CMDh/223/2005

February 2014

Public Assessment Report

Scientific discussion

Forcid Solutab 875 mg/125 mg szájban

diszpergálódó tabletta

Forcid Solutab 875 mg / 125 mg dispersible tablet

Amoxicillinum trihydricum, Kalii clavulanas

HU/H/0386/001
previously
FI/H/0171/001

Date: 26. 06. 2014

 Scientific discussion
during the initial phase

This module reflects the scientific discussion for the approval of Forcid Solutab 875 mg/125 mg
dispersible tablet. The procedure was finalised at 29. 10. 2002. For information on changes after
this date please refer to the module ‘Update’.

This report has been prepared by the original RMS, the Finnish Authority on 26. 06. 2014[S1][S2].
There has been an RMS-transfer of the product on 27. 06. 2014. The PAR has been and will be
updated by the new RMS Hungary.

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 Content

DISCUSSION DURING THE INITIAL PHASE

I. Introduction ..................................................................................................................................... 4

II. Quality aspects

II.1 Introduction .................................................................................................................................. 5
II.2. Drug substances........................................................................................................................... 5
II.3 Medicinal product ........................................................................................................................ 6
II.4 Discussion on chemical, pharmaceutical and biological aspects .................................................... 7

III. Non-clinical aspects

III.1 Introduction ................................................................................................................................ 8
III.5 Ecotoxicity/environmental risk assessment ..................................................................... 8
III.6 Discussion on the non-clinical aspects ............................................................................ 8

IV. Clinical aspects

IV.1 Introduction ................................................................................................................................ 9
IV.2 Pharmacokinetics: the bioequivalence study ................................................................................ 9
IV.3 Risk Management Plan ............................................................................................................. 10
IV.7 Discussion on clinical aspects ................................................................................................... 10

V. Overall conclusion, benefit/risk assessment and recommendation

V.1 Summary.................................................................................................................................... 11
V.2 Package leaflet and user consultation .......................................................................................... 11

VI. UPGRADE: STEPS TAKEN AFTER THE INITIAL PROCEDURE WITH AN INFLUENCE
ON THE PUBLIC ASSESSMENT REPORT.................................................................................... 12

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 I. INTRODUCTION

Marketing authorisation was applied for based on essential similarity with the innovator product.
According to the application forms, the applications are made according to the provisions of Article
10(1) of Directive 2001/83/EC, as amended. 2001/83/EC. Based on the review of the quality,
safety and efficacy data, the Member States have granted a marketing authorisation for this
amoxicillin-clavulanic acid product.

After the initial approval the product information has been harmonized with the outcome of
Augmentin article 30 referral (Ref. EMEA/CHMP/97898/2009).

The product is indicated for the treatment of bacterial infections as agreed in the above
mentioned referral. A comprehensive description of the indications and posology is given in
the SmPC.

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 II. QUALITY ASPECTS

II.1 Introduction

The Forcid 875 mg / 125 mg tablet is an immediate release tablet as well as dispersible tablet
containing known active substances amoxicillin (as amoxicillin trihydrate) and clavulanic
acid (as potassium clavulanate). The basic formula is composed of typical pharmaceutical
ingredients used in manufacture of compressed tablets: dispersible cellulose, microcrystalline
cellulose, crospovidone, vanillin, mandarin flavour, lemon flavour, saccharin and magnesium
stearate. The tablets are packed in double-sided aluminium laminate (PA/Alu/PVC//Alu)
blister packages in an outer carton box.

II.2 Drug Substances

The active substances in Forcid tablets are amoxicillin trihydrate and potassium clavulanate,
both well-known active substances described in the European Pharmacopoeia. Amoxicillin
trihydrate is a semisynthetic product derived from a fermentation product. It is chemically
described as (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. Amoxicillin trihydrate
is white or almost white, crystalline powder. It is slightly soluble in water, very slightly
soluble in ethanol (96%), practically insoluble in fatty oils and it dissolves in dilute acids and
dilute solutions of alkali hydroxides. The amoxicillin molecule possesses four chiral centers:
three in the beta-lactam moiety and one in the side-chain.

Potassium clavulanate is the potassium salt of a clavulanic acid produced by the growth of
certain strains of Streptomyces clavuligerus. Its chemical name is potassium (2R,3Z,5R)-3-(2-
hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo-[3.2.0]heptane-2-carboxylate.

