Domperidone 1 mg/ml Oral Suspension

Public Assessment Report
Decentralised Procedure
Domperidone 1mg/ml Oral Suspension
Procedure No: UK/H/5247/001/DC
UK Licence No: PL 29831/0522
Wockhardt UK Ltd
Domper idone 1 mg/ml Or al Suspension
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Lay Summary
Domperidone 1 mg/ml Oral Suspension
(domperidone)
This is a summary of the public assessment report (PAR) for Domperidone 1 mg/ml Oral
Suspension (PL 29831/0522; UK/H/5247/001/DC). It explains how Domperidone 1 mg/ml
Oral Suspension was assessed and its authorisation recommended, as well as its conditions of
use. It is not intended to provide practical advice on how to use Domperidone 1 mg/ml Oral
Suspension.
For practical information about using Domperidone 1 mg/ml Oral Suspension, patients
should read the Patient Information Leaflet (PIL) or contact their doctor or pharmacist.
What is Domperidone 1 mg/ml Oral Suspension and what is it used for?
Domperidone 1 mg/ml Oral Suspension is a ‘generic medicine’. This means that it is similar
to a ‘reference medicine’, already authorised in the European Union (EU) called Motilium
1 mg/ml suspension.
Domperidone 1 mg/ml Oral Suspension is used in adults and in children to treat nausea
(feeling sick) and vomiting (being sick).
How does Domperidone 1 mg/ml Oral Suspension work?
Domperidone 1 mg/ml Oral Suspension contains the active substance domperidone.
Domperidone belongs to a group of medicines called ‘dopamine antagonists’. It is not clear
exactly how domperidone works to treat nausea and vomiting but its effect may be due to a
combination of affecting the motility within the gut and blocking signals to a particular part
of the brain that regulates the vomiting reflex.
How is Domperidone 1 mg/ml Oral Suspension used?
Domperidone 1 mg/ml Oral Suspension should be taken by mouth, using the oral syringe
provided to measure the dose. This medicine should be taken 15 to 30 minutes before a meal
and, if needed, before going to bed.
Please read Section 3 of the PIL for detailed information on dosing recommendations, the
route of administration, and the duration of treatment.
In adults and teenagers (12 years of age and older, with a body weight of 35 kg or more) the
usual dose is 10 mg taken up to three times a day. In children and adolescents (weighing less
than 35 kg) the prescribing doctor will work out the dose, which will depend on the weight of
the child.
The medicine can only be obtained with a prescription.
What benefits of Domperidone 1 mg/ml Oral Suspension have been shown in studies?
Because Domperidone 1 mg/ml Oral Suspension is a generic medicine, studies in patients
have been limited to tests to determine that it is bioequivalent to the reference medicine,
Motilium 1 mg/ml suspension. Two medicines are bioequivalent when they produce the same
levels of the active substance in the body.
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What are the possible side effects of Domperidone 1 mg/ml Oral Suspension?
Because Domperidone 1 mg/ml Oral Suspension is a generic medicine and is bioequivalent
to the reference medicine, its benefits and possible side effects are taken as being the same as
the reference medicine.
For information about side effects that may occur with using Domperidone 1 mg/ml Oral
Suspension, please refer to the PIL or the Summary of Product Characteristics (SmPC)
available on the Medicines and Healthcare products Regulatory Agency (MHRA) website.
Why is Domperidone 1 mg/ml Oral Suspension approved?
It was concluded that, in accordance with EU requirements, Domperidone 1 mg/ml Oral
Suspension has been shown to have comparable quality and to be bioequivalent to Motilium
1 mg/ml suspension. It was, therefore, decided that, as for Motilium 1 mg/ml suspension, the
benefits are greater than its risk and recommended that it can be approved for use.
What measures are being taken to ensure the safe and effective use of Domperidone 1
mg/ml Oral Suspension?
A Risk Management Plan (RMP) has been developed to ensure that Domperidone 1 mg/ml
Oral Suspension is used as safely as possible. Based on this plan, safety information has been
included in the SmPC and the PIL for this product, 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 and healthcare professionals will be monitored and reviewed continuously as well.
Other information about Domperidone 1 mg/ml Oral Suspension
Ireland and the UK agreed to grant a marketing authorisation for Domperidone 1 mg/ml Oral
Suspension on 05 November 2014. The marketing authorisation in the UK was granted on 03
December 2014.
The full PAR for Domperidone 1 mg/ml Oral Suspension follows this summary.
For more information about treatment with Domperidone 1 mg/ml Oral Suspension, read the
PIL or contact your doctor or pharmacist.
This summary was last updated in February 2015.
