Post on 08-Jan-2017
Public Assessment Report
Decentralised Procedure
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard (Duloxetine hydrochloride)
Procedure No: UK/H/5865/001-004/DC
UK Licence No: PL 27755/0002-0005
Dr. Ebeling & Assoc. GmbH
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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LAY SUMMARY Dutor 20 mg gastro-resistant capsules, hard
PL 27755/0002
Dutor 30 mg gastro-resistant capsules, hard
PL 27755/0003
Dutor 40 mg gastro-resistant capsules, hard
PL 27755/0004
Dutor 60 mg gastro-resistant capsules, hard
PL 27755/0005
(Duloxetine hydrochloride)
This is a summary of the Public Assessment Report (PAR) for Dutor 20 mg, 30 mg, 40 mg
and 60 mg gastro-resistant capsules, hard (UK/H/5865/001-004/DC; PL 27755/0002-0005).
Dutor 20 mg, 30 mg, 40 mg and 60 mg gastro-resistant capsules, hard will be referred to as
Dutor gastro-resistant capsules throughout this report, for ease of reading. It explains how
Dutor gastro-resistant 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 Dutor
gastro-resistant capsules.
For practical information about using Dutor gastro-resistant capsules, patients should read the
package leaflet or contact their doctor or pharmacist.
What are Dutor gastro-resistant capsules and what are they used for?
Dutor gastro-resistant capsules are generic medicines. This means that Dutor 20 mg and
40 mg gastro-resistant capsules are similar to ‘reference medicines’ already authorised in the
European Union (EU) called Yentreve 20 mg and 40 mg hard gastro-resistant capsules, and
Dutor 30 mg and 60 mg gastro-resistant capsules are similar to ‘reference medicines’ already
authorised in the European Union (EU) called Cymbalta 30mg and 60mg hard gastro-resistant
capsules.
Dutor 20 mg and 40 mg gastro-resistant capsules are used to treat Stress Urinary Incontinence
(SUI) in women. Stress urinary incontinence is a medical condition in which patients have
accidental loss or leakage of urine during physical exertion or activities such as laughing,
coughing, sneezing, lifting, or exercise.
Dutor 30 mg and 60 mg gastro-resistant capsules are used to treat:
- Depression
- Generalised anxiety disorder (chronic feeling of anxiety or nervousness), and
- Diabetic neuropathic pain. (This is often described as burning, stabbing, stinging,
shooting or aching, or like an electric shock. There may be loss of feeling in the
affected area, or sensations such as touch, heat, cold or pressure may cause pain).
How do Dutor gastro-resistant capsules work?
Dutor gastro-resistant capsules contain the active substance, duloxetine (as duloxetine
hydrochloride), which increases levels of serotonin and noradrenaline in the nervous system.
How are Dutor gastro-resistant capsules used?
Dutor gastro-resistant capsules should be swallowed whole with a drink of water. Dutor
gastro-resistant capsules can be taken with or without food.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Dutor 20 mg and 40 mg gastro-resistant capsules
The usual dose for Dutor 20 mg and 40 mg gastro-resistant capsules is 40 mg twice a day (to
be taken in the morning and late afternoon or evening). The prescribing doctor may decide to
start treatment with 20 mg twice a day for two weeks before increasing the dose to 40 mg
twice a day.
Dutor 30 mg and 60 mg gastro-resistant capsules
The usual dose for the treatment of depression and diabetic neuropathic pain is 60 mg once a
day but the prescribing doctor will decide on a dose that is correct for the patient.
The usual dose for the treatment of generalised anxiety disorder is 30 mg once a day but the
prescribing doctor will decide on a dose that is correct for the patient.
Please read Section 3 of the package leaflet for further information.
Dutor gastro-resistant capsules can only be obtained with a prescription.
What benefits of Dutor gastro-resistant capsules have been shown in studies? Because Dutor gastro-resistant capsules are generic medicines, studies in patients have been
limited to tests to determine that Dutor gastro-resistant capsules, are bioequivalent to the
reference medicines. Two medicines are bioequivalent when they produce the same levels of
the active substance in the body.
What are the possible side effects from Dutor gastro-resistant capsules?
Because Dutor gastro-resistant capsules are generic medicines, and are bioequivalent to the
reference medicines, their benefits and possible side effects are taken as being the same as the
reference medicines.
