5 ml powder for oral suspension

Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral Suspension UK/H/3242/001-2/DC

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Public Assessment Report

Decentralised Procedure

Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder

for Oral Suspension

(Amoxicillin trihydrate)

Procedure No: UK/H/3242/001-2/DC

UK Licence No: PL 25298/0003-4

BROWN & BURK UK LTD


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LAY SUMMARY Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral Suspension

(Amoxicillin trihydrate)

This is a summary of the Public Assessment Report (PAR) for Amoxicillin Sugar Free 125 mg/ 5 ml and

250 mg/5 ml Powder for Oral Suspension (UK/H/3242/001-2/DC; PL 25298/0003-4). It explains how

Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral Suspension 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 these products.

These products will be referred to as Amoxicillin Sugar Free Suspension in this lay summary for ease of

reading.

For practical information about using Amoxicillin Sugar Free Suspension, patients should read the

package leaflets or contact their doctor or pharmacist.

What is Amoxicillin Sugar Free Suspension and what are they used for?

Amoxicillin Sugar Free Suspension is a ‘generic medicine’. This means that it is similar to the

‘reference medicines’, already authorised in the UK called Amoxil Syrup Sucrose Free/Dye Free 125

mg/5 ml and Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK).

Amoxicillin Sugar Free Suspension is used to treat infections caused by bacteria in different parts of the

body. Amoxicillin Sugar Free Suspension may also be used in combination with other medicines to treat

stomach ulcers.

How does Amoxicillin Sugar Free Suspension work?

Amoxicillin Powder for Oral Suspension contains the active ingredient amoxicillin, which is an

antibiotic that belongs to a group of medicines called penicillins. Amoxicillin works by killing the

bacteria that cause the infection.

How is Amoxicillin Sugar Free Suspension used?

The bottle containing the suspension should be well shaken before each dose. The dose should be spaced

out evenly during the day, at least 4 hours apart.

The usual dose is:

Children weighing less than 40kg:

All doses are worked out depending on the child's body weight in kilograms.

• A doctor will advise patients how much amoxicillin should be given to a baby or child.

• The usual dose is 40 mg to 90 mg for each kilogram of bodyweight a day given in two to three divided

doses

• The maximum recommended dose is 100 mg for each kilogram of body weight a day.

Adults, elderly patients and children weighing 40 kg or more

This suspension is not usually prescribed for adults and children weighing more than 40 kg. Ask your

doctor or pharmacist for advice.

The usual dose in patients with kidney problems might be lower.

This medicine can only be obtained with a prescription.

Please read Section 3 of the patient information leaflet for detailed information on dosing

recommendations, the route of administration and the duration of treatment.


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How has Amoxicillin Sugar Free Suspension been studied?

Because Amoxicillin Sugar Free Suspension is a generic medicine, studies in patients have been limited

to tests to determine that it is bioequivalent to the reference medicines, Amoxil Syrup Sucrose Free/Dye

Free 125 mg/5 ml and Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml. Two medicines are

bioequivalent when they produce the same levels of the active substance in the body.

What are the benefits and risks of Amoxicillin Sugar Free Suspension?

Because Amoxicillin Sugar Free Suspension is a generic medicine, and is bioequivalent to the reference

medicines, Amoxil Syrup Sucrose Free/Dye Free 125 mg/5 ml and Amoxil Syrup Sucrose Free/Dye

Free 250 mg/5ml, their benefits and risks are taken as being the same as the reference medicines.

Why is Amoxicillin Sugar Free Suspension approved?

It was concluded that, in accordance with EU requirements, Amoxicillin Sugar Free Suspension has

been shown to have comparable quality and to be bioequivalent to Amoxil Syrup Sucrose Free/Dye Free

125 mg/5 ml and Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml. Therefore, the view was that, as for

Amoxil Syrup Sucrose Free/Dye Free 125 mg/5 ml and Amoxil Syrup Sucrose Free/Dye Free 250

mg/5ml, the benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of Amoxicillin Sugar Free

Suspension?

A risk management plan has been developed to ensure that Amoxicillin Sugar Free Suspension are used

as safely as possible. Based on this plan, safety information has been included in the Summaries of

Product Characteristics (SmPC) and the package leaflet for Amoxicillin Sugar Free Suspension,

including the appropriate precautions to be followed by healthcare professionals and patients.

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

healthcare professionals will be monitored and reviewed continuously as well.

