Public Assessment Report UK PAR Deferiprone 500mg Film ... · Deferiprone 500mg and 1000mg Film-coated Tablets PL 30306/0763-0764 3 Please read section 3 of the package leaflet for

Public Assessment Report

UK PAR

Deferiprone 500mg Film-coated Tablets


(Deferiprone)

UK Licence No: PL 30306/0763-0764

Actavis Group PTC ehf

Deferiprone 500mg and 1000mg Film-coated Tablets PL 30306/0763-0764

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LAY SUMMARY



(Deferiprone)

This is a summary of the Public Assessment Report (PAR) for Deferiprone 500mg Film-coated Tablets

(PL 30306/0763) and Deferiprone 1000mg Film-coated Tablets (PL 30306/0764). For ease of reading,

the products may be referred to as ‘Deferiprone Tablets’ or ‘Deferiprone 500 mg and 1000mg Tablets’

in this lay summary. The lay summary explains how the applications for Deferiprone 500mg and

1000mg Film-coated Tablets were assessed and their authorisations recommended, as well as the

conditions of use. It is not intended to provide practical advice on how to use Deferiprone 500mg and

1000mg Film-coated Tablets. For practical information about using Deferiprone 500mg and 1000mg

Film-coated Tablets, patients should read the package leaflet or contact their doctor or pharmacist.

What are Deferiprone Tablets and what are they used for?

Deferiprone 500mg and 1000mg Tablets are ‘generic’ medicines’. This means that Deferiprone 500mg

and 1000mg Tablets are similar to ‘reference medicines’ already authorised in the EU called are

Ferriprox 500 mg and 1000 mg film-coated tablets (Apotex Europe B.V., Netherlands), first licensed in

the EU on 25 August 1999..

Deferiprone Tablets are used to treat iron overload caused by frequent blood transfusions in patients

who have a condition called thalassaemia major when deferoxamine therapy is contraindicated or

inadequate.

How do Deferiprone Tablets work?

Deferiprone Tablets contain the active substance, deferiprone, which is a medicine that removes iron

from the body.

How are Deferiprone Tablets used?

Deferiprone Tablets are taken by mouth.

The patient should always take the tablets exactly as advised by his/her doctor or pharmacist. The

patient should check with his/her doctor or pharmacist if he/she is not sure.

Deferiprone Tablets can be taken with or without food; however, the patient may find it easier to

remember to take the medicine if the tablets are taken with meals.

The 500mg and 1000mg tablets can be divided in equal doses. If the tablets are divided, the divided dose

should be taken within 3 days.

Adults

The recommended dose is based on the patient’s body weight.

• The patient’s doctor will decide on the dose.

• The usual dose is 25mg/kg, three times per day (to give a total daily dose of 75 mg/kg).

• The total daily dose should not exceed 100 mg/kg.

• The patient should take the first dose in the morning, the second dose at midday and the third dose in

the evening.


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Please read section 3 of the package leaflet for detailed information on dosing recommendations, route

of administration and the duration of treatment.

Deferiprone Tablets can only be obtained with a prescription.

What benefits of Deferiprone Tablets have been shown in studies?

As Deferiprone 500mg and 1000mg Tablets are generic medicines, studies in patients have been limited

to tests to determine that they are bioequivalent to their respective reference medicines, Ferriprox 500

mg and 1000 mg film-coated tablets (Apotex Europe B.V., Netherlands). Two medicines are

bioequivalent when they produce the same levels of the active substance in the body.

What are possible side effects of Deferiprone Tablets?

Because Deferiprone 500mg and 1000mg Tablets are generic medicines that are considered

bioequivalent to the reference medicines, Ferriprox 500 mg and 1000 mg film-coated tablets (Apotex

Europe B.V., Netherlands), the benefits and possible side effects are taken as being the same as the

respective reference medicines.

For the full list of all side effects reported with Deferiprone Tablets, see section 4 of the package leaflet.

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

Why are Deferiprone Tablets approved?

It was concluded that, in accordance with EU requirements, Deferiprone Tablets have been shown to

have comparable quality and to be bioequivalent to Ferriprox 500 mg and 1000 mg film-coated tablets

(Apotex Europe B.V., Netherlands). Therefore, the MHRA decided that, as for Ferriprox 500mg and

1000mg film-coated tablets (Apotex Europe B.V., Netherlands), the benefits outweigh the identified

risks and recommended that Deferiprone Tablets can be approved for use.