For information about side effects that may occur with using Dutor gastro-resistant capsules,
please refer to the package leaflet or the Summaries of Product Characteristics (SmPCs)
available on the Medicines and Healthcare products Regulatory Agency website.
Why are Dutor gastro-resistant capsules approved?
It was concluded that, in accordance with EU requirements, Dutor 20 mg, 40 mg, 30 mg and
60 mg gastro-resistant capsules have been shown to have comparable quality and to be
bioequivalent to Yentreve 20 mg and 40 mg hard gastro-resistant capsules, and Cymbalta
30mg and 60 mg hard gastro-resistant capsules, respectively. The MHRA, therefore, decided
that, as for Yentreve 20 mg and 40 mg hard gastro-resistant capsules and Cymbalta 30mg and
60 mg hard gastro-resistant capsules, the benefits are greater than the risks and recommended
that Dutor gastro-resistant capsules can be approved for use.
What measures are being taken to ensure the safe and effective use of Dutor gastro-
resistant capsules?
A Risk Management Plan has been developed to ensure that Dutor gastro-resistant capsules
are used as safely as possible. Based on this plan, safety information has been included in the
SmPCs and the package leaflets for Dutor gastro-resistant capsules, including the appropriate
precautions to be followed by healthcare professionals and patients.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Other information about Dutor gastro-resistant capsules
Lithuania, Romania and the UK agreed to grant Marketing Authorisations for Dutor
gastro-resistant capsules on 05 August 2015.
The full PAR for Dutor gastro-resistant capsules follows this summary.
For more information about taking Dutor gastro-resistant capsules, read the package leaflet, or
contact your doctor or pharmacist.
This summary was last updated in October 2015.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Table of Contents
I Introduction Page 6
II Quality aspects Page 8
III Non-clinical aspects Page 11
IV Clinical aspects Page 12
V User consultation Page 17
VI Overall conclusion, benefit/risk assessment and
recommendation
Page 17
Annex - Table of content of the PAR update for MRP and
DCP
Page 29
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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I Introduction
Based on the review of the data on quality, safety and efficacy, the Member States have
granted Marketing Authorisations (MAs) for the medicinal products Dutor 20 mg, 30 mg,
40 mg, and 60 mg gastro-resistant capsules (UK/H/5865/001-004/DC; PL 27755/0002-0005).
Dutor 20 mg and 40 mg gastro-resistant capsules are prescription-only medicines (legal status
POM) indicated for women for the treatment of moderate to severe Stress Urinary
Incontinence (SUI). Dutor 20 mg and 40 mg gastro-resistant capsules are indicated in adults.
Dutor 30 mg and 60 mg gastro-resistant capsules are prescription-only medicines (legal status
POM) indicated in the treatment of:
- major depressive disorder
- diabetic peripheral neuropathic pain
- generalised anxiety disorder.
Dutor 30 mg and 60 mg gastro-resistant capsules are indicated in adults.
The applications were submitted using the Decentralised Procedure (DCP), with the UK as
Reference Member State (RMS) and Lithuania and Romania as Concerned Member States
(CMSs).
The applications were made under Article 10(1) of Directive 2001/83/EC, as amended, as
generic medicinal products. For the reference medicinal products authorised for more than 10
years in the EEA, reference has been made to Yentreve 20 mg and 40 mg hard gastro-resistant
capsules authorised to Eli Lilly Nederland BV on 11 August 2004 through the centralised
procedure (EU/1/004/280/001, 007, 008 and EU/1/04/280/002-006).
The reference medicinal products for Dutor 20 mg and 40 mg gastro-resistant capsules, are
Yentreve 20 mg and 40 mg hard gastro-resistant capsules (EU/1/004/280/001, 007, 008 and
EU/1/04/280/002-006).
The reference medicinal products for Dutor 30 mg and 60 mg gastro-resistant capsules are
Cymbalta 30 mg and 60 mg hard gastro-resistant capsules, which were authorised to Eli Lilly
Nederland BV on 17 December 2004 through the centralised procedure (EU/1/004/296/002-
005&007-008).
Dutor gastro-resistant capsules contain the active ingredient duloxetine (as duloxetine
hydrochloride). Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake
inhibitor (SSNRI) for oral administration.
No new non-clinical studies were conducted, which is acceptable given that the applications
are based on being generic medicinal products of originator products that has been licensed
for over 10 years.
