Public Assessment Report Decentralised Procedure - GOV.UK · Public Assessment Report Decentralised Procedure DUTASTERIDE 0.5 mg SOFT CAPSULES (Dutasteride) Procedure No: UK/H/5482/001/DC

Public Assessment Report

Decentralised Procedure

DUTASTERIDE 0.5 mg SOFT CAPSULES

(Dutasteride)

Procedure No: UK/H/5482/001/DC

UK Licence No: PL 43362/0003

Cipla Europe NV

PAR Dutasteride 0.5 mg Soft Capsules UK/H/5482/001/DC

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LAY SUMMARY Dutasteride 0.5 mg Soft Capsules

(Dutasteride)

This is a summary of the Public Assessment Report (PAR) for Dutasteride 0.5 mg Soft Capsules

(PL 43362/0003, formerly PL 36390/0158). It explains how Dutasteride 0.5 mg Soft Capsules 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 Dutasteride 0.5 mg Soft Capsules.

For practical information about Dutasteride 0.5 mg Soft Capsules, patients should read the Patient

Information Leaflet or contact their doctor or pharmacist.

What are Dutasteride 0.5 mg Soft Capsules and what are they used for?

Dutasteride 0.5 mg Soft Capsules are a ‘generic medicine’. This means that Dutasteride 0.5 mg Soft

Capsules are similar to a ‘reference medicine’ already authorised in the European Union (EU) called

Avodart 0.5 mg Soft Capsules (GlaxoSmithKline, UK Limited).

Dutasteride 0.5 mg Soft Capsules are used to treat men with an enlarged prostate (benign prostatic

hyperplasia) – non-cancerous growth of the prostate gland, caused by the production of too much

dihydrotestosterone. Dihydrotestosterone is a male sex hormone found in the body.

Dutasteride may also be used with another medicine called tamsulosin (used to treat the symptoms of an

enlarged prostate).

How do Dutasteride 0.5 mg Soft Capsules work?

The active ingredient in this medicine is dutasteride. Dutasteride belongs to a group of medicines called

5-alpha reductase inhibitors. As the prostate grows, it can lead to urinary problems, such as difficulty in

passing urine and a need to go to the toilet frequently. It can also cause the flow of urine to be slower

and less forceful. If left untreated, there is a risk that the urine flow will be completely blocked (acute

urinary retention). Dutasteride works by lowering the production of the hormone dihydrotestosterone,

which helps to shrink the prostate and relieve the symptoms. This will reduce the risk of the urine flow

being blocked and, therefore, reduce the need for surgery.

Dutasteride may also be used with another medicine called tamsulosin (used to treat the symptoms of an

enlarged prostate).

How are Dutasteride 0.5 mg Soft Capsules used?

This medicine can only be obtained with a prescription from a pharmacy. The usual prescribed dose of

this medicine is one capsule to be taken once a day. It is recommended to swallow the capsule whole

with water. It is advised not to chew or break open the capsule. Dutasteride 0.5 mg Soft Capsules is a

long-term treatment. Early improvement in the symptoms may be noticed by some patients; however,

others may need to continue treatment with Dutasteride 0.5 mg Soft Capsules for 6 months or more.

Please read Section 3 of the Patient Information Leaflet for detailed information on dosing

recommendations, the route of administration and the duration of treatment.


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What benefits of Dutasteride 0.5 mg Soft Capsules Solution have been shown in studies?

Dutasteride 0.5 mg Soft Capsules are a generic medicine; therefore, studies in patients have been limited

to tests to determine that this medicine is bioequivalent to the reference medicine, Avodart 0.5 mg Soft

Capsules. Two medicines are bioequivalent when they produce the same levels of the active substance in

the body.

What are the possible side effects of Dutasteride 0.5 mg Soft Capsules?

Because Dutasteride 0.5 mg Soft Capsules are a generic medicine and this medicine is considered to be

bioequivalent to the reference medicine, Avodart 0.5 mg Soft Capsules, its benefits and possible side

effects are taken as being the same as the reference medicine.

