Tap the Torah: "Dealing with a Basket Case"

CO-AMOXICLAV/AMOCLAN 125/31 SUGAR FREE ORAL SUSPENSION AND
CO-AMOXICLAV/ AMOCLAN 250/62 SUGAR FREE ORAL SUSPENSION
PL 15413/0006-7
UKPAR
TABLE OF CONTENTS
Lay summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 19
Summary of product characteristics
Page 20
Product information leaflet
Page 35
Labelling
Page 39
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
1
CO-AMOXICLAV/AMOCLAN 125/31 SUGAR FREE ORAL SUSPENSION AND
CO-AMOXICLAV/ AMOCLAN 250/62 SUGAR FREE ORAL SUSPENSION
PL 15413/0006-7
LAY SUMMARY
The Medicines and Healthcare products Regulatory Agency (MHRA) granted Hikma
Farmaceutica Marketing Authorisations (licences) for the medicinal products Co-Amoxiclav
/Amoclan 125/31 Sugar Free Oral Suspensions and Co-Amoxiclav/Amoclan 250/62 Sugar
Free Oral Suspensions. These prescription only medicines (POM) are indicated in cases
when amoxicillin resistant β-lactamase producing strains of bacteria are suspected as the
cause of infection in a patient.
No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Co-Amoxiclav /Amoclan 125/31 Sugar Free Oral
Suspensions and Co-Amoxiclav/Amoclan 250/62 Sugar Free Oral Suspensions outweigh the
risks, hence Marketing Authorisations have been granted.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
2
CO-AMOXICLAV/AMOCLAN 125/31 SUGAR FREE ORAL SUSPENSION AND
CO-AMOXICLAV/ AMOCLAN 250/62 SUGAR FREE ORAL SUSPENSION
PL 15413/0006-7
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction
Page 4
Pharmaceutical assessment
Page 5
Preclinical assessment
Page 14
Clinical assessment
Page15
Overall conclusions and risk benefit assessment
Page 18
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
3
INTRODUCTION
The UK granted Marketing Authorisations for the medicinal products CoAmoxiclav/Amoclan 125/31 Sugar Free Oral Suspensions and Co-Amoxiclav/Amoclan
250/62 Sugar Free Oral Suspensions to Hikma Farmaceutica on 1 August 2006.
These applications were submitted under article 10.1 of Directive 2001/83, claiming essential
similarity to Augmentin 125/31 SF Oral Suspension (PL 00038/0298) and Augmentin 250/62
SF Oral Suspension (PL 00038/0337).
These oral suspensions contain the active ingredients amoxicillin trihydrate (penicillin) and
potassium clavulanate and attack bacterial infections by interfering with bacteria cell wall
production. Potassium clavulanate enhances the action of penicillin by blocking the defences
of the penicillin-resistant bacteria, β-lactamase.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
4
PHARMACEUTICAL ASSESSMENT
1.
INTRODUCTION
These are national abridged applications for Marketing Authorisation in the UK submitted
under article 10.1 of Directive 2001/83 for products claimed to be essentially similar to
Augmentin 125/31 SF Oral Suspension (PL 00038/0298) and Augmentin 250/62 SF Oral
Suspension (PL 00038/0337), both granted to Beecham Group plc in October 1982.
The proposed products are indicated for short term treatment of bacterial infections in the
upper and lower respiratory tracts, genito-urinary tract, abdominal infections and skin and
soft tissue infections. The β-lactamase inhibitory action of clavulanate extends the broad
spectrum of activity of amoxicillin.
2.
DRUG SUBSTANCES
AMOXICILLIN TRIHYDRATE is (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.
C16H19N3O5S,3H2O
Mwt = 419.4
CAS No: 61336-70-7
Amoxicillin trihydrate from the proposed manufacturer has been previously approved for use
in products for oral administration on the UK market. A Ph Eur Certificate of Suitability
[R2-CEP 1994-013-Rev 01] provided for the relevant production site specifies additional
requirements for residual solvents. The commercial grade supplied has been confirmed and a
satisfactory assurance of the consistent quality of the bulk drug material has been provided.
SPECIFICATION
The proposed Drug Substance Specification is consistent with the requirements specified in
the corresponding Ph Eur Certificate of Suitability [R2-CEP 1994-013-Rev 01].
The test methods to be carried out routinely on incoming batches of bulk drug material by the
finished product manufacturer have been confirmed.
PARTICLE SIZE
The proposed particle size specification was based on the historical particle size distribution
data generated.
BATCH ANALYSES
Satisfactory Certificates of Analysis for three batches of amoxicillin trihydrate tested by the
drug substance manufacturer and batch analytical data for the same batches tested by the
proposed finished product manufacturer have been provided. The Certificates of Analysis
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
5
from the active ingredient manufacturer confirm compliance with the corresponding Ph Eur
Certificate of Suitability.
STABILITY DATA
Data supporting a 5 year shelf life were reported from on-going real-time and accelerated
assays and were found to comply with the Ph Eur requirement. A 5 year retest period was
specified on the EDQM certificate issued in May 2002.
is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1azabicyclo[3.2.0]heptane-2-carboxylate.
POTASSIUM CLAVULANATE
C8H8KNO5
Mwt = 237.3
CAS No: 61177-45-5
Potassium clavulanate from the proposed manufacturer has been previously approved for use
in products for oral administration on the UK market. A Ph Eur Certficate of Suitability [R2CEP 1994-013 Rev 01] provided for the relevant production site, dated August 2005,
specifies the additional requirements for residual solvents and reagents.
Potassium clavulanate is supplied as a 1:1 blend of potassium clavulanate and silicon dioxide.
Statements and recent Certificates of Analysis assuring the consistent quality of the
Potassium Clavulanate/Silicon Dioxide 1:1 blend have been provided. A Ph Eur Certificate of
Suitability [R0-CEP 2002-256-Rev 02] issued in July 2005 was provided for the relevant
production site.
SPECIFICATION
The proposed Drug Substance Specification for Potassium Clavulanate diluted with silicone
dioxide in a 1:1 ratio shows full consistency with the requirements specified in the
corresponding Ph Eur Certificate of Suitability [R0-CEP 2002-256-Rev 02]. A copy of the
certificate, which was issued in July 2005, has been provided.
PARTICLE SIZE
The proposed specification for particle size distribution of the potassium clavulanate/silicon
dioxide blend has been provided, however, as the potassium clavulanate/silicon dioxide blend
is water-soluble and, therefore, in solution on reconstitution, particle size is not a concern.
BATCH ANALYSES
Satisfactory Certificates of Analysis for several batches of potassium clavulanate and two
batches of the potassium clavulanate/silicon dioxide (1:1) blend, tested by the drug substance
manufacturer, as well as batch analytical data for the same two batches of blend tested by the
proposed finished product manufacturer, have been provided.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
6
STABILITY DATA
Data supporting a 3 year shelf life were reported from on-going real-time and accelerated
assays and were found to comply with the Ph Eur requirement.
Stability data provided for three batches of the potassium clavulanate/silicon dioxide (1:1)
blend support a 4-year shelf life, despite out of specification results reported for the water
content of 2 batches at 24 months. Reported results for water content under accelerated
conditions and at later time points (36 and 48 months) under real storage conditions were
well within specification, suggesting possible analytical errors at the 24-month time point.
The finished product manufacturer retests the bulk drug material every 6 months.
3.
DOSAGE FORM
FORMULATION AND PHARMACEUTICAL DEVELOPMENT
Both proposed strengths of the preparation are presented as a white to off-white powder for
reconstitution with approximately 90 ml of potable water, to produce 100 ml of an off-white
oral suspension. The qualitative composition of both proposed strengths of the preparation
are summarised as follows.