Potassium clavulanate is white or almost white, crystalline, hygroscopic powder. It is freely

soluble in water, slightly soluble in ethanol (96%) and very slightly soluble in acetone.
Potassium clavulanate has two chiral carbons (carbons 2 and 5).

Polymorphism phenomena are not known for amoxicillin trihydrate or potassium clavulanate.

Manufacture

The Certificates of Suitability of Monographs of the European Pharmacopoeia (CEP) have

been issued to the manufacturers of amoxicillin trihydrate used in the manufacture of Forcid
tablets. The EDQM has granted a CEP also for the manufacturer of potassium clavulanate.
Appropriate information on the packaging materials for both active substances is provided.

Specification

Amoxicillin trihydrate and Potassium clavulanate are controlled according to the Ph. Eur.
monographs and additional specifications laid down by the Certificates of Suitability and
finished product manufacturer. The use or absence of use of material of human or animal
origin in the manufacture of substance has been declared in the Certificates of Suitability of
both active substances.

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Batch analysis data on amoxicillin trihydrate and potassium clavulanate have been provided.
All batches comply with the specifications set and conform batch-to-batch consistency.

Stability

In the Certificates of Suitability re-test periods of 5 / 6 years are granted for amoxicillin
trihydrate. According to the CEP of potassium clavulanate the re-test period is 3 years if
stored under nitrogen at a temperature between 2-8°C.

II.3 Medicinal Product

The strength of the proposed medicinal product is identical with the reference product
Augmentin 875 mg /125 mg containing 875 mg amoxicillin and 125 mg clavulanic acid per
tablet. The basic formula is composed of typical pharmaceutical ingredients used in the
manufacture of compressed tablets: microcrystalline cellulose (diluent), dispersible cellulose
(binder), crospovidone (disintegrant), vanillin, mandarin and lemon flavour (flavouring
agents), saccharin (sweetening agent) and magnesium stearate (tablet lubricant). The
flavouring agents comply with the food flavouring regulations of EU. Other excipients are of
compendial quality. Magnesium stearate is of vegetable origin.
Clavulanate is a hygroscopic substance and sensitive to degradation under influence of
moisture. As the tablets are not coated, special attention has to be paid to the moisture content
of some ingredients.

The aim of the development of Forcid dispersible tablets was to offer optimal patient comfort
by using highest possible concentration of active substances while maintaining the desired
tablet properties namely ability to be taken whole or after dispersion in some water. The tablet
formulation has to comply with the Ph. Eur. requirements for non-coated tablets and in
addition complying with specification in the monograph on dispersible tablet is needed. The
equivalent bioavailability was confirmed in a bioequivalence study in healthy volunteers
using Augmentin 875 mg / 125 mg tablets as reference. Comparative dissolution rates for test
and reference product are presented in the dossier.

Manufacture

The manufacturing process is quite simple and commonly used process consisting out of wet
granulation step, followed by drying and several mixing steps after which the mixture can be
compressed to tablets. Because the clavulanate is sensitive for high levels of moisture, several
stages of the manufacturing process will take place in a humidity controlled environment. A
flow-chart of the manufacturing process has been provided in the dossier. All critical process
parameters have been identified and controlled by appropriate in-process controls.
The manufacturing process has been validated with full-scale production batches using three
different batches of amoxicillin trihydrate and three different batches of potassium
clavulanate. Validation results have been provided. The data presented show that the
production scale batches meet the acceptance criteria of in-process controls and product
specification. The validation results demonstrate batch-to-batch consistency.

Product Specification

The specifications are adequately justified. The release and shelf life specification contain all
relevant tests and limits for this dosage form. The limits are based on relevant guidelines and
batch results. Tests include: colour, appearance, dimensions of tablet, disintegration time,
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fineness of dispersion, pH, friability, free water content, uniformity of dosage, identification
of active substances, dissolution, microbial purity, assay (HPLC) and related substances
(HPLC). Analytical methods are adequately described and suitably validated. Batch analysis
data on three batches have been provided. Batch analysis results indicate satisfactory product
uniformity.

