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Public Assessment Report
UKPAR
Imatinib 100 mg Film-coated Tablets
Imatinib 400 mg Film-coated Tablets
(Imatinib mesilate)
UK Licence No: PL 36687/0208-0209
Torrent Pharma (UK) Limited.
PAR Imatinib 100 and 400 mg Film-coated Tablets PL 36687/0208-0209
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LAY SUMMARY
Imatinib 100 mg Film-coated Tablets
Imatinib 400 mg Film-coated Tablets
(Imatinib mesilate, film-coated tablet, 100 mg or 400mg)
This is a summary of the Public Assessment Report (PAR) for Imatinib 100 mg Film-coated Tablets (PL
36687/0208) and Imatinib 100 mg Film-coated Tablets (PL 36687/0209). It explains how Imatinib 100
mg and 400 mg Film-coated Tablets were assessed and their authorisation recommended, as well as their
conditions of use. It is not intended to provide practical advice on how to use Imatinib 100 mg and 400
mg Film-coated Tablets.
The products will be collectively referred to as Imatinib throughout the remainder of this public
assessment report.
For practical information about using Imatinib patients should read the package leaflet or contact their
doctor or pharmacist.
What is Imatinib and what is it used for?
This medicine is a treatment for adults and children for:
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells
usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia in which
certain abnormal white cells (named myeloid cells) start growing out of control. In adult patients
Imatinib is used to treat a late stage of Chronic Myeloid Leukaemia called “blast crisis”. In children and
adolescents however it may be used to treat all stages of the illness.
- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia
is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute
lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named
lymphoblasts) start growing out of control. Imatinib inhibits the growth of these cells.
This medicine is also a treatment for adults for:
- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood diseases in
which some blood cells start growing out of control. Imatinib inhibits the growth of these cells in a
certain subtype of these diseases.
- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are
blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib
inhibits the growth of these cells in a certain subtype of these diseases.
- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which
some cells start growing out of control. Imatinib inhibits the growth of these cells.
These applications are the same as Imatinib 100 mg and 400 mg film-coated tablets (PL 17509/0068-
0069) which are already authorised.
The company (Intrapharm Laboratories Limited) that makes Imatinib 100 mg and 400 mg film-coated
tablets (PL 17509/0068-0069) has agreed that its scientific data can be used as a basis for the grant of
identical licences for Imatinib (informed consent).
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How does Imatinib work?
This medicine contains the active ingredient called imatinib mesilate which works by inhibiting the
growth of abnormal cells in the diseases listed above. These include some types of cancer.
How is Imatinib used?
The pharmaceutical form of this medicine is a film-coated tablet and the route of administration is oral
(by mouth).
Use in adults
The patient’s doctor will tell them exactly how many tablets of Imatinib to take.
• If the patient is being treated for CML:
Depending on the patient’s condition the usual starting dose is either 400 mg or 600 mg:
- 400 mg to be taken once a day,
- or 600 mg to be taken once a day.
• If the patient is being treated for GIST:
The starting dose is 400 mg, to be taken once a day.
For CML and GIST, the patient’s doctor may prescribe a higher or lower dose depending on how the
patient responds to the treatment. If the patient’s daily dose is 800 mg, they should take 400 mg in the
morning and 400 mg in the evening.
• If the patient is being treated for Ph-positive ALL:
The starting dose is 600 mg to be taken once a day.
• If the patient is being treated for MDS/MPD:
The starting dose is 400 mg, to be taken once a day.
• If the patient is being treated for HES/CEL:
The starting dose is 100 mg, to be taken once a day. The patient’s doctor may decide to increase
the dose to 400 mg, to be taken once a day, depending on how the patient responds to treatment.
• If you the patient is being treated for DFSP:
The dose is 800 mg per day, to be taken as 400 mg in the morning and 400 mg in the
evening.
Use in children and adolescents
The doctor will tell the child’s carer how many tablets of Imatinib to give to their child. The amount of
Imatinib given will depend on the child’s condition, body weight and height. The total daily dose in
children must not exceed 800 mg with CML and 600 mg with Ph+ ALL. The treatment can either be
given to the child as a once-daily dose or alternatively the daily dose can be split into two
administrations (half in the morning and half in the evening).
When and how to take Imatinib
• Take Imatinib with a meal. This will help protect the patient from stomach problems when
taking Imatinib.
• Swallow the tablets with a large glass of water.
The tablet can be divided into equal doses.
If the patient is unable to swallow the tablets, they can dissolve them in a glass of still water or apple
juice:
• Use about 50 ml for each 100 mg tablet or 200 ml for each 400 mg tablet.
• Stir with a spoon until the tablets have completely dissolved.
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• Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved
tablets may be left behind in the glass.