What measures are being taken to ensure the safe and effective use of Deferiprone Tablets?

A Risk Management Plan has been developed to ensure that Deferiprone Tablets 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 Deferiprone Tablets, 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 Deferiprone Tablets

Marketing Authorisations were granted for Deferiprone 500mg and 1000mg Tablets to Actavis Group

PTC ehf on 13 December 2017.

The full PAR for Deferiprone Tablets follows this summary.

For more information about treatment with Deferiprone Tablets read the package leaflet, or contact your

doctor or pharmacist.

This summary was last updated in February 2018.


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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 10

VI Overall conclusion, benefit/risk assessment and recommendation Page 10

Steps taken after Authorisation – Summary Page 20


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Scientific discussion

I INTRODUCTION

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Actavis Group PTC ehf

Marketing Authorisations for the medicinal products Deferiprone 500mg and 1000mg Film-coated

Tablets (PL 30306/0763-0764) on 13 December 2017. For ease of reading, the products may be referred

to as ‘Deferiprone Tablets’ or ‘Deferiprone 500 mg and 1000mg Tablets’ in this scientific discussion.

These are Prescription Only Medicines (POM) indicated for the treatment of iron overload in patients

with thalassaemia major when deferoxamine therapy is contraindicated or inadequate.

The applications for Deferiprone 500mg and 1000mg Tablets were submitted in accordance to Article

10(1) of Directive 2001/83/EC, as amended, as generic applications. The applications cross-refer to the

reference products Ferriprox 500 mg and 1000 mg film-coated tablets (Apotex Europe B.V.,

Netherlands), which were first authorised in the EU via the Centralised Procedure on 25 August 1999..

The active substance, deferiprone, binds to iron in a 3:1 molar ratio. Clinical studies have demonstrated

that deferiprone is effective in promoting iron excretion and that a dose of 25 mg/kg three times per day

can prevent the progression of iron accumulation as assessed by serum ferritin, in patients with

transfusion-dependent thalassaemia. However, chelation therapy may not necessarily protect against

iron-induced organ damage.

A bioequivalence study was submitted to support the applications comparing the applicant’s test product

Deferiprone 1000 mg film-coated tablets (Genepharm S.A., Greece) with the reference product

Ferriprox 1000mg film-coated tablets (Apotex Europe BV, Netherlands), under fasting conditions. The

applicant has stated that the bioequivalence study was conducted in accordance with Good Clinical

Practice (GCP).

With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted,

which is acceptable given that the applications were based on being generic medicinal products of

originator products that have been in clinical use for over 10 years.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place at all sites responsible for the manufacture, assembly and batch release of these products.

No new or unexpected safety concerns arose during review of information provided by the Marketing

Authorisation Holder and it was, therefore, judged that the benefits of Deferiprone Tablets outweigh the

risks and Marketing Authorisations were granted.

II QUALITY ASPECTS

II.1 Introduction

The submitted documentation concerning the proposed products is of sufficient quality and meets the

current EU regulatory requirements.

The quality overall summary has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical aspects of the dossier.

The tablets are white to off-white, film-coated, with a score line on one side and plain on the other, with

dimensions of 14.2mm x 8.2mm (500mg strength tablet) or 19.2mm x 9.2mm (1000mg strength tablet).

The tablets can be divided into equal doses.

Each tablet contains 500mg or 1000mg of the active substance, deferiprone. The products also contain

pharmaceutical excipients in the tablet core and tablet coating, namely pregelatinised maize starch,


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magnesium stearate, hypromellose, hydroxypropylcellulose, titanium dioxide and macrogol. Appropriate

justification for the inclusion of each excipient has been provided.

The finished products are supplied in:

Polyvinylchloride/polyethylene/polvinylidene chloride - aluminium blisters, in a pack size of 50

(1000mg strength tablets only) and 100 (500mg strength tablets only) film-coated tablets.

Satisfactory specifications and Certificates of Analysis for the primary packaging materials have been

provided. All primary packaging complies with current European regulations concerning materials in

contact with foodstuff.

