Procedure No: UK/H/3244/003/DC UK Licence No: PL 25298 ... · Co-amoxiclav 875mg/125mg film-coated Tablets UK/H/3244/0003/DC 3 than 40 kg. The tablets are not suitable for children

Public Assessment Report

Decentralised Procedure

Co-amoxiclav 875mg/125mg film-coated Tablets

Amoxicillin trihydrate and potassium clavulanate, diluted

Procedure No: UK/H/3244/003/DC

UK Licence No: PL 25298/0009

Brown & Burk UK Limited

Co-amoxiclav 875mg/125mg film-coated Tablets UK/H/3244/0003/DC

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LAY SUMMARY Co-amoxiclav 875mg/125mg film-coated Tablets

(amoxicillin trihydrate, potassium clavulanate)

This is a summary of the Public Assessment Report (PAR) for Co-amoxiclav 875mg/125mg film-coated

Tablets (UK/H/3244/003/DC; PL 25298/0009. It explains how Co-amoxiclav 875mg/125mg film-coated

Tablets was assessed and its authorisation recommended, as well as its condition of use. It is not

intended to provide practical advice on how to use Co-amoxiclav 875mg/125mg film-coated Tablets.

The product may be referred to as Co-amoxiclav Tablets throughout the remainder of this lay summary.

For practical information about using Co-amoxiclav Tablets, patients should read the package leaflet or

contact their doctor or pharmacist.

What are Co-amoxiclav Tablets and what are they used for?

Co-amoxiclav Tablets are generic medicines. This means that Co-amoxiclav Tablets are similar to

‘reference medicines’ already authorised in the European Union (EU) called Augmentin 1g Tablets

(Beecham Group Ltd, UK).

Co-amoxiclav Tablets are used in adults and children to treat the following infections:

• middle ear and sinus infections

• respiratory tract infections

• urinary tract infections

• skin and soft tissue infections including dental infections

• bone and joint infections

How do Co-amoxiclav Tablets work?

Co-amoxiclav Tablets belongs to a group of medicines known as antibiotics. Co-amoxiclav Tablets

works by killing bacteria that cause infections. Co-amoxiclav Tablets contains two active ingredients,

amoxicillin (as amoxicillin trihydrate) and clavulanic acid (as potassium clavulanate, diluted).

Amoxicillin belongs to a group of medicines called “penicillins” that can sometimes be stopped from

working (made inactive). The other active component (clavulanic acid) stops this from happening.

How are Co-amoxiclav Tablets used?

The pharmaceutical form of this medicine is a tablet and the route of administration is oral (by mouth).

The patient should always take this medicine exactly as their doctor or pharmacist has told them. The

patient should check with their doctor or pharmacist if they are not sure.

Co-amoxiclav Tablets should be taken with a meal. The tablets should be swallowed whole with a glass

of water. The doses should be evenly spaced out during the day, at least 4 hours apart. The patent should

not take 2 doses in 1 hour.

This medicine should not be taken for more than 2 weeks. If the patient still feels unwell, they should

go back to see the doctor.

Adults and children weighing 40 kg and over

Usual dose - 1 tablet two times a day

Higher dose - 1 tablet three times a day

Children weighing less than 40 kg

Children aged 6 years or less should preferably be treated with Co-Amoxiclav oral suspension or

sachets.

Ask the doctor or pharmacist for advice when giving Co-amoxiclav tablets to children weighing less


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than 40 kg. The tablets are not suitable for children

weighing less than 25 kg.

Patients with kidney and liver problems

• If the patient has kidney problems the dose might be changed. A different strength or a different

medicine may be chosen by the doctor.

• If the patient has liver problems, they may have more frequent blood tests to check how the liver is

working.

For further information on how Co-amoxiclav Tablets are used, refer to the package leaflet and Summary

of Product Characteristics available on the Medicines and Healthcare products Regulatory Agency

(MHRA) website.

This medicine can only be obtained with a prescription.

What benefits of Co-amoxiclav Tablets have been shown in studies?