Other information about Amoxicillin Sugar Free Suspension

The Netherlands and the UK agreed to grant Marketing Authorisations for Amoxicillin Sugar Free

Suspension on 14 December 2011. Marketing Authorisations was granted in the UK on 13 January

2012.

The Concerned Member State, The Netherlands, withdrew from the procedure (UK/H/3242/001-2/DC)

on 21 August 2015. Subsequently, a repeat use procedure (UK/H/3242/01-2/E01) involving the

Concerned Member State, Germany, was concluded on 20 January 2016.

The Marketing Authorisations were granted with the name Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml

Powder for Oral Suspension. Following the grant of a variation application on 08 July 2012, the name

has changed to Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral Suspension.

The full PAR for Amoxicillin Sugar Free Suspension follows this summary.

This summary was last updated in June 2017.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 7

III Non-clinical aspects Page 8

IV Clinical aspects Page 9

V User consultation Page 12

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 13

Table of content of the PAR update for MRP and DCP

Annex – 1

Page 19

Page 20


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I INTRODUCTION

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

applications for Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral Suspension (PL

25298/0003-4; UK/H/3242/001-2/E01), are approvable. These applications were submitted via a repeat

use procedure with the UK as Reference Member State (RMS) and Germany as Concerned Member

State (CMS).

These applications are originally granted in the UK on 13 January 2012 via the Decentralised

Procedures (DCP) (UK/H/3242/001-2/DC) with UK as RMS and The Netherlands as CMS. The

Netherlands [CMS] withdrew from the procedure on 21 August 2015.

Subsequently a repeat use procedure with Germany as CMS was concluded on 20 January 2016.

The products are prescription-only medicines (POM) indicated for the treatment of the following

infections caused by susceptible bacteria in adults and children above the age of 6 months:

acute otitis media

acute exacerbations of chronic bronchitis

community acquired pneumonia

cystitis

Endocarditis: Prophylaxis of endocarditis associated with procedures such as dental extraction,

where indicated in patients at risk of developing bacterial endocarditis.

These applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, cross

referring to the reference products Amoxil Syrup Sucrose Free/Dye Free 125 mg/5 ml and Amoxil

Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK) which have been authorised in the

UK since 14 May 1985.

Amoxicillin is an aminopenicillin and belongs to a group of medicines called Beta-lactam antibiotics. It

is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the

inhibition of one or more enzymes (often referred to as penicillin-binding proteins or PBPs) in the

biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell

wall.

No new non-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.

One bioequivalence study (single dose) was submitted to support these applications, comparing the test

product Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension with the reference product Amoxil

Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK).

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

acceptable given that the applications were for products that are being considered as generic medicinal

products of an originator product that have been licensed for over 10 years. The bioequivalence study

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

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

place for this product types at all sites responsible for the manufacture, assembly and batch release of

these products.

The Member States considered that the applications could be approved with the end of repeat use

procedures (PL 25298/0003-4; UK/H/3242/001-2/E01) involving the CMS, Germany.

The Marketing Authorisations were granted with the name Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml


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Powder for Oral Suspension. Following the grant of a variation application on 08 July 2012, the names

have changed to Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral Suspension.


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II QUALITY ASPECTS

II.1 Introduction

These medicinal products are white to pale yellow free flowing powder for oral suspension containing

125 mg or 250 mg amoxicillin per 5 ml dose, as active ingredient. Other ingredients consist of the

pharmaceutical excipients di-sodium edetate, sodium benzoate (E211), sodium saccharin (E954),

colloidal silicon dioxide (E551), xanthan gum (E415), orange flavour, raspberry flavour, golden caramel

and sorbitol (E420).

All excipients used comply with their respective European Pharmacopoeia monograph with the

exception of orange flavour, raspberry flavour and golden caramel which are controlled to suitable in-

house specifications. Satisfactory Certificates of Analysis have been provided for all excipients.

None of the excipients are of animal or human origin. No genetically modified organisms (GMO) have

been used in the preparation of these products.

All strengths of the finished product are packaged in 150 ml high-density polyethylene (HDPE) bottles

containing powder for suspension and a dosing syringe of 5 ml.

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 – 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

Structure:

Molecular formula: C16H19N3O5S * 3H20

Molecular mass: 419.1 g/mol

Appearance: Amoxicillin trihydrate is a white or almost white, crystalline powder. It is slightly

soluble in water, very slightly soluble in ethanol, practically insoluble in fatty oils

and 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.

