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Public Assessment Report

Decentralised Procedure

CO-AMOXICLAV 250MG/125MG FILM-COATED TABLETS

CO-AMOXICLAV 500MG/125MG FILM-COATED TABLETS

(amoxicillin trihydrate, potassium clavulanate,

diluted)

Procedure No: UK/H/3244/001-2/DC

UK Licence No: PL 25298/0007-8

BROWN AND BURK UK LIMITED

PAR Co-Amoxiclav 250mg/125 and 500mg/125mg Film-Coated Tablets UK/H/3244/001-2/DC

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LAY SUMMARY

Co-amoxiclav 250mg/125mg film-coated Tablets


(amoxicillin trihydrate, potassium clavulanate)

This is a summary of the Public Assessment Report (PAR) for Co-amoxiclav 250mg/125mg film-

coated Tablets (UK/H/3244/001/DC; PL 25298/0007) and Co-amoxiclav 500mg/125mg film-coated

Tablets (UK/H/3244/002/DC; PL 25298/0008). It explains how Co-amoxiclav 250mg/125mg film-

coated Tablets and Co-amoxiclav 500mg/125mg film-coated Tablets were assessed and their

authorisations recommended, as well as their conditions of use. It is not intended to provide practical

advice on how to use Co-amoxiclav 250mg/125mg film-coated Tablets and Co-amoxiclav

500mg/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 375mg and

625mg Film-coated Tablets (Beecham Group plc).

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


• Sinus infection

• Urinary tract infections

• Skin infections

• Dental 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).


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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

250 mg/125 mg film-coated tablets:

The usual dose is 1 tablet three times a day

500 mg/125 mg film-coated tablets:

The usual dose is 1 tablet three times a day

Children weighing less than 40 kg

Co-amoxiclav Tablets are not recommended.

Children aged 6 years or less should preferably be treated with amoxicillin/clavulanic acid oral

suspension or sachets.

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

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

Summaries 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 375mg and 625mg Film-

coated Tablets (Beecham Group plc). 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 medicines

Augmentin 375mg and 625mg Film-coated Tablets (Beecham Group plc) 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.


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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 medicines; Augmentin 375mg and

625mg Film-coated Tablets (Beecham Group plc). Therefore, the MHRA decided that, as for

Augmentin 375mg and 625mg Film-coated Tablets (Beecham Group plc); 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 01

December 2011. Subsequently followed by a national phase, Marketing Authorisations were granted in

the UK on 23 December 2011.

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 6 II QUALITY ASPECTS 7

III NON-CLINICAL ASPECTS 9

IV CLINICAL ASPECTS 9

V User consultation 11 VI Overall conclusion, benefit/risk assessment and recommendation 11 Table of content of the PAR update for MRP and DCP 17


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I INTRODUCTION

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

applications for Co-amoxiclav 250mg/125mg and 500mg/125mg Film-coated Tablets

(PL 25298/0007-8; UK/H/3244/001-2/DC) could be approved. The products are

prescription-only medicines for the treatment of the following bacterial infections in adults

and children:

Co-amoxiclav 250mg/125mg Film-coated Tablets

• Acute bacterial sinusitis (adequately diagnosed)

• Cystitis

• Pyelonephritis

• Cellulitis

• Animal bites

• Severe dental abscess with spreading cellulitis.

Co-amoxiclav 500mg/125mg Film-coated Tablets

• 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

These are applications made under the decentralised procedure (DCP), with the UK as RMS,

and Ireland and Sweden as CMS. The applications were submitted according to Article 10.1

of 2001/83 EC, as amended, claiming to be generic medicinal products of Augmentin 375mg

and 625mg Film-coated Tablets (Beecham Group plc), which were originally granted

Marketing Authorisations in 1981 and 1991, respectively.

Amoxicillin is a member of the penicillin family. The penicillin nucleus consists of a

thiazolidine ring connected to a β-lactam ring, to which a side-chain is attached. The side-

chain determines most of the pharmacological and antibacterial properties of the penicillin in

question. In the case of amoxicillin the benzyl ring in the side chain extends the range of

antimicrobial activity into the Gram-negative bacteria. Amoxicillin kills bacteria by

interfering with the synthesis of the bacterial cell wall. As a result the bacterial cell wall is

weakened, the cell swells and then ruptures. Amoxicillin is readily hydrolysed by the

staphylococcal penicillinase. Its spectrum of activity is extended by administration with the

β-lactamase inhibitor clavulanic acid. Clavulanate by itself has little antibacterial activity.

