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PUBLIC ASSESSMENT REPORT
of the Medicines Evaluation Board
in the Netherlands
Cefixim Schluttig 200 mg and 400 mg, film-coated tablets
Cefixim Schluttig 100 mg/5 ml, power for oral suspension
Pharma Resources Dr. Schluttig GmbH, Germany
cefixime (as trihydrate)
This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
comments on the registration dossier that was submitted to the MEB and its fellow –organisations in all concerned EU
member states.
It reflects the scientific conclusion reached by the MEB and all concerned member states at the end of the evaluation
process and provides a summary of the grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
latter category as the language in this report may be difficult for laymen to understand.
This assessment report shall be updated by a following addendum whenever new information becomes available.
General information on the Public Assessment Reports can be found on the website of the MEB.
To the best of the MEB’s knowledge, this report does not contain any information that should not have been made
available to the public. The MAH has checked this report for the absence of any confidential information.
EU-procedure number: NL/H/1822/001-003/DC
Registration number in the Netherlands: RVG 106302, 106304-106305
17 November 2011
Pharmacotherapeutic group:
ATC code:
Route of administration:
Therapeutic indication:
Prescription status:
Date of authorisation in NL:
Concerned Member States:
Application type/legal basis:
other beta-lactam antibacterials, third-generation cephalosporins
J01DD08
oral
acute otitis media (AOM); acute bacterial pharyngitis;
uncomplicated acute cystitis; uncomplicated acute gonorrhoea
prescription only
7 September 2011
Decentralised procedure with BG, DE and additionally for 400 mg
and 100 mg/5 ml - IT
Directive 2001/83/EC, Article 10(1)
For product information for healthcare professionals and users, including information on pack sizes and
presentations, see Summary of Product Characteristics (SPC), package leaflet and labelling.
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INTRODUCTION
Based on the review of the quality, safety and efficacy data, the member states have granted a marketing
authorisation for Cefixim Schluttig 200 mg and 400 mg, film-coated tablets, and Cefixim Schluttig 100
mg/5 ml, power for oral suspension from Pharma Resources Dr. Schluttig GmbH. The date of
authorisation was on 7 September 2011 in the Netherlands.
The product is indicated for the treatment of the following infections when caused by susceptible
organisms:
• Acute otitis media (AOM)
• Acute bacterial pharyngitis
• Uncomplicated acute cystitis
• Uncomplicated acute gonorrhoea
The use of cefixime should be reserved for infections in which the causative organism is known or
suspected to be resistant to other commonly used antibacterial agents.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
A comprehensive description of the indications and posology is given in the SPC.
Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts
antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the
synthesis of bacterial cell walls. This leads to bacterial cell lysis and cell death.
This decentralised procedure concerns a generic application claiming essential similarity with the
innovator products Fixim 200 mg and 400 mg capsules and 100 mg/ 5 ml powder for oral solution.
For the application in the Netherlands, historical reference products were chosen: Fixim 200 mg capsules
(NL Licence RVG 13029) and Fixim 100 mg/ 5 ml powder for oral suspension (NL Licence RVG 13475),
which were authorised in the Netherlands by Astellas Pharma Europe B.V. between 1990 and 2006.
For the application in Bulgaria a European Reference Product was chosen: Suprax 200 mg as authorised
in Germany.
For the 400 mg strength, reference is made to the currently authorised innovators Suprax (Germany), and
Cefixoral (Italy). For the application in the Netherlands and Bulgaria the European Reference Product is
Suprax as authorised in Germany.
For the 100 mg/5ml powder for oral solution innovator products are available in Italy and Germany. For
the application in the Netherlands the historical reference product Fixim was chosen, for the application in
Bulgaria reference is made to the European Reference Product Suprax (Germany).
The marketing authorisation is granted based on article 10(1) of Directive 2001/83/EC.