Qualitative composition of Amoclan/Co-amoxiclav Sugar Free Oral Suspensions 125/31
and 250/62
Ingredient
Amoxicillin
(as trihydrate) THD
Clavulanic acid
(as potassium
clavulanate/silicon
dioxide 1:1 mixture)
Xanthan gum
Ref std
Ph Eur/
HSE
Ph Eur/
HSE
Function
Active
(antibacterial)
Active
Ph Eur/
NF
Succinic acid
Colloidal silicon
dioxide
Sodium saccharin
HSE
Ph Eur/
USP
Ph Eur/
USP
Ph Eur/
USP
HSE
Thickening/
suspending
agent
pH adjustment
Glidant
Hydroxypropyl
methylcellulose
Strawberry powder
flavour
Orange powder flavour
HSE
Lemon powder flavour
HSE
Silicon dioxide
USP
Sweetener
Suspending
agent
Flavouring
agent
Flavouring
agent
Flavouring
agent
Desiccant
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
7
The necessary amount of amoxicillin THD, potassium clavulanate/silicon dioxide (1:1 blend)
and silicon dioxide used in the formulation depends upon the potency of the amoxicillin and
clavulanic acid.
The overage of potassium clavulanate proposed to account for stability losses is acceptable.
Confirmation of the absence of a proposed overage for amoxicillin has been provided.
CLINICAL TRIAL FORMULA
A bioequivalence study was carried out using a single clinical trial (CT) batch of Amoclan
250/62 Sugar Free Oral Suspension (B/No: 5292). The CT batch was manufactured at the
specified finished product manufacturing site. The qualitative and quantitative composition
of the CT batch was identical to the Amoclan 250/62 Sugar Free Oral Suspension formulation
proposed for marketing. Full batch details were provided. Satisfactory batch analytical data
demonstrating compliance with the proposed Finished Product Specifications were reported.
PHARMACEUTICAL DEVELOPMENT
The proposed products have been developed as generic equivalents to the claimed essentially
similar Augmentin 125/31 SF Oral Suspension (PL 00038/0298) and Augmentin 250/62 SF
Oral Suspension (PL 00038/0337). The generic preparations are intended for the same
indications, dosage regimen and route of administration as the reference products.
Since potassium clavulanate is sensitive to heat and moisture, a dry powder for suspension
was developed. Moisture uptake from the environment has been limited by manufacturing in
an environment with low relative humidity and temperature. Active and inactive materials
having comparable particle size distribution and densities were reportedly used, to ensure
good mixing and to reduce the risk of segregation in the subsequent manufacturing process.
The rationale behind the selection of excipients and optimum levels included in the proposed
formulations has been satisfactorily discussed in relation to development work.
A comparative bioequivalence study of the test generic product, Amoclan 250/62 Sugar Free
Oral Suspension (Hikma), and the claimed essentially similar UK brand leader, Augmentin
250/62 SF Oral Suspension (PL 00038/0337; SKB) has not been carried out. The reference
comparator product used was Augmentan Forte Suspension (SKB Pharma, Germany). In the
absence of a direct comparison of the test Hikma product with the claimed essentially similar
UK brand leader, evidence has been provided confirming that the German Augmentan
preparation is equivalent to that of the claimed essentially similar UK brand leader,
Augmentin 250/62 SF Oral Suspension (PL 00038/0337).
Comparable in vitro dissolution data submitted for the test generic preparation, Amoclan
250/62 Sugar Free Oral Suspension (Hikma) and the reference product, Augmentan Forte
Suspension (SKB Pharma, Germany), are summarised as follows.
In vitro dissolution data on test and reference products used in the bioequivalence study
(AMCL-HIK-S899/44)
Time
(min)
% Dissolution
Amoclan
250/62
(Hikma)
10
Clavulanic acid
106.1
Augmentan
Forte (SKB
Pharma,
Germany)
101.7
Amoclan
125/31
(Hikma)
100.5
Augmentan
(SKB
Pharma,
Germany)
101.7
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
8
20
30
Amoxicillin
102.2
96.5
98.9
96.7
Clavulanic acid
106.0
102.2
102.4
101.7
Amoxicillin
102.5
98.2
101.5
97.0
Clavulanic acid
105.9
102.4
102.0
101.5
Amoxicillin
102.8
98.2
100.9
97.3
Reported dissolution profiles are similar for the test and reference products.
Essential similarity to a single batch each of the UK brand leader products (Augmentin
125/31.25 mg and 250/62.5 mg) and German reference products (Augmentan 125/31.25 mg
and 250/62.5 mg) has been established by comparison of appearance, taste, identification,
suspendability/dissolution, pH, density, degradation products and assay. Comparative levels
of water content have not been reported. The impurity profiles were similar and comparable
levels of suspended amoxicillin and clavulanic acid in deionised water were reported.
Stability of both amoxicillin and clavulanic acid in all reconstituted samples after 7 days
storage was evaluated. The % decrease in content ranged from 0.6-3.0 for amoxicillin and
6.0-13.3 for clavulanic acid.
The HPLC gradient elution method has been used to establish
amoxicillin degradation products.
LOD
and
LOQ
level limits for
A method has been developed for the determination of potassium clavulanate related
substances in the proposed Amoclan suspensions and LOD and LOQ level limits have been
established.
Separate pack/product compatibility studies have not been reported.
EXCIPIENTS
Xanthan gum, colloidal silicon dioxide, saccharin sodium, hydroxypropylmethyl cellulose
(hypromellose) and silicon dioxide are specified as complying with published Ph Eur
monographs. Xanthan gum, colloidal silicon dioxide and hypromellose are additionally
specified as complying with corresponding USP/NF monographs. Satisfactory Certificates of
Analysis have been provided for xanthan gum, saccharin sodium and colloidal hydrated
silicon dioxide. The absence of the specified organic volatile impurities, benzene,
chloroform, dioxane, methylene chloride and trichloroethylene in colloidal silicon dioxide
and hypromellose has been confirmed by named suppliers. An ‘in house’ specification for
succinic acid has been provided, based on the supplier’s own specification. Satisfactory
evidence of compliance has been presented.
In-house specifications have also been provided for the strawberry, orange and lemon
flavouring agents. The specifications include description and physical appearance, colour,
odour, identification (IR), water content and tests for microbial quality. Details of the
individual components of the orange, strawberry and lemon flavouring agents have been
submitted. Evidence of conformity with the flavour specifications has been provided.
Suitable assurances have been given that all of the excipients used in the manufacture of both
strengths of Amoclan suspensions are of non-animal origin.
IMMEDIATE PACKAGING
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
9
The product is packed in 125 ml, amber, Type III glass bottles with white aluminium tamperproof screw caps with EPE/PE liner. Each bottle is packed in an outer cardboard box with an
enclosed polystyrene spoon.
Satisfactory descriptions and specifications proposed for routine use have been provided.
Satisfactory evidence of conformity with pharmacopoeial guidance has been presented.
MANUFACTURE/PROCESS VALIDATION
Both strengths of the proposed product are to be manufactured at a site for which the
suitability of manufacture and assembly of non-sterile co-amoxiclav formulations has been
confirmed. Typical production batch sizes have been stated. The manufacturing process is
relatively straightforward and involves blending and sieving the dry ingredients. The final
blend is then filled into the specified glass bottles. The entire manufacturing process is
carried out under controlled humidity and temperature.
Details of in-process controls have been provided and are satisfactory. Process validation data
reported for 3 full-scale production batches of each strength of the proposed product
demonstrated that the manufacturing process is capable of producing products that comply
with the specified quality attributes and that the batches are of reproducible quality.