Because Co-amoxiclav Tablets are generic medicines, studies in patients have been limited to tests to

determine that they are bioequivalent to the reference product, Augmentin 1g Tablets (Beecham Group

Ltd, UK). Two medicines are bioequivalent when they produce the same levels of the active substance in

the body.

What are the possible side effects of Co-amoxiclav Tablets?

Because Co-amoxiclav Tablets are generic medicines and are bioequivalent to the reference medicine

Augmentin 1g Tablets (Beecham Group Ltd, UK).their benefits and possible side effects are taken as

being the same as those for the reference products.

For the full list of all side effects reported with Co-amoxiclav Tablets, see section 4 of the package leaflet

available on the MHRA website.

Why were Co-amoxiclav Tablets approved?

It was concluded that, in accordance with EU requirements, Co-amoxiclav Tablets have been shown to

have comparable quality and to be bioequivalent to the reference medicine; Augmentin 1g Tablets

(Beecham Group Ltd, UK). Therefore, the MHRA decided that, as for Augmentin 1g Tablets (Beecham

Group Ltd, UK); the benefits are greater than the risks and recommended that they can be approved for

use.

What measures are being taken to ensure the safe and effective use of Co-amoxiclav Tablets?

Safety information has been included in the Summaries of Product Characteristics (SmPCs) and the

package leaflet for Co-amoxiclav Tablets including the appropriate precautions to be followed by

healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore new safety signals reported by

patients/healthcare professionals will be monitored/reviewed continuously. Other information about Co-amoxiclav Tablets

The UK, Ireland and Sweden granted Marketing Authorisations to Co-amoxiclav Tablets on 22 May

2013. Subsequently followed by a national phase, Marketing Authorisations were granted in the UK on

19 June 2019.

The full PAR for Co-amoxiclav Tablets follows this summary.

This summary was last updated in January 2019.


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TABLE OF CONTENTS

I INTRODUCTION 5 II QUALITY ASPECTS 6 III NON-CLINICAL ASPECTS 8 IV CLINICAL ASPECTS 8 V User consultation 10 VI Overall conclusion, benefit/risk assessment and recommendation 10 Table of content of the PAR update for MRP and DCP 15


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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the member states considered that the

application for Co-amoxiclav 875mg/125mg film-coated Tablets (PL 25298/0009;

UK/H/3244/0003/DC) could be approved. The product is a prescription-only medicine (POM).

Co-Amoxiclav 875mg/125mg film-coated Tablets are indicated for the treatment of the following

infections in adults and children:

• acute bacterial sinusitis (adequately diagnosed)

• acute otitis media

• acute exacerbations of chronic bronchitis (adequately diagnosed)

• community acquired pneumonia

• cystitis

• pyelonephritis

• skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading

cellulitis.

• bone and joint infections, in particular osteomyelitis

The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference

Member State (RMS), and Ireland and Sweden as Concerned Member States (CMS). The application

was submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic

medicinal product of Augmentin 1g Tablets (Beecham Group Ltd, UK) which was first authorised in the

UK on 03 April 1981.

Co-Amoxiclav 875mg/125mg film-coated Tablets contain the active ingredients amoxicillin (as

amoxicillin trihydrate) and clavulanic acid (as potassium clavulanate, diluted).

Amoxicillin is a semi-synthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes

(often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial

peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of

peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and

death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and

therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these

enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase

enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically

useful antibacterial effect.

One single-dose, fasting, bioequivalence study was submitted to support the application, comparing the

applicant’s test product Co-amoxiclav Tablets BP 1000mg and the reference product Augmentin 875 mg

+ 125mg, tabletki powlekane Amoxicillinum +Acidum clavulanicum (Glaxo Smithkline, UK). The

bioequivalence study was carried out in accordance with Good Clinical Practice (GCP).

With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted,

which is acceptable given that the application was based on being a generic medicinal product of an

originator product that has been in clinical use for over 10 years.