For the full list of restrictions, see the Patient Information Leaflet.

Why are Dutasteride 0.5 mg Soft Capsules approved?

It was concluded that, in accordance with EU requirements, Dutasteride 0.5 mg Soft Capsules have

shown to have comparable quality and to be comparable to the reference medicine; Avodart 0.5 mg Soft

Capsules. Therefore, the MHRA decided that, as Avodart 0.5 mg Soft Capsules, the benefits are greater

than its risk and recommended that it can be approved to be used to treat men with an enlarged prostate.

What measures are being taken to ensure the safe and effective use of Dutasteride 0.5 mg Soft

Capsules?

A Risk Management Plan has been developed to ensure that Dutasteride 0.5 mg Soft Capsules are used

as safely as possible. Based on this plan, safety information has been included in the Summary of

Product Characteristics and the Patient Information Leaflet for Dutasteride 0.5 mg Soft Capsules,

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 reviewed continuously as well.

Other information about Dutasteride 0.5 mg Soft Capsules

Bulgaria, Cyprus, Denmark, France, Finland, Greece, Ireland, Italy, Malta, Norway, Portugal, Romania,

Slovakia, Spain, Sweden and the United Kingdom agreed to grant a Marketing Authorisation for

Dutasteride 0.5 mg Soft Capsules on 22 June 2014. Following a subsequent national phase, a Marketing

Authorisation was granted in the UK to Cipla (EU) Limited on 23 July 2014.

Following a Change of Authorisation (COA) procedure, the Marketing Authorisation for Dutasteride

0.5 mg Soft Capsules (PL 36390/0158) was granted to Cipla Europe NV (Dutasteride 0.5 mg Soft

Capsules; PL 43362/0003) on 22 November 2014.

Subsequently, with the UK as Reference Member State (RMS) in the Mutual Recognition Procedure

(UK/H/5482/001/E01), the Czech Republic, Germany, Poland and The Netherlands agreed to grant a

Marketing Authorisation on 23 September 2015.

The full PAR for Dutasteride 0.5 mg Soft Capsules follows this summary. For more information about

treatment with Dutasteride 0.5 mg Soft Capsules, read the Patient Information Leaflet or contact your

doctor or pharmacist.


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This summary was last updated in January 2017.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 6

II Quality aspects Page 7

III Non-clinical aspects Page 9

IV Clinical aspects Page 9

V User consultation Page 11

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 11

Table of content of the PAR update for MRP and DCP Page 14

Annex 1 Page 15


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Scientific discussion

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Member States considered that the

application for Dutasteride 0.5 mg Soft Capsules (PL 36390/0158; UK/H/5482/001/DC) could be

approved. This application was submitted via the Decentralised Procedure, with the UK as Reference

Member State (RMS), and Bulgaria, Cyprus, Denmark, France, Finland, Greece, Ireland, Italy, Malta,

Norway, Portugal, Romania, Slovakia, Spain, Sweden as Concerned Member States (CMS).

This product can only be obtained with a prescription (legal classification POM).

This application was made under the Decentralised Procedure (DCP), according to Article 10(1) of

Directive 2001/83/EC, as amended, claiming to be a generic medicinal product of the reference product,

Avodart 0.5 mg Soft Capsules. Avodart 0.5 mg Soft Capsules were granted a marketing authorisation to

GlaxoSmithKline, UK Limited on 17 January 2003 (PL 19494/0006).

Dutasteride 0.5 mg Soft Capsules contains the active substance dutasteride. Dutasteride is prescribed for

the following indication:

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).

Reduction in the risk of acute urinary retention (AUR) and surgery in patients with

moderate to severe symptoms of BPH.

Dutasteride belongs to a group of medicines called 5-alpha reductase inhibitors. Dutasteride reduces

circulating levels of dihydrotestosterone (DHT) by inhibiting both type 1 and type 2, 5 alpha-reductase

isoenzymes which are responsible for the conversion of testosterone to 5α-DHT.