CONTROL TESTS ON INTERMEDIATE PRODUCTS
Before being filled into the specified containers, the final powder blend is tested for
appearance, pH after reconstitution, water content, density after reconstitution, assay, particle
size analysis and tapped bulk density.
CONTROL TESTS ON FINISHED PRODUCTS
Details of the proposed routine Finished Product Specifications at release and end of shelf
lifehave been provided and are satisfactory.
Batch analytical data have been provided for three full-scale production batches of each
strength of the proposed product. Reported data demonstrated full compliance with the
proposed finished product release specifications.
ANALYTICAL METHODS
The HPLC/UV method proposed for identification and assay of amoxicillin and clavulanic
acid is the USP-HPLC assay method applied to amoxicillin and clavulanate potassium for
oral suspension. The method has been adequately validated with respect to linearity,
accuracy, precision and repeatability and its stability-indicating capability has been
confirmed. The composition of the placebo used has been defined.
The proposed ‘in house’ HPLC-gradient elution related substances method has been based on
the USP and Ph Eur HPLC assay methods applied to the bulk drug substance, Amoxicillin
trihydrate. The proposed method has been fully validated with respect to all the named and
unknown related substances due to amoxicillin and potassium clavulanate. Satisfactory
validation data, including typical chromatograms have been provided. Confirmation has been
provided that the cross-validation of the amoxicillin THD and potassium clavulanate working
standards are standardised against the Ph Eur and USP reference standards.
STABILITY
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
10
Stability data were reported for three full-scale production batches of each strength of the
proposed product (125/31 suspension, batch numbers: 5068, 5069 and 5070; 250/62
suspension, batch numbers: 5292, 5293 and 5294) stored in the containers proposed for
marketing at 25° C/60% RH for up to 9 months, 40° C/75%RH for up to 3 months and 30°
C/60% RH for 12 months.
The proposed preparations were tested for appearance of the powder and reconstituted
suspension, initial pH after reconstitution and after one week, water content, density after
reconstitution, sedimentation volume, degradation products of amoxicillin and clavulanic
acid, and assay of amoxicillin and clavulanic acid. Reported analytical data demonstrated
compliance with the proposed finished product shelf life specifications.
The photostability of the proposed product was not specifically addressed, but the intended
immediate packaging, amber glass bottle with aluminium tamper proof screw cap, should
provide adequate light protection for both the powder for oral suspension, as well as the
reconstituted suspension.
BIOAVAILABILITY
A single centre, open, randomised, two-way cross-over, comparative bioequivalence study of
500 mg amoxicillin and 125 mg clavulanic acid, from the test Amoclan 250/62 Sugar Free
Oral Suspension (250 mg amoxicillin/62.5 mg clavulanic acid per 5 ml dose) from Hikma
Pharmaceuticals (B/No: 5292) proposed for marketing and the reference Augmentan Forte
preparation (250 mg amoxicillin/62.5 mg clavulanic acid per 5 ml dose) from SmithKline
Beecham Pharma, Germany (B/No: 56207B), was carried out. Each was given as a single
10-ml dose to 25 healthy adult males (aged 18-24 years) under fasting conditions, with a
washout period of 7 days between the two phases. Twenty four volunteers completed the
study. Plasma samples taken immediately before administration and then at set intervals of
between 25 and 60 minutes up to 8 hours after administration, and were assayed using 2
separate, validated HPLC/UV detection methods to determine AUC, Cmax, Tmax and t½ values
for both clavulanic acid and amoxicillin. Limits of quantification were established for
clavulanic acid and amoxicillin.
The two strengths of the proposed oral suspension formulation have the same qualitative
composition and are completely dose proportional. They are manufactured by the same
finished product manufacturer at the same site, and have similar dissolution profiles. The
pharmacokinetics are linear. Claimed justification for carrying out a bioequivalence study
with only the higher strength preparation is in accordance with CPMP guidance. Results
obtained are summarised as follows.
Summary of amoxicillin pharmacokinetic parameters for Amoclan 250/62 Sugar Free
Oral Suspension (Hikma) and Augmentan Forte Suspension (SKB Pharma, Germany)
(n=24)
Parameter
Cmax (µg/ml)
AUC0→t (µg
hr ml-1)
Treatments
Amoclan 250/62
[test formulation]
(means±SD)
8.42±2.49
17.61±3.81
Augmentan Forte
[ref formulation]
(means±SD)
8.48±2.72
18.35±5.53
90% confidence intervals
(based on parametric testing)
Point
Lower
Upper limit
estimator
limit (%)
(%)
(%)
100
89
113
98
89
109
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
11
AUC0→∞ (µg
hr ml-1)
Tmax (hr)
AUC0→t
/
AUC0→∞ (%)
t½e (hr)
Ke
18.73±3.83
19.90±5.64
1.21±0.32
93.86±2.97
1.28±0.36
93.61±3.17
1.07±0.34
0.70±0.18
1.06±0.28
0.70±0.20
96
86
106
Summary of clavulanic acid pharmacokinetic parameters for Amoclan 250/62 Sugar
Free Oral Suspension (Hikma) and Augmentan Forte Suspension (SKB Pharma,
Germany) (n=24)
Parameter
Cmax (µg/ml)
AUC0→t (µg
hr ml-1)
AUC0→∞ (µg
hr ml-1)
Tmax (hr)
AUC0→t
/
AUC0→∞ (%)
t½e (hr)
Ke
Treatments
Amoclan 250/62
[test
formulation]
(means±SD)
2.79±0.96
6.01±1.48
Augmentan Forte
[ref formulation]
(means±SD)
90% confidence intervals
(based on parametric testing)
Point
Lower
Upper limit
estimator
limit (%)
(%)
(%)
2.79±1.09
5.95±1.87
101
103
90
92
112
115
6.24±1.49
6.24±1.95
102
91
114
1.27±0.76
96.15±1.18
1.24±0.59
95.35±2.75
1.27±0.22
0.56±0.09
1.31±0.41
0.57±0.15
No statistical difference was seen with the branded reference and test generic preparations
with respect to AUC and Cmax. The results reported lie well within the accepted range of 80125% for the rate and extent of absorption required to demonstrate bioequivalence. The
medical assessor has assessed this study and supports the claim that the products are
bioequivalent. The rate of absorption is determined by Cmax, whose results lie between 70143%
Satisfactory Certificates of Analysis were presented for the specified biobatches of test and
reference products.
In the absence of a direct comparison of the test Hikma product with the claimed essentially
similar UK brand leader, evidence has been provided confirming that the German Augmentan
preparation is equivalent to that of the claimed essentially similar UK brand leader,
Augmentin 250/62 SF Oral Suspension (PL 00038/0337).
ESSENTIAL SIMILARITY
Bioequivalence to Augmentan Forte suspension (SKB Pharma, Germany) has been
demonstrated. Comparative analytical data for dissolution rates, amoxicillin and clavulanic
acid assays, and impurity profile reported for the generic Co-amoxiclav sugar free oral
suspensions from the proposed finished product manufacturer and Augmentan suspensions
from SKB Pharma, Germany, indicated pharmaceutical equivalence.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
12
In order to fully address the claim of essential similarity of the generic Co-amoxiclav sugar
free oral suspensions from Hikma to the UK brand leader products, in accordance with article
10.1 of Directive 2001/83, evidence has been provided confirming the equivalence of the
Augmentan oral suspensions (SKB Pharma, Germany) to the Augmentin SF Suspensions
(PLs 00038/0298 & 0337) on the UK market. This information includes details of the
qualitative and quantitative composition in terms of active principles, comparative dissolution
and impurity profiles.
4.
ADMINISTRATIVE DETAILS
PRODUCT LABELLING
All product labelling is satisfactory.