This type of application refers to information that is contained in the pharmacological-toxicological and
clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal
product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological,
pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in
the public domain. Authorisations for generic products are therefore linked to the ‘original’ authorised
medicinal product, which is legally allowed once the data protection time of the dossier of the reference
product has expired. For this kind of application, it has to be demonstrated that the pharmacokinetic profile
of the product is similar to the pharmacokinetic profile of the reference product. To this end the MAH has
submitted three bioequivalence studies in which the pharmacokinetic profile of the product is compared
with the pharmacokinetic profile of the reference product:
- one single dose bioequivalence study under fasting conditions, with the 200 mg tablet using Suprax
200 mg tablet from the UK market as reference
- one single dose bioequivalence study under fasting conditions, with the 400 mg tablet using the Italian
reference Cefixoral 400 mg tablet
- one single dose bioequivalence study under fasting conditions with the 100mg/5ml powder for oral
suspension, using the UK reference product Suprax 100mg/5ml powder for oral suspension.
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A bioequivalence study is the widely accepted means of demonstrating that difference of use of different
excipients and different methods of manufacture have no influence on efficacy and safety. These generic
products can be used instead of their reference product.
No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.
No scientific advice has been given to the MAH with respect to these products and no paediatric
development programme has been submitted, as this is not required for a generic application.
II
II.1
SCIENTIFIC OVERVIEW AND DISCUSSION
Quality aspects
Compliance with Good Manufacturing Practice
The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
this product type at all sites responsible for the manufacturing of the active substance as well as for the
manufacturing and assembly of this product prior to granting its national authorisation.
Active substance
The active substance is cefixime, an established active substance described in the European
Pharmacopoeia (Ph.Eur.*). It is a white or almost white, slightly hygroscopic powder, which is slightly
soluble in water and soluble in methanol. Cefixime corresponds to a semi-synthetic product derived from a
fermentation product.
The CEP procedure is used for the active substance. Under the official Certification Procedures of the
EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can
apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality
of their substance according to the corresponding specific monograph, or the evaluation of reduction of
Transmissible Spongiform Encephalopathy (TSE) risk, according to the new general monograph, or both.
This procedure is meant to ensure that the quality of substances is guaranteed and that these substances
comply with the European Pharmacopoeia.
Manufacturing process
A CEP has been submitted; therefore no details on the manufacturing process have been included.
Quality control of drug substance
The drug substance specification is in line with the Ph.Eur. monograph on cefixime and with the additional
requirements for the highest unknown impurity and residual solvents of the CEP. Moreover, in-house
limits for impurities and particle size were added. The specification is acceptable in view of the various
European guidelines.
Batch analytical data demonstrating compliance with the drug substance specification have been provided
for three commercial-scale batches.
Stability of drug substance
The re-test period for the active substance is 24 months when stored under the stated conditions.
Assessment thereof was part of granting the CEP and has been granted by the EDQM.
* Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
substances are laid down by the authorities of the EU.
Medicinal Product
Film-coated tablets
Composition
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Cefixim Schluttig 200 mg is a white, circular, biconvex film-coated tablet debossed with ‘C’ on one side
and plain surface on the other side.
Cefixim Schluttig 400 mg is a white to off white, film-coated, modified rectangular shaped tablet, having a
partial break line on both sides. The tablet can be divided in equal halves.
The film-coated tablets are packed in Al/PVC-PVdC blisters. For the 400 mg product only, a package of
Al/PVC-Aclar blisters is also available.
The excipients are: anhydrous calcium hydrogen phosphate, pregelatinised starch, microcrystalline
cellulose, colloidal anhydrous silica, magnesium stearate, Opadry White Y-1-7000 containing
hypromellose (E 464), macrogol 400 (E 1520) and titanium dioxide (E 171).
The content of drug substance in the film-coated tablets is about 43%. The compositions of the 200 and
400 mg strengths are not dose proportional.
Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained.
The 400 mg tablet bears a partial break line. A test for subdivision of tablets was performed during
pharmaceutical development, demonstrating that the tablet can be divided into equal halves.
