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Public Assessment Report
Decentralised Procedure
Acamprosate 333 mg Gastro-resistant Tablets
(acamprosate calcium)
Procedure No: UK/H/5445/001/DC
UK Licence No: PL 17871/0206
Jenson Pharmaceutical Services Ltd
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
2
LAY SUMMARY Acamprosate 333 mg Gastro-resistant Tablets
(acamprosate calcium)
This is a summary of the public assessment report (PAR) for Acamprosate 333 mg Gastro-resistant
Tablets (PL 17871/0206). It explains how Acamprosate 333 mg Gastro-resistant Tablets 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 Acamprosate 333 mg Gastro-resistant Tablets.
For practical information about using Acamprosate 333 mg Gastro-resistant Tablets, patients should
read the package leaflet or contact their doctor or pharmacist.
What are Acamprosate 333 mg Gastro-resistant Tablets and what are they used for?
Acamprosate 333 mg Gastro-resistant Tablets is a “generic medicine”. This means that Acamprosate
333 mg Gastro-resistant Tablets are similar to a ‘reference medicine’ already authorised in the European
Union (EU) called Campral EC (Merck Santé s.a.s.; PL 13466/0001).
Acamprosate 333 mg Gastro-resistant Tablets are used for the treatment of alcohol dependence.
Acamprosate in combination with counselling will help a patient to maintain abstinence in alcohol-
dependent patients.
How are Acamprosate 333 mg Gastro-resistant Tablets used?
Acamprosate 333 mg Gastro-resistant Tablets are taken by mouth. The tablet should be swallowed
whole. Patients should avoid chewing or crushing the tablet as this may damage the gastro-resistant
coating.
The recommended dose in adults (18-65 years) with body weight of 60 kg or more is 6 tablets a day (2
tablets in the morning, 2 tablets at noon and 2 tablets in the evening with meals). In patients with body
weight less than 60 kg, the recommended dose is 4 tablets a day (2 in the morning, 1 at noon and 1 in the
evening with meals). It is advised that the patient keeps taking this medicinal product for one year.
Acamprosate 333 mg Gastro-resistant Tablets can only be obtained on prescription from a doctor.
For further information on how Acamprosate 333 mg Gastro-resistant Tablets are used, please see the
Summary of Product Characteristics and package leaflet available on the MHRA website.
How do Acamprosate 333 mg Gastro-resistant Tablets work?
Acamprosate 333 mg Gastro-resistant Tablets is a medicine which acts on the central nervous system
(the brain and the spinal cord). This product works by acting on the chemical changes that have taken
place in the brain during the years that the patient has been drinking alcohol. It does not prevent the
harmful effects of continuous alcohol abuse.
How have Acamprosate 333 mg Gastro-resistant Tablets been studied?
Because Acamprosate 333 mg Gastro-resistant Tablets is a generic medicine, studies in patients have
been limited to tests to determine that it is bioequivalent to the reference medicine, Campral EC (Merck
Santé s.a.s.; PL 13466/0001). Two medicines are bioequivalent when they produce the same levels of
the active substance in the body.
What are the benefits and risks of Acamprosate 333 mg Gastro-resistant Tablets?
As Acamprosate 333 mg Gastro-resistant Tablets is a generic medicine that is bioequivalent to Campral
EC, its benefits and risks are taken as being the same as those for Campral EC (Merck Santé s.a.s.; PL
13466/0001).
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
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Why are Acamprosate 333 mg Gastro-resistant Tablets approved?
It was concluded that, in accordance with EU requirements, Acamprosate 333 mg Gastro-resistant
Tablets have been shown to have comparable quality and to be bioequivalent to Campral EC (Merck
Santé s.a.s.; PL 13466/0001). Therefore, the view was that, as for Campral EC (Merck Santé s.a.s.; PL
13466/0001) the benefit outweighs the identified risk.