PATIENT INFORMATION LEAFLET
The patient information leaflet is satisfactory.
MAA FORM
Section 1 – Administrative Data
All administrative data is satisfactory.
Section 2 - Structured Marketing Authorisation Information
These details are satisfactory.
Section 3 - Summary of Product Characteristics
The SPC is satisfactory.
Section 4 - Additional Data Requirements
All additional data requirements have been met.
Expert Report
The Expert Report was prepared by a suitably qualified expert. The report presented is a
brief but adequate review of pharmaceutical data submitted by the applicant.
5.
ASSESSOR'S CONCLUSIONS
Product licences may be granted.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
13
PRECLINICAL ASSESSMENT
These are National Standard Abridged applications under article 10.1 of Directive 2001/83
for Amoclan 125/31 or 250/62 Sugar Free Oral Suspension and Co-Amoxiclav 125/31 or
250/62 Sugar Free Oral Suspension. Essential similarity is claimed to Augmentin 125/31 (PL
00038/0298) or 250/62 (PL 00038/0337) Sugar Free Oral Suspensions, first licensed in the
UK in 1992. The active ingredients are amoxicillin (as trihydrate, equivalent to 2.5 or 5gm
amoxycillin) and clavulanic acid (as potassium, equivalent to 0.625 or 1.25gm clavulanic
acid).
These suspensions are indicated for the treatment of infections of the upper and lower
respiratory tract, skin and soft tissue as well as genito-urinary and abdominal infections.
Part III of the submission consists of a poorly presented Preclinical Expert report reviewing
published literature as well as brief statements on existing preclinical data and one peerreviewed publication. The references cited in the Expert report are not included in the
submission.
In spite of the above, there are no preclinical objections to the grant of a Product Licence.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
14
CLINICAL ASSESSMENT
1.
INTRODUCTION
These abridged applications for fixed dose combination suspensions of amoxicillin and
clavulinic acid are presented under article 10.1 of Directive 2001/83, claiming essential
similarity to Augmentin.
2.
BACKGROUND
This combination of amoxycillin and clavulinic acid has a broad spectrum of action, with the
β-lactamase inhibitory action of clavulinic acid extending the range to other strains resistant
to β-lactams.
3.
INDICATIONS
Consistent with cross-reference product. Satisfactory
4.
DOSE & DOSE SCHEDULE
Consistent with cross-reference product. Satisfactory
5.
TOXICOLOGY
No new data submitted
6.
CLINICAL PHARMACOLOGY
Th applicant has carried out a comparative bioequivalence trial against the cross-reference
product. This was a single centre, randomised, two way comparison of 500mg amoxicillin
and 125mg clavulinic acid from 2x5ml doses of Amoclan 250/62 suspension and 2x5ml
doses of Augmentin suspension.
Twenty-six subjects enrolled in the study. They received an oral dose of 500mg
amoxicillin/125mg clavulinic acid in a randomised order with a 7 day washout between
doses. Results were as follows:
Cmax
AUCo-t
AUCo-inf
Treatments
Test
Amoxicillin
8.42±2.49
17.61±3.81
18.73±3.83
Treatments
Reference
Amoxicillin
8.84±2.72
18.35±5.53
19.90
90% C I
Point
estimate
100
98
96
Lower limit
Upper limit
89
89
86
113
109
106
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
15
Cmax
AUC0-t
AUC0-inf
Treatments
Test
Clavulinic
acid
2.79±0.96
6.01±1.48
6.24±1.49
Treatments
Reference
Clavulinic
acid
2.79±1.09
5.95±
6.24±
90%CI
Point
estimate
Lower limit
Upper limit
101
103
102
90
92
91
112
115
114
These data fell within the 90% CI range of 80-125% and the test product satisfies the criteria
for bioequivalence.
7.
EFFICACY
No new data were submitted and none are required for this application
8.
SAFETY
No new data submitted and none are required for this application
9.
EXPERT REPORTS
The expert report submitted as part of this MA application is satisfactory.
10.
PATIENT INFORMATION LEAFLET (PIL)
Satisfactory
11.
LABELLING
Satisfactory
12.
APPLICATION FORM (MAA)
Satisfactory
13.
SUMMARY OF PRODUCT CHARACTERISTICS (SPC)
Contraindications: Satisfactory
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
16
Special warnings: Satisfactory
Interactions: Satisfactory
Pregnancy: Satisfactory
Driving: Satisfactory
Undesirable effects: Satisfactory
Overdose: Satisfactory
Pharmacology/Pre-clinical safety: Satisfactory
14.
DISCUSSION
The applicant has satisfactorily demonstrated bioequivalence to the reference product
15.
MEDICAL CONCLUSION
Marketing authorisation is recommended
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
17
OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Co-Amoxiclav /Amoclan 125/31 Sugar Free Oral
Suspensions and Co-Amoxiclav/Amoclan 250/62 Sugar Free Oral Suspensions are well defined
and controlled. The specifications and batch analysis results confirm consistancey from batch to
batch. There are no outstanding quality issues that would have a negative impact on the
benefit/risk balance.
PRECLINICAL
No new preclinical data were submitted and none are required for an application of this type.
EFFICACY
No new or unexpected safety concerns arise from this application.
The SPC, PIL and labelling are satisfactory.
RISK BENEFIT ASSESSMENT
The quality of the product is acceptable and no new preclinical or clinical safety concerns have
been identified. The risk benefit ratio is considered to be positive.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
18
CO-AMOXICLAV/AMOCLAN 125/31 SUGAR FREE ORAL SUSPENSION AND
CO-AMOXICLAV/ AMOCLAN 250/62 SUGAR FREE ORAL SUSPENSION
PL 15413/0006-7
STEPS TAKEN FOR ASSESSMENT
1
The MHRA received the marketing authorisation application on 24
July 2000
2
Following assessment of the application the MHRA requested further
information relating to the quality, preclinical and clinical dossiers on
15 November 2000
3
The applicant responded to the MHRA’s requests, providing further
information on the quality, preclinical and clinical dossiers in
November 2002
4
Following assessment of the response the MHRA requested further
information relating to the quality dossier on 18 February 2003
5
The applicant responded to the MHRA’s requests, providing further
information on the quality dossier on 29 September 2005
6
Following assessment of the response the MHRA requested further
information relating to the quality dossier on 29 September 2005
7
The applicant responded to the MHRA’s requests, providing further
information on the quality dossier on 23 January 2006
8
Following assessment of the response the MHRA requested further
information relating to the quality dossier on 17 May 2006
9
The applicant responded to the MHRA’s requests, providing further
information on the quality dossier on 12 July 2006
10
Following assessment of the response the MHRA requested further
information relating to the quality dossier on 12 July 2006
11
The applicant responded to the MHRA’s requests, providing further
information on the quality dossier on 17 July 2006
12
The application was determined on 1 August 2006
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
19
SUMMARY OF PRODUCT CHARACTERISTICS
Summary of product characteristics for Amoclan 125/31.25mg Sugar Free Oral
Suspension (Co-Amoxiclav), Co-Amoxiclav 125/31.25mg Sugar Free Oral Suspension
(PL 15413/0006):
1
NAME OF THE MEDICINAL PRODUCT
Amoclan 125/31.25mg Sugar Free Oral Suspension
and Co-Amoxiclav 125/31.25mg Sugar Free Oral Suspension
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml dose of the reconstituted suspension contains 125mg amoxicillin and 31.25mg
clavulanic acid. The amoxicillin is present as amoxicillin trihydrate and the clavulanic acid
is present as potassium clavulanate.
See section 6.1 for excipients
3
PHARMACEUTICAL FORM
White to off-white fruity flavoured powder for oral suspension.