The generic product dissolves faster in 0.1 N HCl than the reference product. Dissolution is similar in pH
4.5 acetate buffer and pH 7.2 phosphate buffer. The difference observed in 0.1 N HCl can be accepted, as
the solubility of cefixime is low at a low pH value. Moreover, the assumption was stated that absorption of
cefixime takes place in the intestinal region based on the tmax of 2 to 6 hours. Most importantly,
bioequivalence was shown in vivo. Pharmaceutical development of the product was adequately
performed.
Manufacturing process
The manufacturing process includes steps of sifting, blending, roll compaction, compression and coating.
The process is considered standard and has been adequately validated according to relevant European
guidelines. The manufacturing process corresponds to a conventional process. Process validation data on
the product was presented for three batches of the minimum and three batches of the maximum
commercial batch size of the 200 mg strength. For the 400 mg film-coated tablets, process validation on
full-scale batches will be performed post authorisation.
Control of excipients
With the exception of the coating material, all excipients are of pharmacopoeial grade. The specifications
are acceptable.
Quality control of drug product
The product specification includes tests for description, identification, identification of colourant, water,
microbial limits, disintegration time, average weight, uniformity of dosage units, dissolution, assay, and
chromatographic purity. The release and shelf-life limits differ with regard to the limits for impurities;
qualified limits were set. The analytical methods were adequately described and validated.
Batch analytical data from the proposed production site were provided on three batches of the minimum
and three batches of the maximum commercial batch size, demonstrating compliance with the release
specification.
Stability of drug product
Stability data on the product has been provided for four batches of commercial batch size which have
been stored at 25°C/60% RH (24 months) and 40°C/75% RH (six months). The conditions used in the
stability studies are according to the ICH stability guideline. The batches were stored in Al/PVC-PVdC
blisters and Al/PVC-Aclar blisters (400 mg only). On the basis of the provided stability data, a shelf life of
18 months has been set. As upward trends are observed at 40°C/75% RH, the storage condition is
restricted to ‘do not store above 25°C’. Photostability studies with the drug product have shown that it is
not necessary to store the drug product in the original package in order to protect from light.
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Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
There are no substances of ruminant animal origin present in the product nor have any been used in the
manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
Powder for oral suspension
Composition
Cefixim Schluttig 100 mg/5 ml is an off-white to pale yellow coloured powder with characteristic odour.
Each 5 ml of reconstituted suspension contains 100 mg cefixime (anhydrous) equivalent to 111.917 mg of
cefixime trihydrate.
The powder for oral suspension is packed in type III molded, amber colored, round glass bottle in bottles
of 50 and 100 mL, closed with plastic child resistant cap. Fill weight is 26.0 and 52.0 g, respectively. A 5
ml syringe dosing device graduated in kg body weight measures is supplied with this pack.
The excipients are: xanthan gum, sodium benzoate, anhydrous colloidal silica, strawberry flavour and
sucrose (2.4 g/5ml).
Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. The development of the manufacturing process has been described in sufficient
detail. The formulation contains the same preservative and flavour as the reference product. The
concentration of the flavour was optimised by a palatability study with volunteers.
Dissolution profiles of the generic and reference product are similar in pH 4.5 acetate buffer and pH 7.2
phosphate buffer. As was observed for the film-coated tablets, the reference product dissolves slower in
0.1 N HCl. This has been sufficiently justified and bioequivalence of test and reference was satisfactorily
demonstrated in vivo. Pharmaceutical development of the product was adequately performed.
Manufacturing process
The manufacturing process includes steps of sifting, milling, roll compaction and final blending. The final
blend is filled in bottles. The manufacturing process of two batches of the minimum commercial batch size
was evaluated with a focus on content uniformity. The manufacturing process corresponds to a
conventional process. Validation data on full-scale batches will be provided post authorisation.