What measures are being taken to ensure the safe and effective use of Acamprosate 333 mg
Gastro-resistant Tablets?
A risk management plan has been developed to ensure that Acamprosate 333 mg Gastro-resistant
Tablets are used as safely as possible. Based on this plan, safety information has been included in the
Summary of Product Characteristics and the package leaflet for Acamprosate 333 mg Gastro-resistant
Tablets, including the appropriate precautions to be followed by healthcare professionals and patients.
Other information about Acamprosate 333 mg Gastro-resistant Tablets
Slovak Republic and the UK agreed to grant a Marketing Authorisation for Acamprosate 333 mg
Gastro-resistant Tablets on 12th
September 2014. A Marketing Authorisation was granted in the UK on
14th
October 2014.
The full PAR for Acamprosate 333 mg Gastro-resistant Tablets follows this summary. For more
information about treatment with Acamprosate 333 mg Gastro-resistant Tablets, read the package leaflet
or contact your doctor or pharmacist.
This summary was last updated in December 2014.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
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Information about initial procedure
Product Name
Acamprosate 333 mg Gastro-resistant Tablets
Type of Application
Generic, Article 10(1)
Active Substances
Acamprosate calcium
Form
Gastro-resistant Tablets
Strength
333 mg
MA Holder
Jenson Pharmaceutical Services Ltd
Carradine House, 237 Regent’s Park Road,
London, N3 3LF
United Kingdom
Reference Member State (RMS) UK
Concerned Member States (CMSs)
Slovak Republic
Procedure Numbers
UK/H/5445/001/DC
Timetable
Day 208 – 12th September 2014
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
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TABLE OF CONTENTS
I Introduction Page 6
II Quality aspects Page 7
III Non-clinical aspects Page 8
IV Clinical aspects Page 8
V User consultation Page 12
VI Overall conclusion, benefit/risk assessment and Page 12
Recommendation
Annex 1 – Table of content of the PAR update for Page 13
MRP and DCP
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
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I INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and
Concerned Member State (CMS) considered that the application for Acamprosate 333 mg Gastro-
resistant Tablets (PL 17871/0206; UK/H/5445/001/DC), indicated as therapy to maintain abstinence in
alcohol-dependent patients combined with counselling is approvable.
The application was submitted using the Decentralised Procedure (DCP), with the UK as the RMS and
Slovak Republic as CMS. The application was submitted under Article 10(1) of Directive 2001/83/EC,
as amended. The originator product is Aotal 333 mg, comprimé enrobé gastro-résistant, authorised to
Merck Santé (Exploitant: Merck Serono SAS) on 24th
July 1987. The applicant has cross referred to
Campral EC, which was first licensed to Merck Santé s.a.s. in the UK (PL 13466/0001) on 18th
December 1995.
Acamprosate (calcium acetylhomotaurinate) has a chemical structure similar to that of amino acid
neuromediators, such as taurine or gamma-amino-butyric acid (GABA), including an acetylation to
permit passage across the blood brain barrier.
The applicant has submitted two bioequivalence studies comparing the test product, Acamprosate
calcium 333 mg Gastro-resistant Tablets (Mylan Laboratories Limited), with the reference product Aotal
(acamprosate calcium) 333 mg gastro-resistant Tablets (Merck Serono s.a.s) in healthy, adult, human
subjects under fasting and fed conditions. Bioequivalence studies were carried out in accordance with
Good Clinical Practice (GCP).
With the exception of the bioequivalence studies, no new non-clinical or 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.
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.
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 or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’
issued by the inspection services of the competent authorities (or those countries with which the EEA
has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards
of GMP are in place at those non-Community sites.