After reconstitution, Amoclan 125/31.25mg Sugar Free Oral Suspension is an off-white
suspension with fruity flavour.
4
CLINICAL PARTICULARS
4.1
Therapeutic indications
Amoclan 125/31.25mg sugar free oral suspension is an antibiotic agent with a notable
broad spectrum of activity against the commonly occurring bacterial pathogens in general
practice and hospitals. The  β-lactamase inhibitory action of clavulanate extends the
spectrum of amoxicillin to embrace a wide range of organisms, including many resistant to
other  β- lactam antibiotics. Amoclan/Co-amoxiclav oral suspensions are indicated for short
term treatment of bacterial infections at the following sites when amoxicillin resistant βlactamase producing strains are suspected as the cause. In other situations, amoxicillin
alone should be considered.
Amoclan 125/31.25mg Sugar Free Oral Suspension is used at the following sites:
- Upper respiratory tract infections (including ENT), e.g., recurrent tonsillitis, sinusitis,
otitis media.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
20
These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae*,
and Moraxella catarrhalis* and Streptocococcus pyogenes.
- Lower respiratory tract infections, e.g., acute exacerbations of chronic bronchitis
(especially if considered severe), bronchopneumonia.
These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae*,
and Moraxella catarrhalis*.
- Genito-urinary tract and abdominal infections, e.g., cystitis (especially when recurrent or
complicated - excluding prostatitis), septic abortion, pelvic or puerperal sepsis, intraabdominal sepsis. These infections are often caused by Enterobacteriacea* (mainly
Escherichia coli*), Enterococcus species* and Staphylococcus saprophyticus.
- Skin and soft tissue infections Infections in particular cellulitis, animal bites, severe dental
abscess with spreading cellulitis.
These infections are often caused by Staphylococcus aureus*, Streptococcus pyogenes and
Bacteroides species*:
Organisms sensitive to Amoclan 125/31.25mg Sugar Free Oral Suspension are listed in the
“Pharmacological Properties” section.
* Some members of these species of bacteria produce β-lactamase, rendering them
insensitive to amoxicillin alone.
- Mixed infections caused by amoxicillin-susceptible organisms in conjunction with
Amoclan 125/31.25mg sugar free oral suspension- susceptible  β-lactamase producing
organisms may be treated with Amoclan 125/31.25mg sugar free oral suspension. These
infections should not require the addition of another antibiotic resistant to β- lactamases.
4.2
Posology and method of administration
Usual dosage for treatment of infection
Children under 12 years of age: The usual recommended daily dosage is 25mg/kg/day* in
divided doses every eight hours. The table below presents guidance for children.
Amoclan 125/31.25mg Sugar Free Oral Suspension
Under 1 year 25mg/kg/day*, for example a 7.5kg child would require 2ml of Amoclan
125/31.25mg Sugar Free Oral Suspension three times a day.
1-6 years (10-18kg): 5ml Amoclan 125/31.25mg Sugar Free Oral Suspension three times a
day.
Over 6 years (18-40kg): 5ml Amoclan 250/62.5mg Sugar Free Oral Suspension three times
a day
In more serious infections the dosage may be increased up to 50mg/kg/day in divided doses
every eight hours.
*Each 25mg Amoclan provides 20mg amoxicillin and 5mg clavulanic acid.
Dosage in hepatic impairment:
Dose with caution, monitor hepatic function at regular intervals. There are as yet
insufficient data on which to base a dosage recommendation.
Dosage in renal impairment:
Mild impairment (creatinine clearance >30 ml/min); no change in dosage
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
21
Moderate to severe impairment (creatinine clearance <30ml/min); a reduction in dosage
should be made in proportion to the recommendation for adults.
Oral administration:
Shake well before administering a dose of suspension until all the contents are dispersed.
To minimize potential gastrointestinal intolerance, administer at the start of a meal. The
absorption of Amoclan 125/31.25mg Sugar Free Oral Suspension is optimized when taken
at the start of a meal. Duration of therapy should be appropriate to the indication and
should not exceed 14 days without review.
4.3
Contraindications
Penicillin hypersensitivity:
Attention should be paid to possible cross-sensitivity with other β-lactam antibiotics, e.g.,
cephalosporins.
A previous history of Amoclan 125/31.25mg Sugar Free Oral Suspension or penicillin-associated
jaundice/hepatic dysfunction.
4.4
Special warnings and precautions for use
Before initiating therapy with Amoclan 125/31.25mg Sugar Free Oral Suspension careful
inquiry should be made concerning previous hypersensitivity reaction to any penicillins or
cephalosporins. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions
have been reported in patients on penicillin therapy. These reactions are more likely to
occur in individuals with a history of penicillin hypersensitivity (see Contraindications).
Cholestatic jaundice, which may be severe, but is usually reversible, has been reported.
Signs and symptoms may not become apparent for several weeks after treatment has
ceased.
Erythematous rashes have been associated with glandular fever in patients receiving
amoxicillin.
Amoclan 125/31.25mg Sugar Free Oral Suspension should be used with care in patients
with hepatic dysfunction. Dosage should be adjusted in patients with moderate or severe
renal impairment.
Amoclan 125/31.25mg Sugar Free Oral Suspension should be avoided if infectious
mononucleosis is suspected since the occurrence of a morbilliform rash has been associated
with this condition following the use of amoxicillin.
In patients with reduced urine output, crystalluria has been observed very rarely,
predominantly with parenteral therapy. During the administration of high doses of
amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to
reduce the possibility of amoxicillin crystalluria (see Overdose). In patients with renal
impairment, dosage should be adjusted according to the degree of impairment (see
Posology and method of administration).
Prolonged use of an anti-infective agent may occasionally result in overgrowth of nonsusceptible organisms.
This medicinal product contains strawberry powder flavour, which contains small amounts
of ethanol and benzyl alcohol.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
22
4.5
Interaction with other medicinal products and other forms of interaction
Concomitant use of allopurinol during treatment with amoxicillin can increase the
likelihood of allergic skin reactions. There are no data on the concomitant use of Amoclan
and allopurinol.
Prolongation of bleeding time and prothrombin time have been reported in some patients
receiving Amoclan 125/31.25mg Sugar Free Oral Suspension. Amoclan 125/31.25mg
Sugar Free Oral Suspension should be used with care in patients on anticoagulation
therapy.
In common with other broad spectrum antibiotics Amoclan 125/31.25mg sugar free oral suspension
may reduce the efficacy of oral contraceptives and patients should be warned accordingly.
4.6
Pregnancy and lactation
Reproduction studies performed in pregnant animals (rats and mice) with orally and
parenterally administered Amoclan 125/31.25mg Sugar Free Oral Suspension have shown
no teratogenic effects. There is limited information on the use of Amoclan 125/31.25mg
Sugar Free Oral Suspension in human pregnancy. As with all medicines use should be
avoided in pregnancy especially during the first trimester, unless considered essential by
the physician.
Amoclan 125/31.25mg Sugar Free Oral Suspension may be administered during the period of
lactation. With the exception of the risk of sensitisation associated with the excretion of trace
quantities in breast milk, there are no known detrimental effects for the breast-fed infant.
4.7
Effects on ability to drive and use machines
Not applicable
4.8
Undesirable effects
Undesirable effects, as with amoxicillin, are uncommon and mainly of mild and transitory
nature.
Gastrointestinal reactions: diarrhoea, indigestion, nausea, vomiting and mucocutaneous
candidiasis have been reported. Antibiotic-associated colitis (including pseudomembranous
colitis and haemorrhagic colitis) has been reported rarely. Nausea, although uncommon, is
more often associated with higher oral dosages. If gastrointestinal side effects occur with
oral therapy, they may be reduced by taking Amoclan 125/31.25mg Sugar Free Oral
Suspension at the start of meals.