Since Dutor gastro-resistant capsules are intended for generic substitution, their use will not
lead to an increased exposure to the environment. An Environmental Risk Assessment (ERA)
is, therefore, not deemed necessary.
With the exception of two bioequivalence studies, no new clinical data were provided with
these applications. Two bioequivalence studies were performed, which compared the
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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pharmacokinetics of the Applicant’s Dutor 60 mg gastro-resistant capsules with those of the
reference product, Cymbalta 60 mg hard gastro-resistant capsules, in healthy subjects under
fasting and fed conditions. The bioequivalence studies were conducted in line with current
Good Clinical Practice (GCP).
The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)
are in place for this product type at all sites responsible for the manufacture, assembly and
batch release of these products.
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.
For manufacturing sites outside the Community, the RMS has accepted copies of current
GMP Certificates of satisfactory inspection summary reports issued by the inspection services
of the MHRA as certification that acceptable standards of GMP are in place at those
non-Community sites.
A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been
provided with these applications and are satisfactory.
The RMS and CMSs considered that the applications could be approved at the end of
procedure (Day 206) on 05 August 2015. After a subsequent National phase, licences were
granted in the UK on 03 September 2015.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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II Quality aspects
II.1 Introduction These applications are submitted according to Article 10(1) of Directive 2001/83/EC, as
amended.
Dutor 20 mg gastro-resistant capsules
Dutor 20 mg gastro-resistant capsules are formulated as size ‘4’ hard gelatin capsules having
a light blue cap and body, imprinted with ‘20 mg’ on the body, and ‘1109’ on the cap, with
black ink. The gelatin capsules contain off-white to reddish brown coloured pellets.
Dutor 20 mg gastro-resistant capsules contain 20 mg of the active substance duloxetine (as
hydrochloride). The excipients present in the capsule contents are: hypromellose 2910,
hypromellose acetate succinate, sucrose, sugar spheres (consisting of sucrose, maize starch,
liquid glucose and purified water), talc, titanium dioxide (E 171), triethyl citrate and macrogol
400.
The excipients present in the capsule shell for Dutor 20 mg gastro-resistant capsules are:
gelatin, sodium lauryl sulphate, titanium dioxide (E 171) and indigo carmine (E 132).
The excipients present in the black printing ink are: shellac, black iron oxide (E 172) and
potassium hydroxide.
Dutor 30 mg gastro-resistant capsules
Dutor 30 mg gastro-resistant capsules are formulated as size ‘3’ hard gelatin capsules having
a blue cap and a milky white body, imprinted with ‘30 mg’ on the body with black ink, and
‘30 mg’ on the cap with white ink. The gelatin capsules contain off-white to reddish brown
coloured pellets.
Dutor 30 mg gastro-resistant capsules contain 30 mg of the active substance duloxetine (as
hydrochloride). The excipients present in the capsule contents are: hypromellose 2910,
hypromellose acetate succinate, sucrose, sugar spheres (consisting of sucrose, maize starch,
liquid glucose and purified water), talc, titanium dioxide (E 171), triethyl citrate and macrogol
400.
The excipients present in the capsule shell for Dutor 30 mg gastro-resistant capsules are:
gelatin, sodium lauryl sulphate, titanium dioxide (E 171) and indigo carmine (E 132).
The excipients present in the black printing ink are: shellac, black iron oxide (E 172) and
potassium hydroxide.
The excipients present in the white printing ink are: shellac, titanium dioxide (E 171) and
potassium hydroxide.
Dutor 40 mg gastro-resistant capsules
Dutor 40 mg gastro-resistant capsules are formulated as size ‘2’ hard gelatin capsules having
a light blue cap and an orange body, imprinted with ’40 mg’ on the body, and ‘1112’ on the
cap, with black ink. The gelatin capsules contain off white to reddish brown coloured pellets.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Dutor 40 mg gastro-resistant capsules contain 40 mg of the active substance duloxetine (as
hydrochloride). The excipients present in the capsule contents are: hypromellose 2910,
hypromellose acetate succinate, sucrose, sugar spheres (consisting of sucrose, maize starch,
liquid glucose and purified water), talc, titanium dioxide (E 171), triethyl citrate and macrogol
400.