All involved Member States agreed to grant a Marketing Authorisation for the above product at the end
of the procedure (Day 208 – 12th
September 2014). After a subsequent national phase, the UK granted a
Marketing Authorisation (PL 17871/0206) for this product on 14th
October 2014.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
7
II QUALITY ASPECTS
II.1 Introduction
This product is a gastro-resistant tablet and contains 333.0 mg of acamprosate calcium, as the active
ingredient. The excipients are glycerol dibehenate, cellulose, microcrystalline, hypromellose, silica,
colloidal anhydrous, magnesium stearate making up the tablet core, and hypromellose (tablet seal
coating), methacrylic acid-ethyl acrylate copolymer, talc and propylene glycol (tablet gastro-resistant
coating) and the printing ink (shellac, black iron oxide (E172), propylene glycol (E1520) and
ammonium hydroxide (E527)).
All excipients, except the colouring agent Iron oxide, comply with their respective European
Pharmacopoeia monographs. The printing ink complies with an in-house specification.
None of the excipients are sourced from animal or human origin. Confirmation has been given that the
magnesium stearate used in the tablets is of vegetable origin.
The finished product is packaged in polyvinylchloride (PVC) blister packs containing 84 and 168
tablets. 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 food.
II.2 Drug Substance
INN: Acamprosate calcium
Chemical name(s): 3-(Acetylamino)-1-propanesulfonic acid calcium salt (2:1)
Structure:
Molecular formula: C10H20CaN2O8S2
Molecular weight: 400.5 g/mol
Appearance: white odourless crystalline powder.
Solubility: Freely soluble in water and practically insoluble in ethanol, dichloromethane and
xylene.
Acamprosate calcium is the subject of an active substance master file (ASMF).
Synthesis of the drug substance from the designated starting materials has been adequately described
and appropriate in-process controls and intermediate specifications are applied. Satisfactory
specification tests are in place for all starting materials and reagents, and these are supported by relevant
Certificates of Analysis.
An appropriate specification is provided for the drug substance. Analytical methods have been
appropriately validated and are satisfactory for ensuring compliance with the relevant specifications.
Certificates of Analysis for all working standards have been provided.
Batch analyses data are provided that comply with the proposed specification.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging used to
store the drug substance. Confirmation has been provided that the primary packaging complies with
current guidelines concerning materials in contact with food.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
8
Appropriate stability data have been generated, supporting a suitable retest period when the drug
substance is stored in the packaging proposed.
II.3 Medicinal Product
Pharmaceutical Development
The objective of the development programme was to develop a generic equivalent of Aotal 333
mg/Campral EC tablets (Merck Santé s.a.s).
Comparative dissolution and impurity profiles have been presented for the proposed and reference
products.
Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the product, along with an
appropriate account of the manufacturing process. The manufacturing process has been validated using
the minimum commercial scale batch sizes and has shown satisfactory results. The applicant has
committed to perform further process validation on full scale commercial batches.
Finished Product Specification
The finished product specification is satisfactory. The test methods have been described and adequately
validated. Batch data have been provided that comply with the release specifications. Certificates of
Analysis have been provided for any working standards used.
Stability of the product
Finished product stability studies have been conducted in accordance with current guidelines and in the
packaging proposed for marketing.
Based on the results, a shelf-life of 3 years with no special storage conditions has been set. This is
satisfactory.
Bioequivalence/bioavailability
Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the
bioequivalence studies.
II.3 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 acamprosate calcium are well
known.
No new non-clinical data have been supplied with this application and none are required for applications
of this type. The non-clinical overview has been written by an appropriately qualified person and is a
suitable summary of the non-clinical aspects of the dossier.
Since the proposed product 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.
There are no objections to the approval of this product from a non-clinical point of view.
IV CLINICAL ASPECTS
IV.1 Introduction
In support of this application, the Marketing Authorisation Holder has submitted two bioequivalence
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
9
studies under fasting and fed conditions.
With the exception of the bioavailability studies, no new clinical data have been submitted and none are
required for an application of this type. The applicant’s clinical overview has been written by an
appropriately qualified person and is considered acceptable.