No new non-clinical studies were conducted, which is acceptable given that this application was based

on being a generic medicinal product of the reference product, which has been licensed for over 10

years.

With the exception of the pharmacokinetic study comparing this product with that of the reference

product Avodart 0.5 mg Soft Capsules, no new clinical studies were conducted. This is acceptable given

that this application was based on being a generic medicinal product of an originator product that has

been licensed for over 10 years. The pharmacokinetic study was carried out in accordance with Good

Clinical Practice (GCP).

The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for

this product type at all sites responsible for the manufacture, assembly and batch release of this product.

The RMS and CMS considered that the application could be approved at the end of procedure on

22 June 2014. After a subsequent national phase, a Marketing Authorisation was granted in the UK on

23 July 2014.

Following a Change of Authorisation (COA) procedure, the Marketing Authorisation for Dutasteride

0.5 mg Soft Capsules (PL 36390/0158) was granted to Cipla Europe NV(Dutasteride 0.5 mg Soft

Capsules; PL 43362/0003) on 22 November 2014.

Subsequently, with the UK as the Reference Member State (RMS) in the Mutual Recognition Procedure

(UK/H/5482/001/E01), Cipla Europe NV applied for a Marketing Authorisation for Dutasteride 0.5 mg

soft Capsules in Czech Republic, Germany, Poland and The Netherlands; the Member States agreed to

grant a Marketing Authorisation on 23 September 2015.


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II QUALITY ASPECTS

II.1 Introduction

The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical dossier.

Each soft capsule contains 0.5 mg dutasteride, as the active substance.

Other Ingredients

Other ingredients consist of the following pharmaceutical excipients:

Capsule contents:

Butylated hydroxytoluene (E321), mono and diglycerides of caprylic/capric acid

Capsule shell:

Gelatine, glycerol, titanium dioxide (E171), iron oxide yellow (E172).

Printing Ink:

Allura Red AC Aluminum Lake (E129), propylene glycol (E1520), hypromellose (E464) and titanium

dioxide (E171).

The finished product is packaged in white opaque polyvinylchloride/polyvinylidene/aluminium film

containing 10 soft capsules packed into blister packs of 10, 30, 50, 60 and 90 capsules.

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 foodstuffs.

The Marketing Authorisation Holder has stated that not all pack sizes are intended for marketing.

However, they have committed to providing the relevant licensing authority with the mock-ups for any

pack size before marketing it in that country.

II.2 Drug substance

Dutasteride

rINN: Dutasteride

Chemical name: 17β-N-{2,5- Bis (trifluoromethyl) phenyl}carbamoyl-4-aza-5α-

androst-1-en3-one

Structure:


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Molecular formula: C27H30F6N2O2

Molecular weight: 528.5 g/mol

Appearance: White to off white crystalline powder

Solubility: Soluble in methanol and ethanol

Synthesis of the active 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.

Appropriate proof-of-structure data has been supplied for the active pharmaceutical ingredient. All

potential known impurities have been identified and characterised.

Appropriate specifications are provided for the active substance dutasteride, with suitable test methods

and limits. The methods of testing and limits for residual solvents are in compliance with current

guidelines. Batch analysis data are provided and comply with the proposed specifications.

Suitable Certificates of Analysis have been provided for all reference standards used. Satisfactory

specifications have been provided for all packaging used for storing the active substance, dutasteride.

The primary packaging has been shown to comply with current legislation concerning materials in

contact with foodstuff.

Appropriate stability data have been generated showing the active substance to be physically and

chemically stable. A suitable retest period has been set based on stability data submitted for the active

substance stored in the proposed packaging.

II.3 Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate a globally acceptable, stable and

bioequivalent product containing dutasteride that could be considered a generic medicinal product of

the reference product Avodart 0.5 mg Soft Capsules.

Comparative physico-chemical data, including in vitro dissolution and impurity profiles have been

provided for the proposed product versus the reference product, and pharmaceutical equivalence has

been shown.