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TABLE OF CONTENTS
I
II
III
IV
V
VI
Introduction
Quality aspects
Non-clinical aspects
Clinical aspects
User consultation
Overall conclusion, benefit/risk assessment
and recommendation
Page 5
Page 7
Page 8
Page 9
Page 13
Page 13
Table of content of the PAR update for
MRP and DCP
Page 17
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I
UK/H/5247/001/DC
Introduction
Based on the review of the data on quality, safety and efficacy, the member states have
granted a marketing authorisation (MA) for the medicinal product Domperidone 1 mg/ml
Oral Suspension. The application was submitted using the Decentralised Procedure (DCP),
with the UK as Reference Member State (RMS) and Ireland as a Concerned Member State
(CMS).
Domperidone 1 mg/ml Oral Suspension is a prescription-only medicine (POM), indicated in
adults and children for the relief of the symptoms of nausea and vomiting.
This application was made under Article 10(1) of Directive 2001/83/EC, as amended,
claiming to be a generic medicinal product. The reference medicinal product, which has been
authorised in accordance with Community provisions in force for not less than 10 years in the
European Economic Area, is Motilium 1 mg/ml Suspension (PL 17780/0299), authorised to
Winthrop Pharmaceuticals UK Limited (Trading as Zentiva). This marketing authorisation
was originally granted to Smithkline Beecham (SWG) Limited in UK on 07 April 1987
(PL 00071/0292) but subsequently underwent a change of ownership to Sanofi Winthrop
Limited on 02 January 1994 (PL 11723/0054), before undergoing a change of ownership to
the current MA holder, Winthrop Pharmaceuticals UK Limited (Trading as Zentiva), on 02
July 2007.
The medicinal product contains the active substance domperidone, which is a dopamine
antagonist with anti-emetic properties. Its anti-emetic effect may be due to a combination of
peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor
trigger zone, which lies outside the blood-brain barrier in the area postrema.
No new non-clinical studies were conducted, which is acceptable given that the application
was based on being a generic medicinal product of an originator product that has been
licensed for over 10 years.
Since Domperidone 1 mg/ml Oral Suspension is intended for generic substitution, this will
not lead to an increased exposure to the environment. An environmental risk assessment is,
therefore, not deemed necessary.
With the exception of bioequivalence data, no new clinical data were provided with this
application. One bioequivalence study was performed, which compared the pharmacokinetics
of the applicant’s Domperidone 1 mg/ml Oral Suspension with those of the reference
product, Motilium 1 mg/ml Oral Suspension, in healthy subjects under fasting conditions.
The applicant has stated that the bioequivalence study was 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 and assembly of
this product.
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.
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A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been
provided with this application and are satisfactory.
The RMS and CMS considered that the application could be approved at the end of
procedure (Day 210) on 05 November 2014. The marketing authorisation in the UK was
granted on 03 December 2014.
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II
Quality aspects
II.1
Introduction
UK/H/5247/001/DC
The application is submitted according to Article 10(1) of Directive 2001/83/EC, as
amended. The applicant has specified Motilium 1 mg/ml Oral Suspension, (PL 17780/0299),
as the reference medicinal product for the purpose of determining the expiry period of data
exclusivity (MA holder: Winthrop Pharmaceuticals UK Limited).
The product is formulated as a white to off-white, opaque homogenous suspension containing
the active substance domperidone at a concentration of 1 mg/ml. The excipients present are
liquid sorbitol (non-crystallising, E420), microcrystalline cellulose (E460), carmellose
sodium, saccharin sodium (E954), methyl parahydroxybenzoate (E218), propyl
parahydroxybenzoate (E216), polysorbate 20 (E432) and purified water.
The oral suspension is presented in a 200 ml conventional amber soda glass (Type III) bottle,
fitted with 28 mm child resistant tamper-evident cap. In addition, the product is supplied with
a 5 ml oral dosing syringe and bottle adaptor, and packed in an outer cardboard carton.
II.2
Drug Substance
Domperidone
rINN:
Chemical Name:
Domperidone
5-Chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1
yl)propyl]piperidin-4-yl]-1,3-dihydro-2Hbenzimidazol-2-one
Structure:
Molecular formula:
Molecular weight:
Appearance:
Solubility:
C22H24ClN5O2
425.9
White or almost white powder.
Practically insoluble in water, soluble in dimethylformamide, slightly
soluble in ethanol (96 per cent) and in methanol.
Domperidone is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, domperidone, are covered
by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate
of Suitability.
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II.3
UK/H/5247/001/DC
Medicinal Product
Pharmaceutical development
The objective was to develop a product that is comparable to the UK reference product
Motilium 1 mg/ml Oral Suspension (PL 17780/0299).
All the excipients used in the manufacture of the proposed formulation comply with their
respective European Pharmacopoeia monographs.
Satisfactory certificates of analysis have been provided for all excipients showing compliance
with their proposed specifications.
None of the excipients used contain material of animal or human origin.
No genetically modified organisms (GMO) have been used in the preparation of these
excipients.
Manufacture of the product
A satisfactory batch formula has been provided for the manufacture of the finished product,
together with an appropriate account of the manufacturing process. A satisfactory
manufacturing process has been validated with production scale batches.
