Public Assessment Report

Decentralised Procedure

Cefadroxil 500 mg capsules, hard

Procedure No: UK/H/5172/001/DC

UK Licence No: PL 34088/0032

Alkaloid-INT d.o.o.

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

LAY SUMMARY
On 28 June 2013, the Medicines and Healthcare products Regulatory Agency (MHRA) granted a
Marketing Authorisation to Alkaloid-INT d.o.o. for the medicinal product Cefadroxil 500 mg capsules,
hard (PL 34088/0032; UK/H/5172/001/DC). This medicine is only available on prescription from your
doctor.
Cefadroxil is an antibiotic. It belongs to a group of antibiotics called cephalosporins. These antibiotics
are similar to penicillin.
Cefadroxil kills bacteria and can be used against various types of infections. Like all antibiotics,
cefadroxil is only effective against certain types of bacteria. It is therefore appropriate to treat certain
types of infections. Cefadroxil can be used to treat:
infections of the throat;
uncomplicated infections of the bladder and kidneys;
uncomplicated infections of the skin and soft tissue.
No new or unexpected safety concerns arose from this application and it was therefore judged that the
benefits of taking Cefadroxil 500 mg capsules, hard outweigh the risks and a Marketing Authorisation
was granted.

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

TABLE OF CONTENTS
Module 1: Information about initial procedure

Page 4

Module 2: Summary of Product Characteristics

Page 5

Module 3: Patient Information Leaflet

Page 6

Module 4: Labelling

Page 7

Module 5: Scientific discussion during initial procedure

I Introduction
II About the product
III Scientific overview and discussion
III 1 Quality aspects
III 2 Non-clinical aspects
III 3 Clinical aspects
IV Overall conclusion and benefit/risk assessment

Page 8

Module 6: Steps taken after initial procedure

Page 14

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

Module 1
Information about the initial procedure
Product Name(s)
Type of Application
Active Substance(s)
Form(s)
Strength(s)
MA Holder

Reference Member State (RMS)

Concerned Member States (CMS)
Procedure Number(s)
Timetable

Cefadroxil 500mg capsules, hard

Generic, Article 10(1)
Cefadroxil monohydrate
Capsule, hard
500 mg.
Alkaloid-INT d.o.o.
landrova ulica 4,
1231 Ljubljana - rnue
Slovenia
UK
Austria, Bulgaria, Czech Republic, Germany, France,
Poland, Romania, Slovenia and Slovak Republic
UK/H/5172/001/DC
Day 210 29 May 2013

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

Module 2
Summary of Product Characteristics
In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for
products granted Marketing Authorisations at a national level are available on the MHRA website.

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

Module 3
Patient Information Leaflet
In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted
Marketing Authorisations at a national level are available on the MHRA website.

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

Module 4
Labelling

Cefadroxil 500 mg capsules, hard

UK/H/5172/001/DC

Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the member states considered that the
application for Cefadroxil 500 mg capsules, hard (PL 34088/0032; UK/H/5172/0001/DC) could be
approved. The product is a prescription-only medicine (POM) and is used in the treatment of the
following infections caused by cefadroxil-susceptible organisms, when an oral therapy is indicated:
streptococcal pharyngitis and tonsillitis;
uncomplicated urinary tract infections;
uncomplicated skin and soft tissue infections.
The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference
Member State (RMS), and Austria, Bulgaria, Czech Republic, Germany, France, Poland, Romania,
Slovenia and Slovak Republic 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
Baxan 500 mg capsules (Bristol Myers Squibb, UK), which was first authorised in the UK on
02 November 1979.
Cefadroxil 500 mg capsules, hard contain the active ingredient cefadroxil (as cefadroxil monohydrate
which is a cephalosporin for oral administration. Cefadroxil monohydrate inhibits bacterial wall
synthesis of actively dividing cells by binding to one or more penicillin-binding proteins. The result is
formation of a defective cell wall that is osmotically unstable, and bacterial cell lysis.
One single-dose, fasting, bioequivalence study was submitted to support the application, comparing the
applicants test product Alycef 500 mg capsules (Alkaloid) and the reference product Baxan 500 mg
capsules (Bristol Myers Squibb, 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.
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 29 May 2013. After a subsequent national phase, a licence was granted in the UK on 28 June 2013.

Cefadroxil 500 mg capsules, hard

II.
ABOUT THE PRODUCT
Name(s) of the product(s)in the Reference Member
State
Name(s) of the active substance(s) (INN)
Pharmacotherapeutic classification (ATC code)
Pharmaceutical form(s) and strength(s)
Reference numbers for the Decentralised Procedure
Reference Member State (RMS)
Concerned Member States (CMS)

Marketing Authorisation Number(s)

Name and address of the authorisation holder

UK/H/5172/001/DC

Cefadroxil 500 mg capsules, hard

Cefadroxil monohydrate
Other beta-lactam antibacterials, First-generation
cephalosporins (ATC code: J01DB05)
Capsule, hard
UK/H/5172/001/DC
United Kingdom
Austria, Bulgaria, Czech Republic, Germany,
France, Poland, Romania, Slovenia nd Slovak
Republic
PL 34088/0032
Alkaloid-INT d.o.o.
landrova ulica 4,
1231 Ljubljana - rnue
Slovenia

III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
ACTIVE SUBSTANCE
INN:
Cefadroxil monohydrate
Chemical name:
(6R,7R)-7-[[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5thia-1-azebicyclo[4,2,0]oct-2-ene-2-carboxylic acid monohydrate
Structure:

Molecular formula:
Mr:
Appearance:
Solubility

C16H17N3O5SH2O
381.40g/mol
A white or almost white powder.
Slightly soluble in water and very slightly soluble in alcohol

