Post on 01-Mar-2019
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.
PAR Topotecan Mylan 1mg/ml Concentrate for Solution for Infusion UK/H/3114/001/DC
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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
rubber fluoropolymer film-coated stopper and aluminium flip-off cap.
- 4mg/4ml of Topotecan Mylan in 6R (6ml) colourless type I glass vials, together with bromobutyl
rubber fluoropolymer film-coated stopper and aluminium flip-off cap.
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
It is recommended that a Marketing Authorisation is granted for Topotecan Mylan 1mg/ml concentrate
for solution for infusion.
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
It is recommended that a Marketing Authorisation is granted for Topotecan Mylan 1mg/ml concentrate
for solution for infusion.
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.