Finished Product Specification
The finished product specification is satisfactory. Test methods have been described that
have been adequately validated, as appropriate. Batch data have been provided from two
batches 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 the
finished product, packed in the packaging proposed for marketing. The data from these
studies support a shelf-life of 18 months unopened and 3 months opened, with special storage
conditions of “Do not store above 25°C” and “Keep the bottle in the outer carton in order to
protect from light”.
Suitable post approval stability commitments have been provided.
II.4 Discussion on chemical, pharmaceutical and biological aspects
The grant of a marketing authorisation is recommended.
III Non-clinical aspects
The pharmacodynamic, pharmacokinetic and toxicological properties of domperidone are
well-established. As domperidone is a widely used, well-known active substance, the
applicant has not provided additional studies and further studies are not required. An
overview based on a literature review is, thus, appropriate.
Suitable justification has been provided for non-submission of an Environmental Risk
Assessment (ERA). As the application is for a generic version of an already authorised
product, it is not expected that environmental exposure will increase following approval of
the marketing authorisation for the proposed product.
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IV Clinical aspects
IV.1 Introduction
No new clinical data have been submitted for this application. The applicant’s clinical
overview on the clinical pharmacology, efficacy and safety of the product has been written
by an appropriately qualified person and is adequate.
IV. 2 Pharmacokinetics
In support of this application, the marketing authorisation holder has submitted the following
bioequivalence study:
An open, randomised, 2-way crossover, bioequivalence study in healthy male and female
subjects to compare the fasted bioavailability of 20 mg domperidone from the test
investigational medicinal product (IMP), Domperidone Oral Suspension (1 mg/mL) with
that from the reference IMP, Motilium® Oral Suspension (1mg/mL), following single
dose administration.
Twenty-two (22) subjects were randomised and completed the study. Volunteers received the
test or reference treatment after an overnight fast. Blood samples were taken for the
measurement of pharmacokinetic parameters pre-dose and up to 48 hours post-dose. The two
treatment periods were separated by a minimum 7-day washout period.
The main pharmacokinetic results are presented below:
Summary of derived pharmacokinetic parameters following 20 mg Domperidone
administered as Domperidone Oral Suspension (Test IMP) and Motilium® Oral
Suspension (Reference IMP)
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Summary of the statistical analysis of bioequivalence following 20 mg domperidone
administered as Domperidone Oral Suspension (Test IMP) and Motilium® Oral
Suspension (Reference IMP)
The 90% confidence intervals were within the acceptance criteria of 80.00%-125.00%.
Based on these results, the proposed product, Domperidone 1 mg/ml Oral Suspension, can be
considered to be bioequivalent with the reference product Motilium 1 mg/ml Oral
Suspension.
IV.3 Pharmacodynamics
No new pharmacodynamic data are required for this application and none have been
submitted. An adequate clinical overview has been provided.
IV.4 Clinical efficacy
No new efficacy data were submitted with this application and none were required. An
adequate clinical overview has been provided.
IV.5 Clinical safety
No new safety data were submitted with this application and none were required. An
adequate clinical overview has been provided.
IV.6 Risk Management Plan (RMP)
The marketing authorisation holder 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 Domperidone 1 mg/ml Oral Suspension.
A summary of safety concerns and planned risk minimisation activities, as approved in the
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RMP, are listed below:
Summary of safety concerns
Important identified risks
•
•
•
Important potential risks
Missing information
•
•
Cardiac events (QTc prolongation, Torsades de Pointes,
serious ventricular arrhythmia and sudden cardiac death)
Hypersensitivity (including anaphylaxis)
Off-label use (e.g. stimulation of lactation in breast
feeding women, gastroesophageal reflux disease, diabetic
and non-diabetic gastroparesis, symptoms of postural
hypotension in patients with Parkinson’s disease)
n/a
Risks during pregnancy and lactation
Risks in patients with hepatic impairment
Summary table of risk management measures
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IV.7 Discussion on the clinical aspects
The grant of a marketing authorisation is recommended for this application.
V
User consultation
A user consultation with target patient groups on the PIL has been performed on the basis of
a bridging report making reference to Amitriptyline Oral Solution, which has been
user-tested (PL 29831/0356 and PL 29831/0439, United Kingdom). The bridging report
submitted by the applicant is acceptable.
VI Overall conclusion, benefit/risk assessment and
recommendation
The quality of the product is acceptable, and no new non-clinical or clinical safety concerns
have been identified. The application includes an adequate review of published non-clinical
and clinical data concerning the efficacy and safety of domperidone. The test product
Domperidone 1 mg/ml Oral Suspension can be considered bioequivalent with the reference
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product Motilium 1 mg/ml Oral Suspension. The benefit/risk assessment is, therefore,
considered to be positive.
The Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) 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 version of the
SmPC and PIL for this product are available on the MHRA website.
The currently approved labels are listed 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
(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)
17