How long to take Imatinib
The patient must keep taking Imatinib every day for as long as their doctor tells them.
Please read section 3 of the package leaflet for detailed information on dosing recommendations, the
route of administration, and the duration of treatment.
This medicine can only be obtained with a prescription.
For further information on how Imatinib are used, refer to the package leaflet and Summaries of Product
Characteristics available on the Medicines and Healthcare products Regulatory Agency (MHRA)
website.
What benefits of Imatinib have been shown in studies?
Imatinib is considered identical to previously authorised Imatinib 100 mg and 400 mg film-coated
tablets (PL 17509/0068-0069), with the same benefits and risks. So, no new studies have been provided
for Imatinib but reference is made to the studies for Imatinib 100 mg and 400 mg film-coated tablets (PL
17509/0068-0069).
What are the possible side effects from Imatinib?
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Imatinib is considered to be identical to the previously authorised applications for Imatinib 100 mg and
400 mg film-coated tablets (PL 17509/0068-0069) with the same benefits and risks.
For a full list of all the side effects reported with Imatinib see section 4 of the package leaflet, available
on the Medicines and Healthcare products Regulatory Agency (MHRA) website.
For the full list of restrictions, see the package leaflet.
Why was Imatinib approved?
The MHRA decided that the benefits of Imatinib are greater than the risks and recommended that they
are approved for use.
What measures are being taken to ensure the safe and effective use of Imatinib?
A Risk Management Plan has been developed to ensure that Imatinib are used as safely as possible.
Based on this plan, safety information has been included in the Summaries of Product Characteristics
and the package leaflet for Imatinib 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/reviewed continuously.
Other information about Imatinib
Marketing Authorisations were granted in the UK on 27 October 2017.
The full PAR for Imatinib follows this summary.
For more information about treatment with Imatinib read the package leaflet, or contact your doctor or
pharmacist.
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This summary was last updated in November 2017.
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TABLE OF CONTENTS
I Introduction Page 7
II Quality aspects Page 8
III Non-clinical aspects Page 10
IV Clinical aspects Page 10
V User consultation Page 11
VI Overall conclusion, benefit/risk assessment and
recommendation
Page 11
Table of content of the PAR update Page 17
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I INTRODUCTION
The Medicines and Healthcare products Regulatory Agency (MHRA) granted Torrent Pharma (UK) Ltd
Marketing Authorisations for the medicinal products Imatinib (PL 36687/0208-0209) on 27 October
2017. The products are prescription only medicines (POM) indicated for the treatment of:
• paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+)
chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as
the first line of treatment.
• paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in
accelerated phase or blast crisis.
• adult patients with Ph+CML in blast crisis.
• adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute
lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
• adult patients with relapsed or refractory Ph+ ALL as monotherapy.
• adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with
platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
• adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic
leukaemia (CEL) with FIP1L1-PDGFR rearrangement.
The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.
Imatinib is indicated for
• the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and
adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.
In adult and paediatric patients, the effectiveness of Imatinib is based on overall haematological and
cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic
response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective
response rates in adult patients with unresectable and/or metastatic DFSP. The experience with Imatinib
in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section
5.1). There are no controlled trials demonstrating a clinical benefit or increased survival for these
diseases.
These applications were submitted as simple abridged (informed consent) applications according to
Article 10c of Directive 2001/83/EC, as amended.
The applications cross-refer to the reference products Imatinib 100 mg and 400 mg film-coated tablets
which were first authorised to the marketing authorisation holder (MAH) Intrapharm Laboratories
Limited (PL 17509/0068-0069), on 17 July 2015 via a decentralised procedure (NL/H/3252/001-
002/DC), submitted under article 10(1) of Directive 2001/83/EC, as amended, i.e. as abridged generic
applications, referencing Glivec 100 mg Hard Capsules (EU/1/01/198/002 and EU/1/01/198/006) and
Glivec 400 mg Film-coated Tablets (EU/1/01/198/009, EU/1/01/198/010, EU/1/01/198/013), which are
licenced to Novartis Europharm Limited.
Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the
Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor
(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the
colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and
beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation
of these receptor kinases.
No new data were submitted nor were necessary to be submitted for these applications, as the data are
identical to the data for the previously granted cross-referenced products.
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II QUALITY ASPECTS
II.1 Introduction
These are abridged applications for Imatinib (PL 36687/0208-0209) submitted under Article 10c of
Directive 2001/83/EC, as amended.
The applications cross-refer to the reference Imatinib 100 mg and 400 mg film-coated tablets which
were first authorised to the marketing authorisation holder (MAH) Intrapharm Laboratories Limited (PL
17509/0068-0069), on 17 July 2015. The applications are considered valid.