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The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place 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, 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.

The RMS and CMS considered that the application could be approved at the end of procedure (Day 210)

on 22 May 2013. After a subsequent national phase, a licence was granted in the UK on 19 June 2013.

II QUALITY ASPECTS

II.1. Introduction

The product is packaged aluminium/aluminium blisters. These are packed with the Patient Information

Leaflet into cardboard cartons, in pack sizes of 4, 5, 6, 7, 8, 10, 12, 14, 15, 16, 20, 21, 25, 30, 35, 40, 50,

100 and 500 film-coated tablets.

Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations (Directive

2002/72/EC, as amended) concerning materials in contact with foodstuff.

II.2. Drug substance

ACTIVE SUBSTANCE – AMOXICILLIN TRIHYDRATE

INN: Amoxicillin trihydrate

Ph. Eur: Amoxicillinum trihydricum

Chemical name:

(2S,5R,6R)-6-[[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]-

amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]

heptane-2-carboxylic acid Trihydrate

OR

4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,6-

[[amino(4-hydroxyphenyl)acetyl]amino-3,3-dimethyl-7-

oxo,trihydrate 2S-[2α,[5α,6β (S*)]]

OR

(2S,5R,6R)-6-[(R)-(-)-2-amino-2-(p-hydroxyphenyl)

acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]

heptane-2-carboxylic acid trihydrateStructure:

Molecular formula: C16H19N3O5S·3H2O

Molecular weight: 419.4

Appearance: A white or almost white, crystalline powder.


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Solubility Slightly soluble in water, very slightly soluble in ethanol (96%0,

practically insoluble in fatty oils, it dissolves in dilute acids and dilute

solutions of alkali hydroxides.

Amoxicillin trihydrate is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance amoxicillin trihydrate are covered by

a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.

ACTIVE SUBSTANCE – POTASSIUM CLAVULANATE, DILUTED

INN: Potassium clavulanate

PhEur: Potassium clavulanate, diluted

Chemical name: Potassium (2R, 3Z, 5R)-3-2 (hydroethylidene)-7-oxo-4-oxa-1-azabizyclo

[3.2.0] heptane-2-carboxylate

Formula: C8H8KNO5

Molecular weight 237.3

Structure:

Appearance: A white or almost white crystalline powder, hygroscopic.

Solubility Freely soluble in water

Potassium clavulanate, diluted is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance potassium clavulanate, diluted are

covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of

Suitability.

II.3. MEDICINAL PRODUCT

Other Ingredient

Other ingredients consist of the pharmaceutical excipients in the tablet core and coat namely,

microcrystalline cellulose (E460), sodium starch glycolate, Type A, colloidal anhydrous silica (E551),

magnesium stearate (E470b), titanium dioxide (E171), hypromellose (E464), ethyl cellulose, Talc

(E553b) and macrogol. Appropriate justification for the inclusion of each excipient has been provided.

All excipients comply with their respective European Pharmacopoeia monographs. Certificates of

Analysis have been provided for all excipients, showing compliance with the proposed specification.

None of the excipients contain materials of animal or human origin.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious, stable film-coated

tablets containing amoxicillin trihydrate and potassium clavulanate comparable in performance to the

innovator product Augmentin 1g Tablets (GlaxoSmithkline).

A satisfactory account of the pharmaceutical development has been provided.

Comparative in-vitro dissolution profiles have been provided for the proposed and originator products.


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Manufacturing Process

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 with

production-scale batches and has shown satisfactory results.

Control of Finished Product

The finished product specification for the product is acceptable. Test methods have been described and

have been validated adequately. Batch data have been provided and comply with the release

specifications. Certificates of Analysis have been provided for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of

finished product in the packaging proposed for marketing. The data from these studies support a

shelf-life of 3 years, with the storage conditions “Do not store above 25C.”

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the

bioequivalence study. The bioequivalence study is discussed in Section III.3, Clinical Aspects.

