Public Assessment Report - GOV.UK · PAR Acamprosate 333 mg Gastro-resistant Tablets...

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

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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).


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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.


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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


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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


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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.


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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.


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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


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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.


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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.


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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.


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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, 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.


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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)

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