IV.2 Pharmacokinetics
Study 673/10
This is an open label, balanced, randomised, two-treatment, two-period, two-sequence, single dose,
crossover, bioequivalence study comparing the pharmacokinetics of the test product Acamprosate
333 mg Gastro-resistant Tablets (Mylan Laboratories Limited) with the reference product Aotal
333 mg comprimé enrobé gastro-résistant (Merck Serono s.a.s, France) in 55 healthy, adult,
human subjects under fasting conditions.
Blood samples were collected at pre-dose and at 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 9.00,
10.00, 11.00, 12.00, 13.00, 14.00, 15.00, 16.00, 20.00, 22.00, 24.00, 28.00, 32.00, 36.00 and 48.00 hours
post-dose. The washout period was 11 days.
Pharmacokinetic results in study 673/10 Fasted
The 90% confidence intervals for AUCt, AUC∞ and Cmax were within the pre-defined acceptance criteria
specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/
Corr**). Bioequivalence has been shown for the test formulation (Acamprosate 333 mg Gastro-resistant
tablets) and the reference formulation (Aotal 333 mg comprimé enrobé gastro-résistant) under fasting
conditions.
Study 674/10
This is an open label, balanced, randomised, two-treatment, two-period, two-sequence, single dose,
crossover, bioequivalence study comparing the pharmacokinetics of the test product Acamprosate
333 mg Gastro-resistant Tablets (Mylan Laboratories Limited) with the reference product Aotal
333 mg comprimé enrobé gastro-résistant (Merck Serono s.a.s, France) in 56 healthy, adult,
human subjects under fed conditions.
Blood samples were collected at pre-dose and at 2.00, 4.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00,
13.00, 14.00, 15.00, 16.00, 18.00, 20.00, 22.00, 24.00, 26.00, 28.00, 30.00, 32.00, 36.00, 40.00, 44.00
and 48.00 hours post-dose. The washout period was 13 days.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
10
Pharmacokinetic results in study 674/10 Fed
The 90% confidence intervals for AUCt, AUC∞ and Cmax were within the pre-defined acceptance criteria
specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/
Corr**). Bioequivalence has been shown for the test formulation (Acamprosate 333 mg Gastro-resistant
tablets) and the reference formulation (Aotal 333 mg comprimé enrobé gastro-résistant) under fed
conditions.
Based on the submitted bioequivalence studies the applicant’s Acamprosate 333mg Gastro-resistant
Tablets is considered bioequivalent with Aotal 333 mg comprimé enrobé gastro-résistant.
IV.3 Pharmacodynamics
No new data have been submitted and none are required for applications of this type.
IV.4 Clinical efficacy
No new data on efficacy have been submitted and none are required for this type of application.
IV.5 Clinical safety
No new safety data were submitted and none are required.
IV.6 Risk Management Plan (RMP)
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Acamprosate 333 mg Gastro-resistant
Tablets.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
11
Summary Table of Risk Minimisation Measures
Summary table of Safety concerns
IV.7 Discussion on the clinical aspects
The grant of a Marketing Authorisation is recommended.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
12
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, as amended. 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
Quality
The important quality characteristics of Acamprosate 333 mg Gastro-resistant Tablets 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 applications of this type.
CLINICAL
Bioequivalence has been demonstrated between the applicant’s Acamprosate 333 mg Gastro-resistant
Tablets and the reference product, Aotal 333 mg comprimé enrobé gastro-résistant under fasting and fed
conditions.
No new or unexpected safety concerns arose from this application.
The SmPC, PIL and labelling 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 concerns have been
identified. Bioequivalence has been demonstrated between the applicant’s product and the reference
product. Extensive clinical experience with acamprosate calcium is considered to have demonstrated the
therapeutic value of the compound. The benefit-risk assessment is, therefore, considered to be positive.
PAR Acamprosate 333 mg Gastro-resistant Tablets UK/H/5445/001/DC
13
Annex 1 – 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)