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.
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