Overage
The formulation contains a 4% overage of the drug substance. The overage is based on the chemical
characterization of the reference product and accelerated stability studies conducted for the reference and
the generic product.
Container closure system
The packaging material is inert and commonly used for oral products. The suitability of the container
closure system was demonstrated during development and stability studies.
Microbiological attributes
Efficacy of antimicrobial preservation was tested according to Ph.Eur. 5.1.3 with 2.5, 5, 10, and 15 mg/5
mL sodium benzoate. All concentrations showed sufficient log reductions. The lowest concentration was
finalised as the lower specification limit.
Control of excipients
With the exception of the strawberry flavour, all excipients are of pharmacopoeial grade. The
specifications are acceptable.
Quality control of drug product
The product specification includes tests for description, identification, uniformity of dosage units, uniformity
of mass of delivered doses, dissolution, pH, water, average net content, assay, preservative content,
antimicrobial effectiveness, related substances, viscosity, redispersibility, and microbial limits. The release
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and shelf life limits differ with regard to the limits for impurities. Compared to the specifications of the
tablets, additional in-house specifications impurities are listed for the powder for oral suspension. The
proposed shelf-life limit of one of these impurities slightly exceeds the applicable identification threshold.
Identification should be attempted post-approval.
The analytical methods were adequately described and validated. Batch analytical data from the proposed
production site were provided on two batches of the minimum commercial batch size, demonstrating
compliance with the release specification.
Stability of drug product
Stability data on the product has been provided for two batches of the minimum commercial batch size
which have been stored at 25°C/60% RH (24 months) and 40°C/75% RH (six months). The conditions
used in the stability studies are according to the ICH stability guideline. The batches were stored in type III
amber coloured glass bottles with child resistant closures.
On the basis of the provided stability data, the claimed shelf life of 24 months is acceptable. The drug
product should be stored below 30°C. Photostability of the product packed in amber glass bottles was
demonstrated under ICH conditions.
In-use stability of the suspension reconstituted with water, was demonstrated for a period of 14 days when
stored below 25°. As there are no data on storage at low temperatures, the suspension should not be
refrigerated or frozen.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
There are no substances of ruminant animal origin present in the product nor have any been used in the
manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
Several commitments have been made with regard to the finished products; these can be found on page
12 of this report.
II.2
Non-clinical aspects
This product is a generic formulation of Suprax, which is available on the European market. No new
preclinical data have been submitted, and therefore the application has not undergone preclinical
assessment. This is acceptable for this type of application.
Environmental risk assessment
The product is intended as a substitute for other identical products on the market. The MAH argued that
approval of this product will not result in an increase in the total quantity of cefixime released into the
environment. However, in the Netherlands no cefixim based medicines are currently registered. This
means that approval of these products will lead to an increase in use. Following EMA guidance, this
warrants an ERA. The MAH committed to submit an Environmental Risk Assessment (ERA) in
accordance with EMA guidance before marketing in the Netherlands.
II.3
Clinical aspects
Clinical pharmacokinetics
For this generic application, the MAH has submitted three bioequivalence studies:
• a single dose bioequivalence study under fasting conditions, with the 200 mg tablet using Suprax 200
mg tablet (Rhone-Poulenc, UK) as reference (Study I)
• a single dose bioequivalence study under fasting conditions, with the 400 mg tablet using Cefixoral
400 mg tablet (A. Menarini, IT) as reference (Study II)
• a single dose bioequivalence study under fasting conditions with the 100 mg/5 ml powder for oral
suspension, using Suprax 100mg/5ml powder for oral suspension (Aventis, UK) as reference (Study
III).
The choice of the reference products
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The choice of the reference products used in the bioequivalence studies has been justified by comparison
of dissolution results and compositions of reference products in different member states.
The formula of the bioequivalence batches is identical to the formula proposed for marketing.
Analytical/statistical methods
The analytical methods have been adequately validated and are considered acceptable for analysis of the
plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical
evaluation are considered acceptable.