Cefadroxil monohydrate is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance cefadroxil monohydrate are covered
by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of
Suitability.
MEDICINAL PRODUCT
Other Ingredient
Other ingredients consist of the pharmaceutical excipients in the capsule and capsule shell namely,
microcrystalline cellulose, sodium lauryl sulphate, magnesium stearate, titanium dioxide (E171), Patent
Blue (E131), Brilliant Black BN (E151) and gelatin. Appropriate justification for the inclusion of each
excipient has been provided.
With the exception of titanium dioxide (E171), Patent Blue (E131) and Brilliant Black BN (E151) all
excipients comply with their respective European Pharmacopoeia monographs. Titanium dioxide (E171)
complies with its United States - National Formulary specification. Patent Blue (E131) and Brilliant
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Black BN (E151) are compliant with suitable in-house specifications. In addition the specifications for
titanium dioxide (E171), Patent Blue (E131) and Brilliant Black BN (E151) are in compliance with
current European guidelines concerning the use of colorants. Certificates of Analysis have been
provided for all excipients, showing compliance with the proposed specification.
With the exception of gelatin, none of the excipients contain materials of animal or human origin. The
suppliers of gelatin has provided Certificates of Suitability from the European Directorate for the
Quality of Medicines and Healthcare (EDQM) to show that it is manufactured in line with current
European guidelines concerning the minimising of risk of transmission of Bovine Spongiform
Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE).
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 a safe, efficacious, stable product
comparable in performance to the innovator product Baxan 500 mg capsules (Bristol Myers Squibb,
UK).
A satisfactory account of the pharmaceutical development has been provided.
Comparative in-vitro dissolution profiles have been provided for the proposed and originator products.
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.
Container-Closure System
The product is packaged in a standard aluminium-transparent clear polyvinylchloride blister foil. Each
blister contains 8 hard capsules. The blisters are packed with the Patient Information Leaflet into
cardboard cartons, in pack sizes of 16 capsules (two blisters of 8 capsules each).
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 foodstuff.
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 2 years, with no special storage conditions.
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.
Summary of Product Characteristics (SmPC), Product Information Leaflet (PIL) and Labels
The SmPC, PIL and labels are satisfactory from a pharmaceutical perspective.
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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 results indicate that the package leaflet is well-structured and organised, easy to
understand and written in a comprehensive manner. The test shows that the patients/users are able to act
upon the information that the leaflet contains.
Marketing Authorisation Application (MAA) Form
The MAA form is satisfactory from a pharmaceutical perspective.
Expert Report (Quality Overall Summary)
The quality overall summary has been written by an appropriately qualified person and is a suitable
summary of the pharmaceutical aspects of the dossier.
Conclusion
The grant of a Marketing Authorisation is recommended.
III.2 NON-CLINICAL ASPECTS
As the pharmacodynamic, pharmacokinetic and toxicological properties of cefadroxil are well-known,
no new non-clinical data have been submitted and none were required.
The non-clinical overview was written by an appropriately qualified person and is satisfactory,
providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and
toxicology.
Suitable justification has been provided for the non-submission of an Environmental Risk Assessment.
As this product is intended for generic substitution of an already authorised product no change to the
environmental exposure is anticipated following approval of the Marketing Authorisation for the
proposed product.
The grant of a Marketing Authorisation is recommended.
III.3 CLINICAL ASPECTS
Clinical Pharmacololgy
The clinical pharmacology of cefadroxil is 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.
In support of the application, the Marketing Authorisation Holder submitted the following
bioequivalence study:
An open randomised, two-way, single-dose, crossover study comparing the pharmacokinetics of
the test product Alycef (cefadroxil monohydrate 500 mg capsules; Alkaloid) and the reference
product Baxan (cefadroxil monohydrate 500 mg capsules; Bristol Myers Squibb, UK) in healthy
male 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 16 hours post dose in
each treatment period. The washout period between the two treatment arms was 7 days. The main
pharmacokinetic results are presented below:

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Cefadroxil 500 mg capsules, hard

Cmax
AUC0-t
AUC0-
Cmax
CI

UK/H/5172/001/DC

maximum plasma concentration

area under the plasma concentration-time curve from time zero to t hours
area under the plasma concentration-time curve from time zero to infinity hours
maximum plasma concentration
confidence intervals

The 90 % confidence intervals of the test/reference ratio of geometric means for AUC and Cmax lie
within the acceptable limits of 80.00 % to 125.00 %. Thus, the data support the claim that the applicants
test product Alycef (cefadroxil monohydrate 500 mg capsules, Alkaloid) is bioequivalent to the
reference product Baxan (cefadroxil monohydrate 500 mg capsules; Bristol Myers Squibb, UK).
Efficacy
The efficacy of cefadroxil 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.
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.
Pharmacovigilance System and Risk Management Plan
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.
The application concerns a generic product, for which the active ingredient that has been in use for many
years, and has a well-established safety profile. Routine Pharmacovigilance activities in accordance with
EU regulations will be undertaken whilst the product is authorized. As the safety profile of the drug is
well-established, a Risk Minimisation Plan is not considered necessary.

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Conclusion
The grant of a Marketing Authorisation is recommended.
IV
OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT
QUALITY
The important quality characteristics of Cefadroxil 500 mg capsules, hard 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 cefadroxil 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 applicants Alycef (cefadroxil monohydrate 500 mg
capsules, Alkaloid) and the reference product Baxan (cefadroxil monohydrate 500 mg capsules; Bristol
Myers Squibb, UK).
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 cefadroxil is considered to have demonstrated the
therapeutic value of the compound. The benefit/risk balance is therefore considered to be positive.

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Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted

Application
type

Scope

Outcome

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