II.2 DRUG SUBSTANCE

Deferiprone

INN: Deferiprone

Chemical Name: 1,2-Dimethyl-3-hydroxypyridin-4 one;

1,2-Dimethyl-3-hydroxypyrid-4-one;

1,2-Dimethyl-3-hydroxypyridone-4;

1,2-Dimethyl-3-hydroxy-4-pyridone;

3-Hydroxy-1,2-dimethyl-4(1H)-pyridinone.

Molecular formula: C7H9NO2

Mr: 139.15

Structure:

Appearance: White crystalline powder, almost odourless

Solubility:

Polymorphism Deferiprone does not exhibit polymorphism

Deferiprone is not the subject of a European Pharmacopoeia monograph.

Synthesis of the active substance from the designated starting materials 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. Appropriate proof-of-structure data have been supplied. All potential known

impurities have been identified and characterised.

An appropriate specification is provided for the active substance. Analytical methods have been

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

Batch analyses data are provided that comply with the proposed specification.

Satisfactory Certificates of Analysis have been provided for all working standards.

Suitable specifications have been provided for all packaging used. The primary packaging has been

shown to comply with current guidelines concerning contact with foodstuff.


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Appropriate stability data have been generated to support a suitable retest period when stored in the

proposed packaging.

II.3 MEDICINAL PRODUCT

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious, stable film-coated

tablets, which were bioequivalent to Ferriprox 500 mg and 1000 mg film-coated tablets (Apotex Europe

B.V., Netherlands). Suitable pharmaceutical development data have been provided for these

applications.

Comparative in vitro dissolution profiles have been provided for these products and the respective

reference products. The dissolution profiles were satisfactory.

All excipients comply with their respective European Pharmacopoeia monographs. Satisfactory

Certificates of Analysis have been provided for all excipients.

None of the excipients contain materials of animal or human origin.

These products do contain or consist of genetically modified organisms (GMO).

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of all strengths of the product,

along with an appropriate description of the manufacturing process. The manufacturing process has been

validated with pilot scale batches and has shown satisfactory results. The Marketing Authorisation

Holder has committed to performing process validation studies on future full-scale production batches.

Control of Finished Product

The finished product specifications are acceptable. Test methods have been described that have been

validated adequately. Batch data that comply with the release specifications have been provided.

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

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines, on batches of

finished product in the packaging proposed for marketing. Based on the results, a shelf life of 48 months

for the unopened product, with no special storage conditions, has been accepted. Half tablets can be

stored for 3 days at room temperature (below 25°C) in the original packaging.

Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the

bioequivalence study.

II.4 Discussion on chemical, pharmaceutical and biological aspects

It is recommended that Marketing Authorisations are granted for these applications for Deferiprone

Tablets, from a quality of view.


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III NON-CLINICAL ASPECTS

III.1 Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of deferiprone are well known. No

new non-clinical data have been submitted for these applications 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 relevant non-clinical pharmacology, pharmacokinetics and toxicology.

III.2 Pharmacology

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

III.1, Introduction, above.

III.3 Pharmacokinetics



III.4 Toxicology



III.5 Ecotoxicity/Environmental Risk Assessment (ERA)

Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As

these products are intended for generic substitution with products that are already marketed, no increase

in environmental exposure to deferiprone is anticipated. Thus, the justification for non-submission of an

Environmental Risk Assessment is accepted.

III.6 Discussion of the non-clinical aspects

It is recommended that Marketing Authorisations are granted for Deferiprone Tablets, from a

non-clinical point of view.

IV. CLINICAL ASPECTS

IV.1 Introduction

The clinical pharmacology of deferiprone is well-known.

In accordance with the regulatory requirements CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, Guideline on

the Investigation of Bioequivalence, the Marketing Authorisation Holder submitted the results from a

bioequivalence study to support these generic applications.

With the exception of data from the bioequivalence study, no new pharmacodynamic or

pharmacokinetic data are provided or required for these applications.

IV.2 Pharmacokinetics

The clinical pharmacokinetic properties of deferiprone are well-known.

In support of the applications, a bioequivalence study was submitted. Details of the study are provided

below.