As with other antibiotics, the incidence of gastrointestinal reactions may be raised in
children under two years. In clinical trials, however, only 4% of children under two years
were withdrawn from treatment.
Superficial tooth discolouration has been reported rarely, mostly with suspension, it can
usually be removed by brushing.
Genito-urinary effects: vaginal itching, soreness and discharge may occur.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
23
Hepatic effects: moderate and asymptomatic rises in AST and/or ALT and alkaline
phosphates have been reported occasionally. Hepatitis and cholestatic jaundice have been
reported rarely. These hepatic reactions have been reported more commonly with Amoclan
125/31.25mg Sugar Free Oral Suspension than any other penicillins.
After Amoclan 125/31.25mg Sugar Free Oral Suspension hepatic reactions have been
reported more frequently in males and elderly patients, particularly over 65 years. The risk
increases with duration of treatment longer than 14 days. These reactions have been rarely
reported in children.
Signs and symptoms usually occur during or shortly after treatment but in some cases may
occur until several weeks after treatment has ended. Hepatic reactions are usually reversible
but they may be severe and very rarely, deaths have been reported.
Hypersensitivity reactions: urticartical and erythematous rashes sometimes occur. Rarely
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and bullous
exfoliative dermatitis, serum sickness-like syndrome and hypersensitivity vasculitis have
been reported. Treatment should be discontinued if one of these disorders occur. In
common with other β-lactam antibiotics angioedema and anaphylaxis have been reported,
interstitial nephritis can occur rarely.
Haematological effects: as with other β-lactam transient leucopenia, thrombocytopenia and
haemolytic anaemia have been reported rarely. Prolongation of bleeding time and
prothrombin time has also been reported rarely (see interaction with other medicaments and
other forms of interaction section).
CNS effect: CNS effects have been seen very rarely. These include: reversible
hyperactivity, dizziness, headache and convulsions. Convulsions may occur with impaired
renal function or in those receiving high doses.
Renal and urinary tract disorders:
Crystalluria has been reported very rarely (see Overdose).
4.9
Overdose
Problems of overdosage with Amoclan 125/31.25mg Sugar Free Oral Suspension are
unlikely to occur. If encountered gastrointestinal symptoms and disturbances of the fluid
and electrolyte balances may be evident. They may be treated symptomatically with
attention to the water/ electrolyte balance. Amoclan 125/31.25mg Sugar Free Oral
Suspension may be removed from the circulation by haemodialysis.
Amoxicillin crystalluria, in some cases leading to renal failure, has been observed see
Special warnings and precautions for use).
5
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC code: J01CR02
Pharmacotherapeutic group: Combination of penicillins including β–lactamase inhibitors
Amoclan 125/31.25mg Sugar Free Oral Suspension is an antibiotic agent with a notably
broad spectrum of activity against the commonly occurring bacterial pathogens in general
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
24
ORAL SUSPENSION, PL15413/0006-7
practice and hospital. The beta lactamase inhibitory action of clavulanate extends the
spectrum of amoxicillin to embrace a wider range of organisms, including many resistant to
other beta lacatamase antibiotics.
Resistance to many antibiotics is caused by bacterial enzymes, which destroy the antibiotic
before it can act on the pathogen. The clavulanate in Amoclan 125/31.25mg Sugar Free
Oral Suspension anticipates this defence mechanism by blocking the β-lactamase enzymes,
thus rendering the organisms sensitive to amoxicillin’s rapid bactericidal effect at
concentrations readily attainable in the body. Clavulanate by itself has little antibacterial
activity; however, in association with amoxicillin as Amoclan 125/31.25mg Sugar Free
Oral Suspension, it produces an antibiotic agent of broad spectrum with application in
hospital and general practice. Amoclan 125/31.25mg Sugar Free Oral Suspension is
bactericidal to a wide range of organisms including:
Gram-positive
Aerobes: Enterococcus faecalis*, Enterococcus faecium*, Streptococcus pneumoniae,
Staphlococcus aureus*, coagulase-negative Staphylococci (including Staphylococcus
epidermidis), Corynebacterium species, Bacillus anthracis*, Listeria monocytogenes.
Anaerobes : Clostridium species, Peptococcus species, Peptostreptococcus.
Gram-negative
Aerobes: Haemophilus influenzae*, Proteus mirabilis*, Proteus vulgaris*, Escherichia
coli*, Klebsiella species*, Moraxella catarrhalis*, (Branhamella catarrhalis), Shigella
species*, Bordetella pertussis, Brucella species, Neisseria gonorrhoeae*, Neisseria
meningitidis*, Vibrio cholerae, Pasteurella multocida, Salmonella species*.
Anaerobes: Bacteroides species* including B.fragilis
* Some members of these species of bacteria produce beta lactamase, rendering them
insensitive to amoxicillin alone.
5.2
Pharmacokinetic properties
The pharmacokinetics of the two components of Amoclan 125/31.25mg Sugar Free Oral
Suspension are closely matched. Peak serum levels of both occur about one hour after oral
administration. Absorption of Amoclan 125/31.25mg sugar free oral suspension is
optimised at the start of a meal. Both clavulanate and amoxicillin have low levels of serum
binding; about 70% remains free in serum.
Doubling the dosage of Amoclan 125/31.25mg Sugar Free Oral Suspension approximately
doubles the serum levels achieved.
5.3
Preclinical safety data
Not relevant.
6
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Xanthan gum
Succinic acid
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
25
Colloidal silicon dioxide
Sodium saccharin
Hydroxypropyl methyl cellulose
Strawberry powder flavour (containing benzyl alcohol and ethanol)
Orange powder flavour
Lemon powder flavour
Silicon dioxide
6.2
Incompatibilities
None
6.3
Shelf life
Dry powder: 18 months
Reconstituted suspension: 7 days
6.4
Special precautions for storage
Storage conditions of the dry powder: Do not store at temperatures above 25oC.
Store in the original container. Keep the container tightly closed.
Storage of the suspension after reconstitution: Store at 2oC-8oC. Do not freeze.
6.5
Nature and contents of container
125ml amber Type III glass bottle with white aluminium tamper proof screw cap
containing 13.15gram powder for oral suspension to produce 100ml on reconstitution with
water.
6.6
Special precautions for disposal
Invert bottle and shake powder loose. Add 92 ml of potable water and shake until all
contents are dispersed. Shake well before use. This should be carried out at time of
dispensing.
7
MARKETING AUTHORISATION HOLDER
Hikma Farmaceutica
Cruzamento de vila verde
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
26
Estrada Nacional 9
Fervenca, Sintra
Portugal
8
MARKETING AUTHORISATION NUMBER(S)
PL15413/0006
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/08/2006
10
DATE OF REVISION OF THE TEXT
01/08/2006
Summary of product characteristics for Amoclan 250/62.5mg Sugar Free Oral
Suspension (Co-Amoxiclav), Co-Amoxiclav 250/62.5mg Sugar Free Oral Suspension
(PL 15413/0007):
1
NAME OF THE MEDICINAL PRODUCT
Amoclan 250/62.5mg Sugar Free Oral Suspension
and Co-Amoxiclav 250/62.5mg Sugar Free Oral Suspension
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml dose of the reconstituted suspension contains 250mg amoxicillin and 62.5mg
clavulanic acid. The amoxicillin is present as amoxicillin trihydrate and the clavulanic acid
is present as potassium clavulanate.
See section 6.1 for excipients
3
PHARMACEUTICAL FORM
White to off-white fruity flavoured powder for oral suspension.