Stability

Stability tests on the finished product were performed under ICH stability conditions.
Stability batches were tested at 25°C / 60% RH. In addition stability tests at intermediate
condition of 30°C/ 65% and at accelerated condition of 40°C / 75% RH were conducted.
Parameters tested are stability indicating. The stability data provided confirm the proposed
shelf life of 24 months when stored below 25°C.

Discussion on chemical, pharmaceutical and biological aspects

The quality of Forcid 875 mg / 125 mg dispersible tablets is adequately established.

Satisfactory chemical and pharmaceutical documentation has been submitted. There are no
major deviations from EU and ICH requirements.

The active substances are well known and are described in Ph. Eur. monographs. The quality
of the active substances is regarded to be suitable for the intended use and appropriately
controlled by the applicant. The excipients are commonly used in these types of formulations.
They are compendial or food grade quality. The packaging material is commonly used. The
manufacturing process of the finished product is quite simple and has been adequately
described. Because the clavulanate is sensitive for high levels of moisture, several stages of
the manufacturing process will take place in humidity controlled environment. Appropriate
in-process controls are set and the manufacturing process has been adequately validated.
Batch analysis results indicate satisfactory product uniformity. Stability data indicate that the
product is stable when stored at 25°C for the proposed shelf life.

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 III. NON-CLINICAL ASPECTS

III.1 Introduction

No new data were provided, as the scope of the applicant was to prove essential similarity with an
already approved product. The non-clinical overview on the preclinical pharmacology,
pharmacokinetics, and toxicology is adequate. There are no preclinical objections to granting the
marketing authorisation.

III.2 Ecotoxicity/environmental risk assessment (ERA)

Since this amoxicillin-clavulanic acid product is intended for generic substitution, this will
not lead to an increased exposure to the environment. An environmental risk assessment is
therefore not deemed necessary.

III.3 Discussion on the non-clinical aspects

Abridged applications of products containing a known active ingredient avoid the need for
repetitive tests on animals and humans. The marketing authorization application of the
originator product contains the full documentation on amoxicillin-clavulanic acid
combination.

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 IV. CLINICAL ASPECTS

IV.1 Introduction

This application is an abridged form for Marketing Authorisation for amoxicillin - clavulanic
acid preparations which are essentially similar products to Augmentin (SmithKline Beecham)
which is already marketed in more than 150 countries world-wide.

No new studies on the pharmacodynamics or clinical efficacy or safety of the product have
been submitted except the bioequivalence study.

IV.2 Pharmacokinetics, the bioequivalence study

Bioequivalence between Forcid Solutab 875/125 mg tablet and Augmentin 875 mg tablet, the
originator, has been shown. The Applicant carried out one pharmacokinetic (PK)
bioequivalence study which was a four way cross-over study with 48 healthy male and female
volunteers (single oral dose of 875/125 mg). Forcid Solutab 875/125 mg tablet taken either
intact or after prior dispersal was compared with Augmentin 875/125 and Co-Amoksiclav 1 g
tablets. The study revealed that clavulanate had considerably higher intra-subject variability
regarding both AUC and Cmax (CV = 34.6 % and 33.4 %, respectively) than amoxicillin (CV
= 13.4 % and 18.1 %, respectively). For the present study it was assumed that the intra-
subject variability of both amoxicillin and clavulanate for the new 875/125 mg tablet would
be comparable. With respect to amoxicillin pharmacokinetics the usual bioequivalence range
of 0.80 – 1.25 was applicable. Because of the high intra-subject variability, for clavulanate a
wider bioequivalence range of 0.70 – 1.43 was considered appropriate. From each subject,
plasma samples for assay of amoxicillin and clavulanate were taken upt to 7 hours post
dosing. Area under the plasma concentration - time curve and the maximal plasma
concentration (AUC0-inf and Cmax) were used as criteria for evaluation of bioequivalence.
AUC0-last, Tmax, T½elim, CL/F, VD/F were used as secondary parameters. The PK-
parameters were assessed both for amoxicillin and clavulanic acid.