II.3 MEDICINAL PRODUCTS

Pharmaceutical Development

The objective of the programme was to develop two strengths of powder formulation for oral suspension

containing 125 mg/5ml and 250 mg/5ml amoxicillin as the active substance.

Suitable pharmaceutical development data have been provided for these applications.


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

originator products.

Manufacture of the products

Satisfactory batch formulae have been provided for the manufacture of the products, along with an

appropriate account of the manufacturing process. The manufacturing process has been validated at pilot

scale and has shown satisfactory results. In addition the marketing authorisation holder has committed to

conduct process validation on commercial scale batches prior to release of the product on the market.

Finished Product Specifications

The finished product specifications proposed are acceptable. The test methods have been described and

have been adequately validated. 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 products

Stability studies were performed in accordance with current guidelines on batches of the finished

product packed in the packaging proposed for marketing. The data from these studies support a shelf-life

of 24 months for the unopened product which reduces to 14 days upon reconstitution with the storage

conditions “Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within

14 days. If dilution of the reconstituted product is required, water should be used.”

Bioequivalence/bioavailability

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

bioequivalence studies.

II.4 Discussion on chemical, pharmaceutical and biological aspects

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

III NON-CLINICAL ASPECTS

III.1 Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of amoxicillin are well known. No

new non-clinical data have been submitted for these applications and none are required.

The applicant has provided an overview based on published literature. The non-clinical overview has

been written by an appropriately qualified person and is satisfactory, providing an appropriate review of

the relevant non-clinical pharmacology, pharmacokinetics and toxicology.

III.2 Pharmacology

Not applicable, see Section III.1 Introduction, above.

III.3 Pharmacokinetics


III.4 Toxicology



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III.5 Ecotoxicity/Environmental Risk Assessment (ERA)

Suitable justification has been provided for not submitting an Environmental Risk Assessment. As the

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

environmental exposure to amoxicillin is anticipated. Thus, the justification for not submitting an

Environmental Risk Assessment is accepted.

III.6 Discussion of the non-clinical aspects

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

IV CLINICAL ASPECTS

IV.1 Introduction

The clinical pharmacology of amoxicillin is well-known. With the exception of data from the

bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided

or are required for this type of applications.

No new efficacy or safety studies have been performed and none are required for this type of

applications. A comprehensive review of the published literature has been provided by the Applicant,

citing the well-established clinical pharmacology, efficacy and safety of amoxicillin.

Based on the data provided, Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension can be considered

bioequivalent to Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK). This

conclusion also applies to Amoxicillin 125 mg/5ml Powder for Oral Suspension.

IV.2 Pharmacokinetics

In support of these applications, the marketing authorisation holder has submitted the following

bioequivalence study:

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

to compare the pharmacokinetics of the test product Amoxicillin 250 mg/ 5 ml Powder for Oral

Suspension versus the reference product Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml

(GlaxoSmithKline, UK) in healthy adult volunteers under fasted conditions.

All volunteers received a single oral dose of 250mg (5 ml) of either the test or reference product

administered with 240 ml of water under fasting conditions. Blood samples were taken for the

measurement of pharmacokinetic parameters at pre- and up to 12 hours post dose. The washout period

between treatment periods was at least 7 days.

The pharmacokinetic results for amoxicillin are presented below (log-transformed values; mean, ratios

and 90% confidence intervals):

Treatment AUC0-t

ng/ml/h

AUC0-∞

ng/ml/h

Cmax

ng/ml

Test 20718.73 20882.65 7487.47

Reference 22314 22492.18 7859.65

*Ratio (90% CI)

93.18

(88.77-97.82%)

93.18

(88.8-97.77%)

95.71

(88.79-103.17%)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity

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

Cmax maximum plasma concentration

*ln-transformed values

The 90% confidence intervals for AUC and Cmax for test versus reference product for amoxicillin are

within predefined acceptance criteria specified in the ”Guideline on the Investigation of Bioequivalence”

(CPMP/EWP/QWP/1401/98 Rev 1/, Corr). Thus, the data support the claim that the test product is

bioequivalent to the reference product.


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As the 125 mg/5ml and 250 mg/5ml strengths of the product meet the criteria specified in the ”Guideline

on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and

conclusions of the bioequivalence study on the 250 mg/5ml strength can be extrapolated to the 125

mg/5ml strength.

IV.3 Pharmacodynamics

No new pharmacodynamic data were submitted and none were required for these applications.