After reconstitution, Amoclan 250/62.5mg Sugar Free Oral Suspension is an off-white
suspension with fruity flavour.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
27
4
CLINICAL PARTICULARS
4.1
Therapeutic indications
Amoclan 250/62.5mg sugar free oral suspension is an antibiotic agent with a notable broad
spectrum of activity against the commonly occurring bacterial pathogens in general
practice and hospitals. The β-lactamase inhibitory action of clavulanate extends the
spectrum of amoxicillin to embrace a wide range of organisms, including many resistant to
other β- lactam antibiotics.
Amoclan/Co-amoxiclav oral suspensions are indicated for short term treatment of bacterial
infections at the following sites when amoxicillin resistant β-lactamase producing strains
are suspected as the cause. In other situations, amoxicillin alone should be considered.
Amoclan 250/62.5mg Sugar Free Oral Suspension is used at the following sites:
- Upper respiratory tract infections (including ENT), e.g., recurrent tonsillitis, sinusitis,
otitis media.
These infections are often caused by Streptococcus pneumoniae, Haemophilus
influenzae*,and Moraxella catarrhalis* and Streptocococcus pyogenes.
- Lower respiratory tract infections, e.g., acute exacerbations of chronic bronchitis
(especially if considered severe), bronchopneumonia.
These infections are often caused by Streptococcus pneumoniae, Haemophilus influenzae*,
and Moraxella catarrhalis*.
- Genito-urinary tract and abdominal infections, e.g., cystitis (especially when recurrent or
complicated - excluding prostatitis), septic abortion, pelvic or puerperal sepsis, intraabdominal sepsis. These infections are often caused by Enterobacteriacea* (mainly
Escherichia coli*), Enterococcus species* and Staphylococcus saprophyticus.
- Skin and soft tissue infections: after animal bites, severe dental abscess with spreading
cellulitis.
These infections are often caused by Staphylococcus aureus*, Streptococcus pyogenes and
Bacteroides species*.
A comprehensive list of sensitive organisms provided in the pharmacological properties
section.
* Some members of these species of bacteria produce β-lactamase, rendering them
insensitive to amoxicillin alone.
Mixed infections caused by amoxicillin-susceptible organisms in conjunction with
Amoclan 250/62.5mg sugar free oral suspension- susceptible β-lactamase producing
organisms may be treated with Amoclan 250/62.5mg sugar free oral suspension. These
infections should not require the addition of another antibiotic resistant to β- lactamases.
4.2
Posology and method of administration
Usual dosage for treatment of infection
Children under 12 years of age: The usual recommended daily dosage is 25mg/kg/day* in
divided doses every eight hours. The table below presents guidance for children.
Amoclan 250/62.5mg Sugar Free Oral Suspension
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
28
Under 1 year 25mg/kg/day*, for example a 7.5kg child would require 2ml of Amoclan
125/31.25mg Sugar Free Oral Suspension three times a day.
1-6 years (10-18kg) - 5ml Amoclan 125/31.25mg Sugar Free Oral Suspension three times a
day.
Over 6 years (18-40kg) - 5ml Amoclan 250/62.5mg Sugar Free Oral Suspension three
times a day
In more serious infections the dosage may be increased up to 50mg/kg/day in divided doses
every eight hours.
*Each 25mg Amoclan provides 20mg amoxicillin and 5mg clavulanic acid.
Dosage in hepatic impairment:
Dose with caution, monitor hepatic function at regular intervals. There are as yet
insufficient data on which to base a dosage recommendation.
Dosage in renal impairment:
Mild impairment (creatinine clearance >30 ml/min); no change in dosage
Moderate to severe impairment (creatinine clearance <30ml/min); a reduction in dosage
should be made in proportion to the recommendation for adults.
Oral administration :
Shake well before administering a dose of suspension until all the contents are dispersed
To minimise potential gastrointestinal intolerance, administer at the start of a meal.
Amoclan 250/62.5mg Sugar Free Oral Suspension may be taken without regard to meals;
however, absorption of potassium clavulanate is optimised with Amoclan 250/62.5mg
Sugar Free Oral Suspension is administered at the start of a meal. Treatment should not be
extended beyond 14 days without review.
4.3
Contraindications
Use in patients with a history of hypersensitivity to penicillins including semisynthetic
penicillins and cephalosporins.
Amoclan is contra-indicated in patients with a previous history of Amoclan associated
jaundice/hepatic dysfunction.
4.4
Special warnings and precautions for use
Before initiating therapy with Amoclan 250/62.5mg Sugar Free Oral Suspension careful
inquiry should be made concerning previous hypersensitivity reaction to any penicillins or
cephalosporins. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions
have been reported in patients on penicillin therapy. These reactions are more likely to
occur in individuals with a history of penicillin hypersensitivity (see Contraindications).
Cholestatic jaundice, which may be severe, but is usually reversible, has been reported.
Signs and symptoms may not become apparent for several weeks after treatment has
ceased.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
29
Erythematous rashes have been associated with glandular fever in patients receiving
amoxicillin.
Amoclan 250/62.5mg Sugar Free Oral Suspension should be used with care in patients with
hepatic dysfunction. Dosage should be adjusted in patients with moderate or severe renal
impairment.
Amoclan 250/62.5mg Sugar Free Oral Suspension should be avoided if infectious
mononucleosis is suspected since the occurrence of a morbilliform rash has been associated
with this condition following the use of amoxicillin.
In patients with reduced urine output, crystalluria has been observed very rarely,
predominantly with parenteral therapy. During the administration of high doses of
amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to
reduce the possibility of amoxicillin crystalluria (see Overdose). In patients with renal
impairment, dosage should be adjusted according to the degree of impairment (see
Posology and method of administration).
Prolonged use of an anti-infective agent may occasionally result in overgrowth of nonsusceptible organisms.
This medicinal product contains strawberry powder flavour, which contains small amounts
of ethanol and benzyl alcohol.
4.5
Interaction with other medicinal products and other forms of interaction
Concomitant use of allopurinol during treatment with amoxicillin can increase the
likelihood of allergic skin reactions. There are no data on the concomitant use of Amoclan
and allopurinol.
Prolongation of bleeding time and prothrombin time have been reported in some patients
receiving Amoclan 250/62.5mg Sugar Free Oral Suspension. Amoclan 250/62.5mg Sugar
Free Oral Suspension should be used with care in patients on anticoagulation therapy.
In common with other broad spectrum antibiotics Amoclan 250/62.5mg sugar free oral
suspension may reduce the efficacy of oral contraceptives and patients should be warned
accordingly.
Concurrent use of allopurinol during treatment with Amoclan 250/62.5mg Sugar Free Oral
Suspension, can increase the likelihood of allergic reaction.
4.6
Pregnancy and lactation
Reproduction studies performed in pregnant animals (rats and mice) with orally and
parenterally administered Amoclan 250/62.5mg Sugar Free Oral Suspension have shown
no teratogenic effects. There is limited information on the use of Amoclan 250/62.5mg
Sugar Free Oral Suspension in human pregnancy. As with all medicines use should be
avoided in pregnancy especially during the first trimester, unless considered essential by
the physician.
Amoclan 250/625.mg Sugar Free Oral Suspension may be administered during the period
of lactation. With the exception of the risk of sensitisation associated with the excretion of
trace quantities in breast milk, there are no known detrimental effects for the breast-fed
infant.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
30
4.7
Effects on ability to drive and use machines
Not applicable
4.8
Undesirable effects
Undesirable effects, as with amoxicillin, are uncommon and mainly of mild and transitory
nature.