The excipients present in the capsule shell for Dutor 30 mg gastro-resistant capsules are:
gelatin, sodium lauryl sulphate, titanium dioxide (E 171), indigo carmine (E 132), yellow iron
oxide (E172) and red iron oxide (E172).
The excipients present in the black printing ink are: shellac, black iron oxide (E 172) and
potassium hydroxide.
Dutor 60 mg gastro-resistant capsules
Dutor 60 mg gastro-resistant capsules are formulated as size ‘1’ hard gelatin capsules having
an opaque blue cap and a yellow body, imprinted with ‘60 mg’ on the body, and ‘1111’ on the
cap, with white ink. The gelatin capsules contain off white to reddish brown coloured pellets.
Dutor 60 mg gastro-resistant capsules contain 60 mg of the active substance duloxetine (as
hydrochloride). The excipients present in the capsule contents, common to all strengths, are:
hypromellose 2910, hypromellose acetate succinate, sucrose, sugar spheres (consisting of
sucrose, maize starch, liquid glucose and purified water), talc, titanium dioxide (E 171),
triethyl citrate, macrogol 400.
The excipients present in the capsule shell for Dutor 60 mg gastro-resistant capsules are:
gelatin, sodium lauryl sulphate, titanium dioxide (E 171), indigo carmine (E 132) and yellow
iron oxide (E172).
The excipients present in the white printing ink are: shellac, sodium hydroxide, povidone K16
and titanium dioxide (E 171).
Dutor 20 mg, 30 mg, 40 mg and 60 mg gastro-resistant capsules are packed into:
- oriented polyamide (OPA)/aluminium (Al)/ polyvinyl chloride (PVC)/aluminium (Al)
blisters in pack sizes of 7, 28 and 56 capsules. Additionally, the 40 mg and 60 mg
strengths are packed in OPA/Al/PVC/Al blisters in pack sizes of 98, 140 and 196 (2 x
98) capsules and the 60 mg strength is packed in OPA/Al/PVC/Al blisters in pack
sizes 84 capsules.
- High Density Polyethylene (HDPE) bottles with a polypropylene screw cap in pack
sizes of 28, 98 and 100 or 30 capsules.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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II.2 Drug Substance Duloxetine
rINN: Duloxetine Hydrochloride
Structure:
Molecular formula: C18H20ClNOS
Molecular weight: 333.9
Appearance: White or almost white powder
Solubility: Sparingly soluble in water, freely soluble in methanol, practically
insoluble in hexane.
Duloxetine hydrochloride is the subject of a European Pharmacopoeia (Ph. Eur) monograph.
The manufacture and control of the active substance, duloxetine hydrochloride, are covered
by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate
of Suitability. Satisfactory information has been provided on the stability of the active
substance.
II.3 Medicinal Product Pharmaceutical development
The objective of the development studies was to develop a stable, scalable, bioequivalent and
robust formulation of Duloxetine hydrochloride 20 mg, 30 mg, 40 mg and 60 mg
gastro-resistant capsules.
The development of the products has been adequately described. Satisfactory justification for
the excipients used in the final formulation and the manufacturing process has been provided.
Comparative dissolution was demonstrated between the test product and reference product
used in the bioequivalence studies and between the Dutor 60 mg gastro-resistant capsules and
Dutor 20 mg, 30mg and 40mg gastro-resistant capsules under a variety of pH conditions.
All of the excipients used in the manufacture of the finished product, with the exception of
hypromellose acetate succinate and the gelatin capsules, comply with their respective Ph. Eur.
monograph. Hypromellose acetate succinate complies with its United States Pharmacopoeia-
National Formulary (USP-NF) monograph and the gelatin capsules are controlled by suitable
in house specifications. Colourants used in the gelatin capsules comply with EC requirements
for colorants.
Satisfactory Certificates of Analysis have been provided for the excipients showing
compliance with their proposed specifications.
None of the excipients are sourced from animal or human origin, except for gelatin. 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
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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current European guidelines concerning the minimising of risk of transmission of Bovine
Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE).
No genetically modified organisms (GMO) have been used in the preparation of this product.
Manufacture of the product
Satisfactory batch formulae have been provided for the manufacture of the Dutor
gastro-resistant capsules, together with appropriate accounts of the manufacturing process.
Process validation data provided on the lower scale batches is satisfactory. The Applicant has
committed to provide full process validation data on three consecutive maximum batch sizes
of each strength product after completion.