Study I - 200 mg film-coated tablet
Design
A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study
was carried out under fasted conditions in 28 healthy male subjects, aged 18-29 years. Each subject
received a single dose (200 mg) of one of the 2 cefixime formulations. The tablet was orally administered
with 240 ml water after an overnight fast. Fasting was continued for 4 hours after dosing. There were 2
dosing periods, separated by a washout period of 7 days.
Blood samples were collected pre-dose at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 16 and 24
hours after administration of the products.
Results
There were 2 drop-outs, as 2 subjects did not report for the check in of Period II. The remaining 26
subjects were included in the pharmacokinetic analysis.
Table 1.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of cefixime under fasted conditions.
Treatment
N=26
Test
25.7 ± 7.6
26.4 ± 7.8
3.01 ± 0.84
4.5(3.5 – 6.0)
3.9 ± 0.6
Reference
26.3 ± 7.3
27.0 ± 7.5
3.02 ± 0.84
4.5 (3.5 – 6.0)
3.9 ± 0.6
*Ratio (90%
CI)
0.98
(0.92-1.03)
0.98
(0.92-1.03)
1.00
(0.95-1.05)
--
--
11.6
11.3
10.1
--
--
CV (%)
AUC0-t
AUC0-∞
Cmax
tmax
µg.h/ml
µg.h/ml
µg/ml
h
t1/2
h
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
half-life
t1/2
*ln-transformed values
The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are in agreement with those
calculated by the MAH and are within the bioequivalence acceptance range of 0.80–1.25. Based on the
pharmacokinetic parameters of cefixime under fasted conditions, it can be concluded that Cefixim
Schluttig 200 mg and Suprax 200 mg tablets are bioequivalent with respect to rate and extent of
absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP Note for Guidance.
Study II - 400 mg film-coated tablet
Design
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A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study
was carried out under fasted conditions in 26 healthy male subjects, aged 19-42 years. Each subject
received a single dose (400 mg) of one of the 2 cefixime formulations. The tablet was orally administered
with 240 ml water after an overnight fast. Fasting was continued for 4 hours after dosing. There were 2
dosing periods, separated by a washout period of 7 days.
Blood samples were taken pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 16 and
24 hours after administration of the products.
Results
One subject was withdrawn before Period II, because of an AE (insect bite reaction). Pharmacokinetic and
statistical analysis was carried out on 25 subjects.
Table 2.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of cefixime under fasted conditions.
Treatment
N=25
Test
57.5 ± 14.3
59.7 ± 15.2
6.18 ± 1.23
5.0(3.5 – 6.5)
4.3 ± 0.5
Reference
55.5 ± 12.3
57.5 ± 12.9
6.11 ± 1.35
4.5 (3.0 – 5.5)
4.3 ± 0.5
*Ratio (90%
CI)
1.03
(0.97-1.10)
1.04
(0.98-1.10)
1.02
(0.97-1.07)
--
--
12.2
12.3
9.7
--
--
CV (%)
AUC0-t
µg.h/ml
AUC0-∞
µg.h/ml
Cmax
µg/ml
tmax
h
t1/2
h
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
*ln-transformed values
The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are in agreement with those
calculated by the MAH and are within the bioequivalence acceptance range of 0.80–1.25. Based on the
pharmacokinetic parameters of cefixime under fasted conditions, it can be concluded that Cefixim
Schluttig 400 mg and Cefixoral 400 mg tablets are bioequivalent with respect to rate and extent of
absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP Note for Guidance.
Study III - 100 mg/5 ml powder for oral suspension
Design
A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study
was carried out under fasted conditions in 24 healthy male subjects, aged 20-41 years. Each subject
received a single dose (100 mg suspension) of one of the 2 cefixime formulations: 5 ml of the
reconstituted powder was administered to the subjects. The administration syringe was rinsed with 10 ml
of water which was also administered to the subjects. In addition, up to a total of 240 ml water was
administered. The formulations were given after an overnight fast. Fasting was continued for 4 hours after
dosing. There were 2 dosing periods, separated by a washout period of 7 days.