Gastrointestinal reactions: diarrhoea, indigestion, nausea, vomiting and candidiasis have
been reported. Antibiotic-associated colitis (including pseudomembranous colitis and
haemorrhagic colitis) has been reported rarely. Nausea, although uncommon, is more often
associated with higher oral dosages. If gastrointestinal side effects occur with oral therapy,
they may be reduced by taking Amoclan 250/62.5mg Sugar Free Oral Suspension at the
start of meals.
As with other antibiotics, the incidence of gastrointestinal reactions may be raised in
children under two years. In clinical trials, however, only 4% of children under two years
were withdrawn from treatment.
Superficial tooth discolouration has been reported rarely, mostly with suspension, it can
usually be removed by brushing.
Genito-urinary effects: vaginal itching, soreness and discharge may occur.
Hepatic effects: moderate and asymptomatic rises in AST and/or ALT and alkaline
phosphates have been reported occasionally. Hepatitis and cholestatic jaundice have been
reported rarely. These hepatic reactions have been reported more commonly with Amoclan
250/62.5mg Sugar Free Oral Suspension than any other penicillins. After Amoclan
250/62.5mg Sugar Free Oral Suspension hepatic reactions have been reported more
frequently in males and elderly patients, particularly over 65 years. The risk increases with
duration of treatment longer than 14 days. These reactions have been rarely reported in
children.
Signs and symptoms usually occur during or shortly after treatment but in some cases may
occur until several weeks after treatment has ended. Hepatic reactions are usually reversible
but they may be severe and very rarely, deaths have been reported.
Hypersensitivity reactions: urticartical and erythematous rashes sometimes occur. Rarely
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and bullous
exfoliative dermatitis, serum sickness-like syndrome and hypersensitivity vasculitis have
been reported. Treatment should be discontinued if one of these disorders occur. In
common with other β-lactam antibiotics angioedema and anaphylaxis have been reported,
interstitial nephritits can occur rarely.
Haematological effects: as with other β-lactam transient leucopenia, thrombocytopenia and
haemolytic anaemia have been reported rarely. Prolongation of bleeding time and
prothrombin time has also been reported rarely (see interaction with other medicaments and
other forms of interaction section).
CNS effect: CNS effects have been seen very rarely. These include: reversible
hyperactivity, dizziness, headache and convulsions. Convulsions may occur with impaired
renal function or in those receiving high doses.
Renal and urinary tract disorders:
Crystalluria has been reported very rarely (see Overdose).
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
31
4.9
Overdose
Problems of overdosage with Amoclan 250/625.mg Sugar Free Oral Suspension are
unlikely to occur. If encountered gastrointestinal symptoms and disturbances of the fluid
and electrolyte balances may be evident. They may be treated symptomatically with
attention to the water/ electrolyte balance. Amoclan 250/625.mg Sugar Free Oral
Suspension may be removed from the circulation by haemodialysis.
Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see
Special warnings and precautions for use).
5
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC code: J01CR02
Pharmacotherapeutic group: Combination of penicillins including β–lactamase inhibitors
Amoclan 250/625.mg Sugar Free Oral Suspension is an antibiotic agent with a notably
broad spectrum of activity against the commonly occurring bacterial pathogens in general
practice and hospital. The beta lactamase inhibitory action of clavulanate extends the
spectrum of amoxicillin to embrace a wider range of organisms, including many resistant to
other beta lacatamase antibiotics.
Resistance to many antibiotics is caused by bacterial enzymes, which destroy the antibiotic
before it can act on the pathogen. The clavulanate in Amoclan 250/62.5mg Sugar Free Oral
Suspension anticipates this defence mechanism by blocking the β- lactamase enzymes, thus
rendering the organisms sensitive to amoxicillin’s rapid bactericidal effect at
concentrations readily attainable in the body. Clavulanate by itself has little antibacterial
activity; however, in association with amoxicillin as Amoclan 250/62.5mg Sugar Free Oral
Suspension, it produces an antibiotic agent of broad spectrum with application in hospital
and general practice. Amoclan 250/62.5mg Sugar Free Oral Suspension is bactericidal to a
wide range of organisms including:
Gram-positive
Aerobes: Enterococcus faecalis*, Enterococcus faecium*, Streptococcus pneumoniae,
Staphlococcus aureus*, coagulase-negative Staphylococci (including Staphylococcus
epidermidis), Corynebacterium species, Bacillus anthracis*, Listeria monocytogenes.
Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus.
Gram-negative
Aerobes: Haemophilus influenzae*, Proteus mirabilis*, Proteus vulgaris*, Escherichia
coli*, Klebsiella species*, Moraxella catarrhalis*, (Branhamella catarrhalis), Shigella
species*, Bordetella pertussis, Brucella species, Neisseria gonorrhoeae*, Neisseria
meningitidis*, Vibrio cholerae, Pasteurella multocida, Salmonella species*.
Anaerobes: Bacteroides species* including B.fragilis
* Some members of these species of bacteria produce beta lactamase, rendering them
insensitive to amoxicillin alone.
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
32
5.2
Pharmacokinetic properties
The pharmacokinetics of the two components of Amoclan 250/62.5mg Sugar Free Oral
Suspension are closely matched. Peak serum levels of both occur about one hour after oral
administration. Absorption of Amoclan 250/62.5mg sugar free oral suspension is optimised
at the start of a meal. Both clavulanate and amoxicillin have low levels of serum binding;
about 70% remains free in serum.
Doubling the dosage of Amoclan 250/62.5mg Sugar Free Oral Suspension approximately
doubles the serum levels achieved.
5.3
Preclinical safety data
Not relevant.
6
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Xanthan gum
Succinic acid
Colloidal silicon dioxide
Sodium saccharin
Hydroxypropyl methyl cellulose
Strawberry powder flavour (containing benzyl alcohol and ethanol)
Orange powder flavour
Lemon powder flavour
Silicon dioxide
6.2
Incompatibilities
None
6.3
Shelf life
Dry powder: 18 months
Reconstituted suspension: 7 days
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
33
6.4
Special precautions for storage
Storage conditions of the dry powder: Do not store at temperatures above 25oC.
Store in the original container. Keep the container tightly closed.
Storage of the suspension after reconstitution: Store at 2oC-8oC. Do not freeze.
6.5
Nature and contents of container
125ml amber Type III glass bottle with white aluminium tamper proof screw cap
containing 17.0gram powder for oral suspension to produce 100ml on reconstitution with
water.
6.6
Special precautions for disposal
Invert bottle and shake powder loose. Add 90 ml of potable water and shake until all
contents are dispersed. Shake well before use. This should be carried out at time of
dispensing.
7
MARKETING AUTHORISATION HOLDER
Hikma Farmaceutica
Cruzamento de vila verde
Estrada Nacional 9
Fervenca, Sintra
Portugal
8
MARKETING AUTHORISATION NUMBER(S)
PL15413/0007
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/08/2006
10
DATE OF REVISION OF THE TEXT
01/08/2006
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
34
PATIENT INFORMATION LEAFLET
Patient Information Leaflet for for Amoclan 125/31.25mg Sugar Free Oral Suspension (CoAmoxiclav), Co-Amoxiclav 125/31.25mg Sugar Free Oral Suspension (PL 15413/0006):
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
35
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
36
Patient Information Leaflet for Amoclan 250/62.5mg Sugar Free Oral Suspension (CoAmoxiclav), Co-Amoxiclav 250/62.5mg Sugar Free Oral Suspension (PL 15413/0007):
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
37
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
38
LABELLING
PL 15413/0006:
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
39
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
40
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
41
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
42
PL15413/0007:
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
43
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
44
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
45
CO-AMOXICLAV 125/31 & AMOCLAN 125/31 AND CO-AMOXICLAV 250/62 & AMOCLAN 250/62 SUGAR FREE
ORAL SUSPENSION, PL15413/0006-7
46
`