No new non-clinical studies were conducted, which is acceptable given that the applications

were generics of originator products which have been licensed for over 10 years. The

bioequivalence studies were carried out in accordance with Good Clinical Practice (GCP).

With the exception of the bioequivalence study, no new clinical studies were conducted,

which is acceptable given that the applications were based on being generic medicinal

products of originator products that have been licensed for over 10 years.


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The RMS has been assured that acceptable standards of GMP are in place for these product

types at all sites responsible for the manufacture and assembly of these products.

II. QUALITY ASPECTS

II.1. Introduction

Both strengths of tablets are packaged in aluminium blister strips, which are then enclosed in

a cardboard box. Pack sizes for both strengths are 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 are to be marketed.

However, the Marketing Authorisation Holder has committed to submitting the mock-ups for

any pack size to the relevant regulatory authorities for approval before marketing.

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

ACTIVE SUBSTANCE – AMOXICILLIN TRIHYDRATE

INN: Amoxicillin trihydrate

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 trihydrate

Molecular Formula: C16H19N3O5S·3H2O

Chemical Structure:

Molecular Weight: 419.4

Appearance: A white or almost white, crystalline powder, slightly soluble in water,

very slightly soluble in ethanol (96 per cent), practically insoluble in

fatty oils, chloroform and ether. 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 (EDQM) certificate of

suitability.

ACTIVE SUBSTANCE – POTASSIUM CLAVULANATE

INN: Potassium clavulanate


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

azabizyclo [3.2.0] heptane-2-carboxylate

Molecular Formula: C8H8KNO5

Chemical Structure:

Molecular Weight: 237.3

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

soluble in water

Potassium clavulanate is the subject of a European Pharmacopoeia monograph.

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

covered by a European Directorate for the Quality of Medicines (EDQM) certificate of

suitability.

II.3. Medicinal Product

Other Ingredients

Other ingredients consist of pharmaceutical excipients microcrystalline cellulose (E460),

sodium starch glycolate (Type A), colloidal anhydrous silica (E551), magnesium stearate

(E572), titanium dioxide (E171), hypromellose (E464), ethyl cellulose, Talc (E553b)

and polyethylene glycol.

All excipients are controlled to their respective European Pharmacopoeia monograph.

Suitable batch analysis data have been provided for each excipient, showing compliance with

their respective monograph.

None of the excipients is sourced from animal or human origin. No genetically modified

organisms (GMO) have been used in the preparation of these products.

Pharmaceutical Development

The objective of the development programme was to formulate stable, efficacious and

tolerable film-coated tablets containing amoxicillin trihydrate and potassium clavulanate that

can be considered generic medicinal products of Augmentin 375mg and 625mg Film-coated

Tablets (Beecham Group plc).

A satisfactory account of the pharmaceutical development has been provided.

Comparative in vitro dissolution and impurity profiles have been provided for the proposed

and originator products.

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of both strengths of

product, along with an appropriate account of the manufacturing process. The manufacturing

process has been validated and has shown satisfactory results.


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Finished Product Specification

The finished product specifications proposed for both strengths are acceptable. Test methods

have been described and have been adequately validated. Batch data have been provided and

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 all

strengths of finished product packed in the packaging proposed for marketing. The data from

these studies support a shelf-life of 24 months, with the storage conditions ‘Do not store

above 25°C’.

Suitable post approval stability commitments have been provided to follow-up the batches

from the current studies.

Bioequivalence/bioavailability

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

used in the bioequivalence study.

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 is well-

known. With the exception of data from the bioequivalence studies detailed below, no new


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pharmacodynamics or pharmacokinetic data are provided or are required for these

applications.

IV.2. Pharmacokinetics

In support of these applications, the Marketing Authorisation Holder has submitted the

following bioequivalence studies:

An open-label, randomised, two-period, two-treatment, two-sequence, single-dose,

crossover study to compare the pharmacokinetics of the test product Co-amoxiclav

500mg/125mg Film-coated Tablets versus the reference product Augmentin 625mg

Tablets (Beecham Group plc, UK) in healthy male volunteers under fasted conditions.