Blood samples were taken pre-dose and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 16 and 24
hours after administration of the products.
Results
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One subject was withdrawn before Period II, because this subject tested positive for drug abuse and one
subject did not check in for Period II. Pharmacokinetic and statistical analysis was carried out on 22
subjects.
Table 3.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of cefixime under fasted conditions.
Treatment
N=22
Test
16.9 ± 5.7
17.4 ± 5.8
Reference
16.5 ± 5.0
*Ratio (90%
CI)
CV (%)
AUC0-t
AUC0-∞
Cmax
tmax
µg.h/ml
µg.h/ml
µg/ml
1.85 ± 0.55
h
t1/2
h
4.0(3.0 – 4.5)
4.0 (3.0 – 4.5)
17.0 ± 5.2
1.82 ± 0.53
4.0 ± 0.4
4.1 ± 0.4
1.01
(0.94-1.08)
1.01
(0.94-1.08)
1.01
(0.95-1.08)
--
--
13.4
13.3
12.6
--
--
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax
maximum plasma concentration
tmax
time for maximum concentration
t1/2
half-life
*ln-transformed values
The 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax are in agreement with those
calculated by the MAH and are within the bioequivalence acceptance range of 0.80–1.25. Based on the
pharmacokinetic parameters of cefixime under fasted conditions, it can be concluded that Cefixim
Schluttig 100 mg/5 ml and Suprax 100 mg/5 ml powder for oral suspension are bioequivalent with respect
to rate and extent of absorption, and fulfil the bioequivalence requirements outlined in the relevant CHMP
Note for Guidance.
Cefixime may be taken with or without food. From the literature it is known that food does not interact with
the absorption of cefixime. Therefore, a food interaction study is not deemed necessary. The
bioequivalence studies under fasting conditions are in accordance with CPMP/EWP/QWP/1401/98 Note
for Guidance on the investigation of bioavailability and bioequivalence.
The MEB has been assured that the bioequivalence studies have been conducted in accordance with
acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory
Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).
Clinical efficacy
In this application several reference products are used, including a historical reference product Fixim
(authorised in NL between 1990 and 2006). The assessment of indications and therapeutic used is based
on the indications of historical reference product Fixim, NL supplemented with current data available and
in reference to current CHMP guidelines.
The MAH provided a clinical overview of publications evaluating the efficacy of cefixime in the claimed
indications and other infections.
Acute otitis media
This indication was considered acceptable for cefixime especially in cases due to lactamase-producing
organisms. The proposed limitation by the Applicant “The use of cefixime should be reserved for infections
in which the causative organism is known or suspected to be resistant to other commonly used
antibacterial agents or when treatment failure may carry significant risk” could be supported. In the 2nd
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round 4 publications were submitted providing further support for the indication acute otitis media. There is
however, a tendency in the comparative trials towards cefixime being less efficacious in patients infected
with S. pneumoniae (one of) the most relevant pathogens.
Acute bacterial pharyngitis
Overall, there is reasonable beneficial evidence in support of the use of cefixime in children and adults
with pharyngitis, although some of the submitted documentation comes from an old review and a metaanalysis and methodology of the mentioned studies can therefore not be assessed. Dosing regimes for
both populations are not clear. More evidence is needed to determine the correct dosage for this
indication both in children and adults. The applicant should submit the relevant original, prospective,
comparative studies from the review and meta-analysis for the efficacy of cefixime in pharyngitis and
discuss the dosage regimes for this specific indication for children and adults. The additionally submitted
publication of Block submitted in the Day 106 Response provides further support for the indication acute
bacterial pharyngitis. The dosage regimen for cefixime used in the trial is in line with the recommended
regimen in the latest SPC proposal of the MAH in the case of children aged from 6 months to 11 years (8
mg/kg/day as a single dose or in two divided doses) for a period of 7 consecutive days. On the basis of
the documentation submitted the indication acute bacterial pharyngitis is approvable.