A satisfactory account of the pharmaceutical development has been provided.

All excipients with the exception of iron oxide yellow (E172 (iii)) and mono and diglycerides of

caprylic/capric acid comply with their respective European Pharmacopoeia monographs.

Iron oxide yellow (E172 (iii)) and mono and diglycerides of caprylic/capric acid comply with the

national formulary.

All colouring agents used have been shown to comply with EU Directive 95/45/EC, concerning the use

of colours in foodstuff.

With the exception of gelatine none of the excipients contain materials of animal or human origin.

No genetically modified organisms (GMO) have been used in the preparation of this product.

The suppliers of gelatin have provided Certificates of Suitability from the European Directorate for the

Quality of Medicines and Healthcare (EDQM) to show that it is manufactured in line with current


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European guidelines concerning minimising of risk of transmission of Bovine Spongiform

Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE).

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. Suitable in-process controls are in place to ensure the

quality of the finished product.

Process validation has been carried out on three production-scale batches of finished product. The

results are satisfactory.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described and have

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

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

Stability of the product

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

manufactured by the finished product manufacturer and packed in the packaging proposed for

marketing. The results from these studies support a shelf-life of 2 years with the storage conditions of

“Store at a temperature not exceeding 25°C”.

Bioequivalence/bioavailability

A pharmacokinetic study was performed comparing the test product Dutasteride 0.5 mg Soft Capsules

(Cipla (EU) Limited) versus the reference product Avodart 0.5 mg Soft Capsules. Suitable certificates of

analysis have been provided for the test and reference products used in both studies.

Conclusion

The grant of a Marketing Authorisation is recommended.

III NON-CLINICAL ASPECTS

As the pharmacodynamic, pharmacokinetic and toxicological properties of dutasteride are well-known,

no further non-clinical studies are required and none have been provided.

The applicant’s non-clinical expert report has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the product’s pharmacology and toxicology.

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

As this product is intended for generic substitution with products that are currently marketed, no

increase in environmental burden is expected.

There are no objections to the approval of this product from a non-clinical viewpoint.

IV CLINICAL ASPECTS

Pharmacokinetics and Pharmacodynamics

With the exception of the following study, no new pharmacodynamic or pharmacokinetic data have been

submitted with this application and none are required.

In support of this application, the Marketing Authorisation Holder has submitted the following

bioequivalence study:


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A randomized, two-treatment, two-sequence, two-period, crossover, single-dose pharmacokinetic

study of the test product, Dutasteride 0.5 mg Soft Capsules (Cipla (EU) Limited) versus the

reference product Avodart 0.5 mg Soft Capsules in healthy male volunteers under fasting

conditions.

Following an overnight fast of at least 10 hours, subjects were dosed orally with either the test or

reference product in each study period. Blood samples were taken pre-dose and up to 72 hours post

dose. There was a washout period of 31 days between each dosing period.

A summary of the main pharmacokinetic results is presented in the tables below:

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

Cmax maximum plasma concentration

The 90% confidence interval of the test/reference ratio for log-transformed pharmacokinetic variables

Cmax, AUC0-∞ and AUC0-72 were within the pre-defined limits of 80.00-125.00%, as specified in the

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

in conclusion, the applicant’s test product Dutasteride 0.5 mg Soft Capsules is considered to be

bioequivalent to the reference product Avodart 0.5 mg Soft Capsules.

Efficacy

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

Safety

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

submitted and none were required. No new or unexpected safety issues arose from these studies.

SmPC, PIL and Labels

The SmPC, PIL and labels are acceptable from a clinical perspective.

Pharmacovigilance System and Risk Management Plan

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 Risk Management Plan has been developed to ensure that Dutasteride 0.5 mg Soft Capsules are used

as safely as possible. Based on this plan, safety information has been included in the SmPC and the PIL

for Dutasteride 0.5 mg Soft Capsules, including the appropriate precautions to be followed by healthcare

professionals and patients.