IV.4 Clinical Efficacy

No new efficacy data were submitted and none were required for these applications.

IV.5 Clinical Safety

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

submitted and none were required for these applications. No new or unexpected safety issues were

highlighted by the bioequivalence data.

IV.6 Risk Management Plan

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 Amoxicillin Sugar Free 125 mg/ 5 ml and

250 mg/5 ml Powder for Oral Suspension.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,

is listed below:


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Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

IV.7 Discussion of the clinical aspects

It is recommended that Marketing Authorisations are granted for Amoxicillin Sugar Free 125 mg/ 5 ml

and 250 mg/5 ml Powder for Oral Suspension, from a clinical point of view.

V USER CONSULTATION

A package leaflet has been submitted to the MHRA along with results of consultations with target

patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as

amended. The leaflet conforms to the requirements. The test shows that the patients/users are able to act

upon the information that the leaflet contains.


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VI OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

QUALITY

The important quality characteristics of Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral

Suspension 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 were required for applications of this type.

EFFICACY

With the exception of the bioequivalence study, no new data were submitted and none are required for

applications of this type.

Bioequivalence has been demonstrated between the applicant’s Amoxicillin 250 mg/ 5 ml Powder for

Oral Suspension and its respective reference product (Amoxil Syrup Sucrose Free/Dye Free 250

mg/5ml, GlaxoSmithKline, UK). As the 125 mg/5ml and 250 mg/5ml strength of the product meets the

biowaiver criteria specified in the ”Guideline on the Investigation of Bioequivalence”

(CPMP/EWP/QWP/1401/98 Rev 1/, Corr), the results and conclusions of the bioequivalence study on

the 250 mg/5ml strength can be extrapolated to the 125 mg/5ml strength.

SAFETY

With the exception of the bioequivalence study, no new data were submitted and none are required for

applications of this type. As the safety profile of amoxicillin is well-known, no additional data were

required. No new or unexpected safety concerns arose from the safety data from the bioequivalence

study.

PRODUCT LITERATURE

The SmPCs, PIL and labelling are satisfactory and consistent with those for the reference product, where

appropriate.

BENEFIT-RISK ASSESSMENT

The quality of the products is acceptable and no new non-clinical 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 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, Patient Information Leaflet & Labels In accordance with Directive 2012/84/EU, the current approved UK versions of the

SmPCs and PIL for these products are available on the MHRA website.


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Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

The following table lists non safety update to the Marketing Authorisations for these products that has

been approved by the MHRA since the products were first licensed. The table includes updates that are

detailed in the annex to this PAR. This is not a complete list of the post-authorisation changes that have

been made to these Marketing Authorisations.

Date

submitted

Application

type

Scope Outcome

21/12/2015 Type II To update sections 2, 4.1, 4.2, 4.3, 4.4,

4.5, 4.6, 4.8, 4.9, 5.1, 5.2, 5.3 and 6.5 of

the SmPC and the PIL in line with the

reference medicinal product Amoxil,

Article 30 referral EMEA/H/A-30/1372,

as per quality review documents (QRD)

template and additionally as per

comments received during the repeat

use procedure for Amoxicillin

125mg/5ml and 250 mg/5 ml Powder

for Oral Suspension. The product

labelling has also been amended in

Germany only.

Approved on

12 May 2017


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Annex 1

Reference: PL 25298/0003-0004 - 0031

Product: Amoxicillin Sugar Free 125 mg/ 5 ml and 250 mg/5 ml Powder for Oral

Suspension

Marketing Authorisation Holder: Brown & Burk UK Ltd

Active Ingredient: Amoxicillin trihydrate

Reason:

To update sections 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 4.9, 5.1, 5.2, 5.3 and 6.5 of the SmPC and the PIL

in line with the reference medicinal product Amoxil, Article 30 referral EMEA/H/A-30/1372, as per

quality review documents (QRD) template and additionally as per comments received during the repeat

use procedure for Amoxicillin 125mg/5ml and 250 mg/5 ml Powder for Oral Suspension. The product

labelling has also been amended in Germany only.

Supporting evidence

The applicant has submitted updated section of the SmPC and PIL.

Evaluation

The amended sections of the SmPC and the PIL are satisfactory.

Conclusion

The updated SmPC fragments have been incorporated into these Marketing Authorisations. The

proposed changes are acceptable.

Decision: Grant

Date: 12 May 2017

5 ml powder for oral suspension

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