A randomised, open-label, two-treatment, two-period, two-sequence, single-dose, crossover

bioequivalence study comparing the pharmacokinetics of the applicant’s test product Deferiprone

1000 mg film-coated tablets (Genepharm S.A., Greece) and the reference product Ferriprox

1000mg film-coated tablets (Apotex Europe BV, Netherlands) in healthy adult human male

subjects under fasting conditions.


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The subjects were administered one tablet of either the test or the reference product with 240 ml of

water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and

including 24 hours after each administration. The washout period between the treatment phases was

5 days. The statistical results for primary pharmacokinetic parameters of deferiprone are summarised

below:

Table 1: Geometric Means, Ratio of Means, and 90% Confidence Intervals for deferiprone

Cmax maximum plasma concentration

AUC0-t area under the plasma concentration-time curve from time zero to t hours

AUC0-inf area under the plasma concentration-time curve from time zero to infinity

CV% Coefficient of variation

Ratios and 90% CI calculated from ln-transformed data

The 90% confidence intervals of the test/reference ratio for Cmax and AUC values lie within the

acceptable limits of 80.00% to 125.00%, in line with the Guideline on the Investigation of

Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Thus, the data support the claim that the

applicant’s test product, Deferiprone 1000 mg film-coated tablets (Genepharm S.A., Greece), is

bioequivalent to the reference product, Ferriprox 1000mg film-coated tablets (Apotex Europe BV,

Netherlands), under fasting conditions.

As the 500mg and 1000mg strength tablets of the test product meet the criteria for a biowaiver specified

in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), the

results and conclusions from the bioequivalence study with the 1000mg strength tablet can be

extrapolated to the 500mg strength tablet.

IV.3 Pharmacodynamics

The clinical pharmacodynamic properties of deferiprone are well-known. No new pharmacodynamics

data were submitted and none are required for applications of this type.

IV.4 Clinical Efficacy

The clinical efficacy of deferiprone is well-known. No new efficacy data were presented for applications

of this type.

IV.5 Clinical Safety

With the exception of the safety data generated during the bioequivalence study no new safety data were

submitted and none are required for applications of this type. The safety profile of deferiprone is

well-known. No new or unexpected safety issues were raised during the bioequivalence study.

IV.6 Risk Management Plan

The MAH has submitted a Risk Management Plan, 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 Deferiprone Tablets.


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A summary of safety concerns is listed in the table below:

Routine pharmacovigilance activities are acceptable to monitor all the safety concerns described in the

Risk Management Plan.

Routine risk minimisation activities are acceptable to monitor the safety concerns with the exception of

‘neutropenia’, ‘agranulocytosis’ and ‘use in pregnancy’.

Additional risk minimisation activities for the safety concerns ‘neutropenia’, ‘agranulocytosis’ and ‘use

in pregnancy’ include provision of the following:

• wallet-sized, tear-away, patient/carer reminder cards within the product pack to increase patient

awareness about the importance of regular monitoring of the neutrophil count during treatment with

deferiprone and to increase awareness of the significance of any symptoms of infection while taking

deferiprone.

•

IV.7 Discussion of the clinical aspects

It is recommended that Marketing Authorisations are granted for Deferiprone Tablets.

V. USER CONSULTATION

A 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, as amended. The language used for the purpose of

user testing the pack leaflet was English.

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

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

identified. Extensive clinical experience with deferiprone is considered to have demonstrated the

therapeutic value of the compound. Bioequivalence between the test and reference products has been

demonstrated in accordance with the current CHMP guidelines.

The benefit/risk assessment is therefore considered to be positive.

The grant of Marketing Authorisations is recommended.


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The SmPCs, PIL and labelling text are satisfactory and in line with current guidance.

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

MHRA website. The current labelling is presented below.

The Marketing Authorisation Holder has submitted the text version only and has committed to

submitting mock-up livery to the regulatory authorities for approval before packs are marketed.


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Deferiprone 500mg Film-coated Tablets:


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Deferiprone 1000mg Film-coated Tablets:


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(Deferiprone)

PL 30306/0763-0764

STEPS TAKEN AFTER AUTHORISATION-SUMMARY

Date submitted Application

type

Scope Outcome

Documents

Public Assessment Report UK PAR Deferiprone 500mg Film ... · Deferiprone 500mg and 1000mg Film-coated Tablets PL 30306/0763-0764 3 Please read section 3 of the package leaflet for