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Clinical Expert Report

The clinical expert report has been written by an appropriately qualified physician and is a suitable

summary of the clinical aspects of the dossier.

Conclusion

The grant of a Marketing Authorisation is recommended.

V USER CONSULTATION

A package leaflet has been submitted to the MHRA along with results of consultations with target

patient groups (“user testing”), in accordance with Article 59 of Council Directive 2001/83/EC, as

amended. The results indicate that the package leaflet is well-structured and organised, easy to

understand and written in a comprehensive manner. The test shows that the patients/users are able to act

upon the information that it contains.

VI OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY

The important quality characteristics of Dutasteride 0.5 mg Soft Capsules are well-defined and

controlled. The specifications and batch analytical results indicate consistency from batch to batch.

There are no outstanding quality issues that would have a negative impact on the benefit-risk balance.

NON-CLINICAL

No new non-clinical data were submitted and none are required for an application of this type.

CLINICAL

Bioequivalence has been demonstrated between the applicant’s Dutasteride 0.5 mg Soft Capsules and

the relevant reference product.

No new or unexpected safety concerns arose from this application.

The SmPC, PIL and labels are satisfactory and consistent with those for the reference product.

BENEFIT-RISK ASSESSMENT

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

identified. Bioequivalence has been demonstrated between the applicant’s product and the reference

product. Extensive clinical experience with dutasteride is considered to have demonstrated the

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


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

the MHRA website. The current labelling is presented 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

Y/N (version)

To update sections 2 (Qualitative and

quantitative composition), 4.2 (Posology

and method of administration), 4.3

(Contraindications), 4.4 (Special

warnings and precautions for use), 4.5

(Interaction with other medicinal

products and other forms of interaction),

4.6 (Fertility, pregnancy and lactation),

4.8 (Undesirable effects), 4.9

(Overdose), 5 (Pharmacological

properties) and 6.1 (List of excipients)

and 6.6 (Special precautions for

disposal) of the Summary of Product

Characteristics (SmPC) and

consequentially the leaflet in line with

the recommendation of a competent

authority.

UK/H/5482/001/II/012 SmPC

PIL

23/09/2016 06/12/2016 Approval Yes (Annex 1)


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Annex 1

Our Reference: PL 43362/0003, Application 0015

Product: Dutasteride 0.5 mg Soft Capsules

Marketing Authorisation Holder: Cipla Europe NV

Active Ingredient(s): Dutasteride

Type of Procedure: Mutual Recognition

Submission Type: Variation

Submission Category: Type II

Submission Complexity: Standard

EU Procedure Number (if applicable): UK/H/5482/001/II/012

Reason:

To update Sections 2 (Qualitative and quantitative composition), 4.2 (Posology and method of

administration), 4.3 (Contraindications), 4.4 (Special warnings and precautions for use), 4.5 (Interaction

with other medicinal products and other forms of interaction), 4.6 (Fertility, pregnancy and lactation),

4.8 (Undesirable effects), 4.9 (Overdose), 5 (Pharmacological properties) and 6.1 (List of excipients)

and 6.6 (Special precautions for disposal) of the Summary of Product Characteristics (SmPC) and

consequentially the leaflet in line with the recommendation of a competent authority.

Supporting Evidence

Revised SmPC fragments

Updated leaflet.

Evaluation

The proposed changes to the SmPC and leaflet are considered satisfactory.

Conclusion

The proposed changes to the SmPC and leaflet are considered acceptable and there are no objections to

approval.

In accordance with Directive 2010/84/EU the SmPCs and PILs for products granted Marketing

Authorisations at a national level are available on the MHRA website.

Decision

Approved on 05 December 2016.

Documents

Public Assessment Report Decentralised Procedure - GOV.UK · Public Assessment Report Decentralised Procedure DUTASTERIDE 0.5 mg SOFT CAPSULES (Dutasteride) Procedure No: UK/H/5482/001/DC