report was circulated to all CHMP members on 08 July 2010.

 During the meeting on 18 November 2010, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 19

November 2010.

 The applicant submitted the responses to the CHMP consolidated List of Questions on 18 March 2011

 The Rapporteur circulated the Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 13 May 2011.

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 During the CHMP meeting on 19 May 2011 the CHMP agreed on a list of outstanding issues to be addressed in writing and in an oral explanation by the applicant.

 The applicant submitted the