Product Specifications
The finished product specifications are satisfactory. Satisfactory batch analysis has been
submitted, for each capsule strength. 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 three batches each
of Dutor 20 mg, 30 mg, 40 mg and 60 mg gastro-resistant capsules, packed in the packaging
proposed for marketing. The data from these studies support a shelf life for of 2 years. After
the first opening of the bottle, the shelf life for the 28 capsule HDPE bottle is 30 days and the
shelf life for the 98 and 100 capsule HDPE bottle is 100 days.
There are no special storage conditions for Dutor 20 mg, 30 mg, 40 mg and 60 mg gastro-
resistant capsules.
Suitable post approval stability commitments have been provided.
II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of Marketing Authorisations is recommended.
III Non-clinical aspects No new non-clinical studies have been submitted in support of these applications. The
pharmacodynamic, pharmacokinetic and toxicological properties of duloxetine are
well-known. As duloxetine is a widely used, well-known active substance, the Applicant has
not provided additional studies and further studies are not required. A satisfactory non-clinical
overview, based on a review of the literature, has been supplied.
The non-clinical sections of the SmPCs are in line with the reference product SmPCs.
There are no objections to approval of Dutor gastro-resistant capsules from a non-clinical
point of view.
Environmental Risk Assessment (ERA)
Since Dutor gastro-resistant capsules are intended to be used in place of other similar
products, this will not lead to an increased exposure to the environment. An ERA is, therefore,
not deemed necessary.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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IV Clinical aspects
IV.1 Introduction The applications have been submitted under Article 10(1) according to Directive 2001/83/EC,
as amended. With the exception of bioequivalence data for Dutor 60 mg gastro-resistant
capsules, no new clinical data was submitted with these applications and none are required.
The Applicant sought a biowaver of clinical studies for Dutor 20 mg, 30 mg and 40 mg
gastro-resistant capsules and this was accepted – please see Section and IV.2.
The clinical overview has been written by an appropriately qualified person and provides an
adequate summary of published literature on the clinical pharmacology, efficacy and safety of
duloxetine. This is considered acceptable.
IV.2 Pharmacokinetics In support of these applications, the Marketing Authorisation holder has submitted two
bioequivalence studies:
Study 1 - 60 mg single dose crossover study, under fasting conditions.
Study 2 - 60 mg single dose crossover study under fed conditions.
Study 1
An Open Label, Randomised, 2-Period, 2-Treatment, 2-Sequence, Crossover,
Single-Dose Bioequivalence Study of Dutor 60 mg gastro-resistant capsules (Test) versus
Cymbalta 60 mg Hard Gastro-Resistant Capsules (Reference) in Healthy Human
Volunteers under Fasting Condition.
After an overnight fast of at least 10 hours the subjects received a single dose of either the test
or reference treatment with 200 ml water at room temperature. Blood samples were taken for
the measurement of pharmacokinetic parameters pre-dose and up to 72 hours post-dose. The
two treatment periods were separated by a 12-day washout period.
The main pharmacokinetic results are presented below:
PK - Pharmacokinetics
LSM – least square mean
CV – Coefficient of variation
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Study 2
An Open Label, Randomised, 2-Period, 2-Treatment, 2-Sequence, Crossover,
Single-Dose Bioequivalence Study of Dutor 60 mg gastro-resistant capsules (Test) versus
Cymbalta 60 mg Hard Gastro-Resistant Capsules (Reference) in Healthy Human
Volunteers under Fed Condition.
After an overnight fast of at least 8 hours, and 30 minutes after starting a high-fat high-calorie
breakfast, the subjects received a single oral dose of the test or reference treatment with
200 ml water at room temperature. Blood samples were taken for the measurement of
pharmacokinetic parameters pre-dose and up to 72 hours post-dose. The two treatment periods
were separated by a 10-day washout period.
The main pharmacokinetic results are presented below:
Pharmacokinetic conclusion For both studies the 90% confidence intervals for the primary variables AUC0-t, AUC0-inf and
Cmax are well within the acceptance range of 80.00-125.00%. Based on the submitted
bioequivalence studies bioequivalence of Dutor 60 mg gastro-resistant capsules to Cymbalta
60 mg hard gastro-resistant capsules may be concluded.