II.2. Drug Substance
Drug substance specifications
The proposed drug substance specifications are consistent with the details registered for the cross-
reference products.
II.3. Medicinal Product
Name
The proposed product names for these applications are Imatinib 100 and 400 mg Film-coated Tablets.
The products have been named in line with current requirements.
Strength, pharmaceutical form, route of administration, container and pack sizes
Each film coated tablet contains 100 mg or 400 mg imatinib (as mesilate). Both strengths of this
medicine are packed into:
• Aluminium/Aluminium blisters. The 100 mg tablet strength is available in pack sizes of 20, 60,
120 or 180 tablets and the 400 mg tablet strength is available in pack sizes of 10, 30 or 90 tablets.
• High-density polyethylene (HDPE) containers. The 100 mg tablet strength is available in a pack
size of 90 tablets and the 400 mg pack size is available in a pack size of 30 tablets.
Not all pack sizes may be marketed.
The proposed shelf life of the unopened product for both presentation types (blisters and containers) is 2
years with no special storage conditions.
The proposed packaging, shelf-life and storage conditions are consistent with the details registered for
the cross-reference product.
Legal status
Prescription only medicine (POM).
Marketing Authorisation Holder/Contact Persons/Company
Torrent Pharma (UK) Ltd, Unit 4, Charlwood Court, County Oak Way, Crawley, West Sussex, RH11
7XA, UK.
The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV has been
provided.
Manufacturers
The proposed manufacturing sites are consistent with those registered for the cross-reference products
and evidence of Good Manufacturing Practice (GMP) compliance has been provided.
Qualitative and quantitative compositions
The proposed compositions are consistent with the details registered for the cross-reference products.
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Manufacturing process
The proposed manufacturing processes are consistent with the details registered for the cross-reference
products and the maximum batch size is stated.
Finished product/shelf-life specifications
The proposed finished product specifications are in line with the details registered for the cross-reference
products.
TSE Compliance
None of the excipients used contain material of animal or human origin.
Bioequivalence
No bioequivalence data are required to support these simple abridged applications because the proposed
products are manufactured to the same formulae utilising the same processes as the cross-reference
products, Imatinib 100 mg and 400 mg film-coated tablets (PL 17509/0068-0069).
Expert Report
The applicant cross-refers to the data for Imatinib 100 mg and 400 mg film-coated tablets (PL
17509/0068-0069) to which these applications are claimed to be identical. This is acceptable.
Product Name and Appearance
See Section II.3 ‘Medicinal Product; Name’ for details of the proposed product names. The appearance
of the products is identical to that of the cross-reference products.
II.4 Discussion on chemical, pharmaceutical and biological aspects
The data submitted with the applications is acceptable. The grant of Marketing Authorisations is
recommended.
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III NON-CLINICAL ASPECTS
Introduction
As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no
new non-clinical data have been supplied and none are required.
Ecotoxicity/environmental risk assessment (ERA)
Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As
the applications are identical versions of already authorised products, it is not expected that
environmental exposure will increase following approval of the Marketing Authorisations for the
proposed products.
Discussion on the non-clinical aspects
The grant of Marketing Authorisations is recommended.
IV CLINICAL ASPECTS
Introduction
As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended, no
new clinical data have been supplied and none are required.
Risk Management Plan (RMP)
The marketing authorisation holder (MAH) has submitted a risk management plan (RMP), in accordance
with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities
and interventions designed to identify, characterise, prevent or minimise risks relating to Imatinib.
A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are
listed below:
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Summary table of safety concerns:
Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.
Discussion on the clinical aspects
The grant of Marketing Authorisations is recommended.
V User consultation
A user consultation with target patient groups on the package information leaflet (PIL) has been
performed on the basis of a bridging report making reference to the PIL Glivec 400 mg film-coated
tablets (Novartis Europharm Limited) for content and Levetiracetam Hetero 750 mg Film-Coated tablets
for layout (hetero Europe, S.L). The bridging report submitted by the applicant is acceptable.
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 applicant’s product is identical to the cross-reference product. Extensive clinical
experience with imatinib mesilate is considered to have demonstrated the therapeutic value of the
compound. The benefit/risk balance is, therefore, considered to be positive.
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Summaries of Product Characteristics (SmPC), Patient Information Leaflets (PIL) and Labels
The SmPC and PIL are consistent with the details registered for the cross-reference products.
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and
Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are
available on the MHRA website.
The approved labelling for this medicine is presented below:
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Annex 1
Table of content of the PAR update
Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II
variations, PSURs, commitments)
Scope Procedure
number
Product
information
affected
Date of
start of the
procedure
Date of end
of
procedure
Approval/
non
approval
Assessment
report
attached
Y/N
(version)