There were no marked differences in the test and reference preparations considering AUC.
The 90% confidence intervals (CI) for AUC 0-last as well as AUC 0-inf were within 80–125%
range for both active ingredients, and compared to both comparators. The 90% confidence
interval for Cmax for clavulanic acid was within 80–125% range compared to Augmentin.
Cmax of clavulanate of Co-Amoksiclav was slightly lower, and the 90% CI fits in the broader
interval (0.70 - 1.43) range. The broader interval range can be accepted here with Cmax,
because the products are formally bioequivalent according to AUC, and due to nature of the
active ingredient. In general, with antimicrobial agents it essential that concentrations in
plasma (and tissue) are above certain minimal level individual for each pathogen. It is not
essential from efficacy point of view, how much the maximal concentration is above the
minimal inhibitory concentration (MIC). Clinically more relevant is the duration when the
concentration is above the MIC. However, this duration (with some more or less artificial
MIC) or mean retention time have not been reported.

The wider ranges for the Cmax were supported also by the fact that there is more variability in
the Cmax values than in the AUC values.

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Conclusion on the bioequivalence study: based on the submitted bioequivalence study Forcid
Solutab is considered bioequivalent with Augmentin.

IV.3 Risk Management Plan

This is a generic version of amoxicillin-clavulanic acid which is a well-known combination of

active substances marketed in the EU for more than 10 years. No safety concerns requiring additional
risk minimisation activities have been identified so far. It is the opinion of the RMS that routine
pharmacovigilance activities are sufficient and additional risk management plan is not required.

IV.4 Discussion on the clinical aspects

Abridged applications of products containing a known active ingredient avoid the need for
repetitive tests on animals and humans. The marketing authorization application of the
originator product contains the full documentation on amoxicillin-clavulanic acid. For generic
products the bioequivalence studies are pivotal and have been described above in section IV
1.

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 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT
AND RECOMMENDATION

V.1 Summary

It may be concluded that the benefit/risk-ratio of this product is positive and marketing authorisation
may be granted.

V.2 Package leaflet and 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 during the renewal process.
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.

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 Modul 6
Steps taken after the initial procedure with an influence on
the Public Assessment Report

Procedure Type of Date of start of Date of end of Approval/non Assessment

Scope
number modification the procedure procedure approval report attached
Change in the test procedure FI/H/071/001/007 IA 25. 01. 2005 08. 02. 2005 approval no
SmPC update after
FI/H/071/001/008 II 24. 02. 2005 21. 07. 2005 approval no
FI/H/171/01/E01
Submission of new CEP FI/H/071/001/009 IA 25. 01. 2005 08. 02. 2005 approval no
Change of the marketing
authorisation holder FI/H/071/001/010 IA 15. 09. 205 14. 10. 2005 approval no
(Yamanouchi to Astellas)
Change in the name of the
FI/H/071/001/011 IB 15. 09. 2005 25. 10. 2005 approval no
medicinal product
Submission of new CEP FI/H/071/001/012
FI/H/071/001/014
IA 08. 12. 2005 20.12.2005 approval no
Change of the active substance
FI/H/071/001/013 IB 08. 12. 2005 28. 12. 2005 approval no
specification
Change in the primary packaging
FI/H/071/001/015 IA 02. 04. 2007 17. 04. 2007 approval no
material
Change in the test method and
FI/H/071/001/016 II 14. 08. 2007 12. 10. 2007 approval no
specification
Submission of new CEP FI/H/071/001/017
FI/H/071/001/018
IA 02. 04. 2007 17. 04. 2007 approval no
Change of the active substance
FI/H/071/001/019 IB 04. 09. 2004 04. 10. 2004 approval no
specification
Submission of new CEP FI/H/071/001/020 IA 04. 09. 2007 04. 10. 2007 approval no
Change in the name/address of
the marketing authorisation FI/H/071/001/021 IA 30. 04. 2009 14. 05. 2009 approval no
holder
Deletion of a manufacturing site FI/H/071/001/022 IA 30. 04. 2009 14. 05. 2009 approval no
Change in the SmPC and PIL FI/H/071/001/024 IB 11. 01. 2011 02. 02. 2011 approval no
Change in the name/address of
the marketing authorisation FI/H/071/001/026 IA 25. 05. 2012 24. 06. 2012 approval no
holder
Change in the name/address of
the marketing authorisation FI/H/071/001/027 IA 01.11.2012 01.12.2012 approval no
holder
Submission of new CEP FI/H/071/001/028 IA 16. 01. 2013 15. 02. 2013 approval no
Change in the name/address of
the marketing authorisation FI/H/071/001/029 IA 21. 01. 2013 20. 02. 2013 approval no
holder

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