Although the indications and strengths for Yentreve and Cymbalta are different, they belong
to the same global marketing authorisation. Therefore the Applicant’s approach to use
Cymbalta 60 mg for the purpose of demonstrating bioequivalence is acceptable.
Biowaiver
The Applicant has justified conducting the bioequivalence study with the highest strength, in
accordance with the CPMP “Guideline on the investigation of bioequivalence”
(CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) for products with linear pharmacokinetics.
A biowaiver for Dutor 20 mg, 30 mg and 40 mg gastro-resistant capsules has been requested
based on the following:
1. The pharmaceutical products Dutor 20 mg, 30 mg, 40 mg and 60 mg gastro-resistant
capsules are manufactured by the same manufacturing process.
2. The qualitative composition of the different strengths (Dutor 20 mg, 30 mg, 40 mg and
60 mg gastro-resistant capsules) is the same.
3. The composition of the strengths is quantitatively proportional for Dutor 20 mg, 30
mg, 40 mg and 60 mg gastro-resistant capsules i.e. the ratio between the amount of
each excipient to the amount of active substance(s) is the same for 20 mg, 30 mg,
40 mg and 60 mg strengths.
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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4. Appropriate in vitro dissolution data confirms the adequacy of waiving additional in
vivo bioequivalence testing.
Based on the known pharmacokinetics characteristics of duloxetine, the highest strength of
the product is the appropriate choice for the biostudies. The bioequivalence package of two
single dose crossover studies under fasting and fed conditions on the highest 60 mg strength is
in compliance with guidelines (CPMP/EWP/QWP/1401/98 Rev. 1/Corr** and EMA/CPMP/EWP/280/96 Corr1).
The justification for biowaiver for the 20 mg, 30 mg and 40 mg strengths of the product can
be accepted as the Applicant’s 20 mg, 30 mg, 40 mg and 60 mg strength gastro-resistant
capsules meet the biowaiver criteria specified in the Guideline on the Investigation of
Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**).
IV.3 Pharmacodynamics No new pharmacodynamic data are required and none have been submitted. The Applicant’s
review of the literature in the clinical overview is acceptable.
IV.4 Clinical efficacy No new clinical efficacy data are required and none have been submitted. The Applicant’s
review of the literature in the clinical overview is acceptable.
IV.5 Clinical safety With the exception of the bioequivalence studies, no new data have been provided and none
are required for these applications.
IV.6 Risk Management Plan (RMP) The Applicant has submitted an 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 Dutor gastro-resistant
capsules.
A summary of safety concerns and risk minimisation measures, as approved in the RMP, are
listed below:
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Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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Summary table of risk minimisation measures
The grant of Marketing Authorisations is recommended.
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V User consultation The 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. The language used for the
purpose of user testing the PIL 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 these products is acceptable, and no new non-clinical or clinical safety
concerns have been identified. The test product, Dutor 60 mg gastro-resistant capsules, can be
considered bioequivalent with the reference product, Cymbalta 60 mg Hard Gastro-Resistant
capsules. A justification for a biowaver for Dutor 20 mg. 30 mg and 40 mg gastro-resistant
capsules has been accepted.
The benefit/risk assessment is, therefore, considered to be positive.
The Summaries of Product Characteristics (SmPCs), package leaflets and labelling are
satisfactory, in line with current guidelines and consistent with the reference product. In
accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs and
package leaflets for these products are available on the Medicines and Healthcare products
Regulatory Agency website.
The currently approved labels are listed below:
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
blister packs
1. NAME OF THE MEDICINAL PRODUCT
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Duloxetine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
Dr Ebeling & Assoc GmbH
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot:
5. OTHER
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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PARTICULARS TO APPEAR ON THE INNER PACKAGING (HDPE BOTTLES)
1. NAME OF THE MEDICINAL PRODUCT
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Duloxetine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each gastro-resistant capsule, hard contains 20 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 30 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 40 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 60 mg duloxetine (as hydrochloride).