II.4 Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of these applications from a pharmaceutical viewpoint.

III. NON-CLINICAL ASPECTS

III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of amoxicillin trihydrate and

potassium clavulanate are well-known, no further studies are required and none have been provided.

The applicant’s non-clinical overview is satisfactory, providing an appropriate review of the products’

pharmacology and toxicology.

A suitable justification has been provided for non-submission of an environmental risk assessment. As

these products are intended for generic substitution with products that are already marketed, no increase

in environmental burden is anticipated.

III.2 Pharmacology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.3 Pharmacokinetics


III.4 Toxicology


III.6 Discussion on the non-clinical aspects

There are no objections to the approval of these applications from a non-clinical viewpoint.

IV. CLINICAL ASPECTS

IV.1. Introduction

The clinical pharmacology of amoxicillin trihydrate and potassium clavulanate are well-known. With

the exception of data from the bioequivalence study detailed below, no new pharmacodynamic or

pharmacokinetic data were provided or required for this application.


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IV.2. Pharmacokinetics

In support of the application, the Marketing Authorisation Holder submitted the following

bioequivalence study:

A randomised, open-label, two-period, two-treatment, two-sequence, single-dose, crossover study

comparing the rate and extent of absorption of the test product Co-amoxiclav Tablets BP 1000mg

(amoxicillin/clavulanic acid 875mg/125 mg; Micro Labs Ltd) and the reference product

Augmentin 875 mg + 125mg, tabletki powlekane Amoxicillinum +Acidum clavulanicum

(GlaxoSmithkline, UK) in healthy male and female subjects under fasting conditions.

Subjects were administered one dose of either the test or the reference product with 240 ml of water,

after at least a 10 hour fast. Blood sampling was performed pre-dose and up to 12 hours post dose in

each treatment period. The washout period between the two treatment arms was 13 days. The main

pharmacokinetic results are presented below:

Pharmacokinetic parameters (geometric means and 90% confidence intervals [CI]) for amoxicillin

*Geometric Mean % Ratio 90% Confidence Interval for

Log-transformed data

Test (A) Reference (B) A/B Lower Limit Upper Limit

AUC0-t 34608.86 34889.08 99.1968 92.9128 105.9059

Cmax 10413.66 10736.64 96.9919 91.3202 103.0158

AUC0-t area under the plasma concentration-time curve from time zero to t hours

Cmax maximum plasma concentration

*Geometric mean has been taken as the antilog (exponential) of the least square mean of the log transformed data.

Pharmacokinetic parameters (geometric means and 90% confidence intervals [CI]) for clavulanic acid

*Geometric Mean % Ratio 90% Confidence Interval for

Log-transformed data

Test (A) Reference (B) A/B Lower Limit Upper Limit

AUC0-t 8132.05 7822.01 103.9637 95.3089 113.4045

Cmax 3362.04 3207.38 104.8221 94.3561 116.0158

AUC0-t area under the plasma concentration-time curve from time zero to t hours

Cmax maximum observed plasma concentration

*Geometric mean has been taken as the antilog (exponential) of the least square mean of the log transformed data.

The 90 % confidence intervals of the test/reference ratio of geometric means for AUC0-t and Cmax lie

within the acceptable limits of 80.00 % to 125.00 %. Thus, the data support the claim that the applicant’s

test product Co-amoxiclav Tablets BP 1000mg (amoxicillin/clavulanic acid 875mg/125 mg) is

bioequivalent to the reference product Augmentin 875 mg + 125mg, tabletki powlekane Amoxicillinum

+Acidum clavulanicum (GlaxoSmithkline, UK).

Efficacy

The efficacy of amoxicillin trihydrate and clavulanic acid is well-known. No new efficacy data have

been submitted and none are required for this type of application.

Safety

With the exception of the safety data generated during the bioequivalence study, no new safety data

were submitted. No new or unexpected safety issues were raised during the bioequivalence study.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels

The SmPC, PIL and labels are acceptable from a clinical perspective. The PIL is consistent with the

details in the SmPC and in line with the current guidance. The labelling is also in line with the current

guidance.