Volunteers were dosed with either treatment. Blood samples were taken for the measurement

of pharmacokinetic parameters at pre- and up to 12 hours post dose. The two treatment arms

were separated by a 7-day washout period.

The results are presented below: Amoxicillin (based on geometric means)

Parameter Test (T) Reference (R) % Ratio T/R 90% CI

Cmax (ng/ml) 7734.46 7269.43 106.39 98.06-115.44

AUC0-t 24651.87 23510.96 104.85 97.54-112.70

AUC0-inf 25152.51 24019.26 104.71 97.61-112.34

Clavulanic Acid (based on geometric means)

Parameter Test (T) Reference (R) % Ratio T/R 90% CI

Cmax (ng/ml) 2744.60 2726.76 100.65 88.36-114.65

AUC0-t 6266.60 6315.38 99.22 88.12-111.72

AUC0-inf 6490.39 6545.58 99.15 88.37-111.25

The test and reference products are within conventional 90% confidence intervals of 80-

125% for amoxicillin and clavulanic acid. In conclusion, bioequivalence has been shown

between the test and reference products.

An open-label, randomised, two-period, two-treatment, two-sequence, single-dose,

crossover study to compare the pharmacokinetics of the test product Co-amoxiclav

250mg/125mg Film-coated Tablets versus the reference product Augmentin 375mg

Tablets (Beecham Group plc, UK) in healthy male volunteers under fasted conditions.

Volunteers were dosed with either treatment. Blood samples were taken for the measurement

of pharmacokinetic parameters at pre- and up to 12 hours post dose. The two treatment arms

were separated by a 7-day washout period.

The results are presented below: Amoxicillin (based on geometric means)

Parameter Test Reference Ratio T/R % 90% CI

Cmax (ng/ml) 3939.22 4231.30 93.10 88.04-98.44

AUC0-t 12576.86 13214.18 95.18 90.77-99.80

Clavulanic Acid (based on geometric means)

Parameter Test Reference Ratio T/R % 90% CI

Cmax (ng/ml) 2462.74 2637.35 93.38 84.32-103.42

AUC0-t 5864.74 6354.97 92.29 83.62-101.85


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The test and reference products are within conventional 90% confidence intervals of

80-125% for amoxicillin and clavulanic acid. In conclusion, bioequivalence has been shown

between the test and reference products.

Efficacy

No new data on the efficacy of either active substance are submitted and none are required

for these types of applications.

Safety

No new or unexpected safety issues were raised by the bioequivalence data.

SmPC, PIL, Labelling

The SmPCs, PIL and labelling are medically acceptable. The SmPCs are consistent with

those for the originator products.

Conclusion

The grant of Marketing Authorisations 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.

A suitable justification has been provided for not submitting a risk management plan for

these products.

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


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The important quality characteristics of Co-amoxiclav 250mg/125mg and 500mg/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 and none are required for applications of this type.

EFFICACY

Bioequivalence has been demonstrated between the applicant’s Co-amoxiclav 250mg/125mg

and 500mg/125mg Film-coated Tablets and their respective originator products.

No new or unexpected safety concerns arise from these applications.

The SmPCs, PIL and labelling are satisfactory and consistent with those for the originator

products.

RISK-BENEFIT ASSESSMENT

The quality of the products is acceptable, and no new preclinical or clinical safety concerns

have been identified. The bioequivalence study supports the claim that the applicant’s

products and the originator products are interchangeable. Extensive clinical experience with

amoxicillin and clavulanic acid is considered to have demonstrated the therapeutic value of

the compound. The benefit-risk 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 available on the MHRA website.

The approved labelling for these medicines is presented below:


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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 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

4/001-

002/II/026

SmPC and

PIL

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


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Annex 1.1

Our Reference: PL 25298/0007 Application 0041 PL 25298/0008 Application 0036

Product Co-amoxiclav 250 mg/125 mg film-coated Tablets Co-

amoxiclav 500 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/3244/001-002/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:

These variation applications are submitted to update the product information as agreed during

the repeat use procedure for Co-amoxiclav 250 mg/125 mg and 500 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 available on the MHRA website.

Decision – Approved on 21/12/2018

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