3. LIST OF EXCIPIENTS
Contains sucrose. See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
Gastro-resistant capsule, hard
Dutor 20 mg gastro-resistant capsules, hard
28 capsules
98 capsules
100 capsules
Dutor 30 mg gastro-resistant capsules, hard
28 capsules
98 capsules
100 capsules
Dutor 40 mg gastro-resistant capsules, hard
28 capsules
98 capsules
100 capsules
Dutor 60 mg gastro-resistant capsules, hard
28 capsules
98 capsules
100 capsules
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
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5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE
STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Shelf life after first opening of the bottle:
28’s container: 30 days
98’s and 100’s container: 100 days
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH
MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Dr Ebeling & Assoc GmbH
Isestrasse 5
Hamburg
D-20144
Germany
12. MARKETING AUTHORISATION NUMBER(S)
PL 27755/0002
PL 27755/0003
PL 27755/0004
PL 27755/0005
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
21
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
POM
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER WRAPPER LABEL
ON MULTIPACKS (2 X 98 CAPSULES, 40/60 MG) WRAPPED IN FOIL
1. NAME OF THE MEDICINAL PRODUCT
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Duloxetine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each gastro-resistant capsule, hard contains 40 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 60 mg duloxetine (as hydrochloride).
3. LIST OF EXCIPIENTS
Contains sucrose. See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
Multipack comprising 2 packs, each containing 98 capsules
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE
STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Shelf life after first opening of the bottle:
100 days
9. SPECIAL STORAGE CONDITIONS
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
23
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH
MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Dr Ebeling & Assoc GmbH
Isestrasse 5
Hamburg
D-20144
Germany
12. MARKETING AUTHORISATION NUMBER(S)
PL 27755/0002
PL 27755/0003
PL 27755/0004
PL 27755/0005
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
POM
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING (CARTON FOR BLISTER
AND BOTTLES)
1. NAME OF THE MEDICINAL PRODUCT
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Duloxetine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each gastro-resistant capsule, hard contains 20 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 30 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 40 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 60 mg duloxetine (as hydrochloride).
3. LIST OF EXCIPIENTS
Contains sucrose. See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
Gastro-resistant capsule, hard
<OPA/Al/PVC//Al blister>
<Dutor> 20 mg
7 capsules
28 capsules
56 capsules
98 capsules
<Dutor> 30 mg
7 capsules
28 capsules
56 capsules
98 capsules
<Dutor> 40 mg
7 capsules
28 capsules
56 capsules
98 capsules
140 capsules
196 (2 x 98) capsules
<Dutor> 60 mg
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
25
7 capsules
28 capsules
56 capsules
84 capsules
98 capsules
140 capsules
196 (2x98) capsules
<HDPE-bottles>
<Product name> 20, 30, 40, 60 mg
28 capsules
98 capsules
100 capsules
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE
STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
only bottles:
Shelf life after first opening of the bottle:
28’s container: 30 days
98’s and 100’s container: 100 days
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH
MEDICINAL PRODUCTS, IF APPROPRIATE
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
26
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Dr Ebeling & Assoc GmbH
Isestrasse 5
Hamburg
D-20144
Germany
12. MARKETING AUTHORISATION NUMBER(S)
PL 27755/0002
PL 27755/0003
PL 27755/0004
PL 27755/0005
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
POM
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Dutor 20 mg gastro-resistant capsules, hard
Dutor 30 mg gastro-resistant capsules, hard
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON FOR 98
CAPSULES (40/60 MG) AS INTERMEDIATE PACK / COMPONENT OF A MULTIPACK
1. NAME OF THE MEDICINAL PRODUCT
Dutor 40 mg gastro-resistant capsules, hard
Dutor 60 mg gastro-resistant capsules, hard
Duloxetine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each gastro-resistant capsule, hard contains 40 mg duloxetine (as hydrochloride).
Each gastro-resistant capsule, hard contains 60 mg duloxetine (as hydrochloride).
3. LIST OF EXCIPIENTS
Contains sucrose. See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
Gastro-resistant capsule, hard
98 capsules
Component of a multipack comprising 2 packs, each containing 98 capsules.
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE
STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Shelf life after first opening of the bottle:
100 days
9. SPECIAL STORAGE CONDITIONS
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
28
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH
MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Dr Ebeling & Assoc GmbH
Isestrasse 5
Hamburg
D-20144
Germany
12. MARKETING AUTHORISATION NUMBER(S)
PL 27755/0004
PL 27755/0005
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
POM
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Dutor 40 mg gastro-resistant capsules, hard Dutor 60 mg gastro-resistant capsules, hard
Dutor 20 mg, 30 mg, 40 mg, and 60 mg gastro-resistant capsules, hard UK/H/5865/001-004/DC
29
Annex - 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
(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)