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Clinical Expert Report (Clinical Overview)

The clinical overview has been written by an appropriately qualified physician and is a suitable

summary of the clinical aspects of the dossier.

Conclusion

The grant of a Marketing Authorisation is recommended.

IV.3 Pharmacodynamics

No new pharmacodynamic data were submitted and none were required for applications of this type.

IV.4 Clinical efficacy

No new efficacy data were submitted, and none were required for applications of this type.

IV.5 Clinical safety

No new safety data were submitted and none are required.

IV.6 Risk Management Plan (RMP) and Pharmacovigilance System

The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides

adequate evidence that the applicant has the services of a qualified person responsible for

pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected

of occurring either in the Community or in a third country.

Suitable justification has been provided for not submitting a Risk Management Plan for this product.

IV.7 Discussion on the clinical aspects

The grant of marketing authorisations is recommended for these applications from a clinical viewpoint.

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 AND BENEFIT/RISK ASSESSMENT

QUALITY

The important quality characteristics of Co-Amoxiclav 875mg/125mg film-coated 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. As the pharmacokinetics, pharmacodynamics and toxicology

of amoxicillin trihydrate and potassium clavulanate are well-known, no additional data were required.

EFFICACY

With the exception of the bioequivalence study, no new data were submitted.

Bioequivalence has been demonstrated between the applicant’s Co-amoxiclav Tablets BP 1000mg

(amoxicillin/clavulanic acid 875mg/125 mg) and the reference product Augmentin 875 mg + 125mg,

tabletki powlekane Amoxicillinum +Acidum clavulanicum (GlaxoSmithkline, UK).


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SAFETY

With the exception of the safety data from the bioequivalence study, no new data were submitted. No

new or unexpected safety concerns arose from the bioequivalence study.

PRODUCT LITERATURE

The SmPC, PIL and labelling are satisfactory and in line with current guidance.

BENEFIT/RISK ASSESSMENT

The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been

identified. Extensive clinical experience with amoxicillin trihydrate and potassium clavulanate is

considered to have demonstrated the therapeutic value of the compounds. The benefit/risk balance is

therefore considered to be positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are


The approved labelling for this medicine is presented below:


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14


15

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 Procedur

e number

Product

informati

on

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessme

nt report

attached

Y/N

(version)

To update

sections 4.2,

4.4, 4.8 and

5.1-5.2 of the

SPC as per

repeat use

commitment

Consequently

impacting the

PIL.

UK/H/324

4/003/II/0

26

SmPC and

PIL

30/05/2018 21/12/2018 Approval Y


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Annex 1.1

Our Reference: PL 25298/0009 Application 0030

Product: Co-amoxiclav 875 mg/125 mg film-coated Tablets

Marketing Authorisation Holder: BROWN & BURK UK LIMITED

Active Ingredient(s): AMOXICILLIN TRIHYDRATE ,POTASSIUM

CLAVULANATE.

Type of Procedure: Mutual Recognition

Submission Type: Variation

Submission Category: Type II

Submission Complexity: Standard

EU Procedure Number: UK/H/3244/003/II/026

Reason:

To update sections 4.2, 4.4, 4.8 and 5.1-5.2 of the SmPC as per repeat use commitment. Consequently,

impacting the PIL.

Supporting Evidence:

This variation application is submitted to update the product information as agreed during the repeat use

procedure for Co-amoxiclav 875 mg/125 mg film-coated Tablets

Evaluation

The updated SmPC sections are satisfactory. The updated PIL is satisfactory. The updated SmPC

fragments and PIL have been incorporated into the Marketing Authorisation.

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are


Decision Approved – 21/12/2018

Documents

Procedure No: UK/H/3244/003/DC UK Licence No: PL 25298 ... · Co-amoxiclav 875mg/125mg film-coated Tablets UK/H/3244/0003/DC 3 than 40 kg. The tablets are not suitable for children