Uncomplicated acute Cystitis
Cefixime 400 mg for 7 days was considered potentially acceptable provided the MAH submits the quoted
prospective comparative studies for such an indication and dosage quoted in the review of Brogden and
Campoli-Richards (1989). Subsequently 3 publications were submitted to support the indication “cystitis”.
The studies performed by Hoberman and Iravani were well designed and further support the proof of
efficacy and safety of cefixime in uncomplicated acute cystitis. Due to the limitation of data no definitive
conclusion can be drawn on the use of cefixime in complicated cystitis and this indication is not
approvable. Moreover, the MAH did not request this indication. On the basis of the documentation
submitted the indication ‘uncomplicated acute cystitis’ is approvable.
Uncomplicated acute gonorrhoea
At first the applicant wanted to add the indication “acute, gonococcal urethritis” no additional data were
provided. However, Neisseria gonorrhoeae is mentioned in the valid susceptibility table in section 5.1 in
the list of susceptible micro-organisms. Section 5.1 is updated every year by the institutes Z.A.R.S
(Zentralstelle für die Auswertung von Resistenzdaten bei systemisch wirkenden Antibiotika) and PEG
(Arbeitsgemeinschaft „Empfindlichkeitsprüfungen und Resistenz“ der Paul-Ehrlich-Gesellschaft). Besides,
in the SPC of the German reference product Suprax (originator), the indication “acute, gonococcal
urethritis” is also sought. This indication is also approved for other Cefixim containing products in the EU,
as it is shown in the overview table of all approved indications in the different EU member states. The
associated potential dosage was also assumed from the reference SPC (Suprax): the recommended
dosage for therapy of acute, gonococcal urethritis is the administration of a single dose of 400 mg
cefixime. Although the requested additional documentation to support the proof of efficacy and safety of
cefixime in “gonorrhoea” has not been submitted, Neisseria gonorrhoeae is mentioned in the valid
susceptibility table in SPC section 5.1 in the list of susceptible micro-organisms. Furthermore the following
articles give further support to this indication with the posology of one single dose of 400 mg: Hook EW
3rd et al., 1997, Miller Jr. JM, 1997, Mroczkowski TF et al., 1997, Woodward and Fisher, 1999, Crabbe F
et al., 2000, Donders GG, 2000 and Ison CA et al., 2004 The indication ‘uncomplicated acute gonorrhoea’
is approvable.
Clinical safety
Cefixime is a well known 3rd generation cephalosporin and the safety of 400 mg cefixime has been
accepted in several EU countries and outside the EU e.g. in the USA and Canada. As bioequivalence has
been demonstrated, all data regarding safety, which were established for the originator product, can be
extrapolated to the generic formulation.
Risk management plan
Cefixime was first approved in 1987, and there is now more than 10 years post-authorisation experience
with the active substance. The safety profile of cefixime can be considered to be well established and no
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product specific pharmacovigilance issues were identified pre- or post authorisation which are not
adequately covered by the current SPC. Additional risk minimisation activities have not been identified for
the reference medicinal product. The MAH has a pharmacovigilance system at their disposal, which is
based on the current European legislation. Routine pharmacovigilance activities are sufficient to identify
actual or potential risks and a detailed European Risk Management Plan is not necessary for this product.
Product information
SPC
The content of the SPC approved during the decentralised procedure is in accordance with that accepted
for the reference product Suprax.
Readability test
The package leaflet has been evaluated via a user consultation study in accordance with the requirements
of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test consisted of a pilot round with two
participants, followed by two rounds with 10 participants each.
The questions used to test for user-friendliness were well chosen, and represent the main safety issues of
the patient leaflet. The questions were asked in random order. The user test report gives a good
impression how the user test was performed. The patient leaflet was adapted after the pilot round with
additional bolding. This is not line with the guideline and made the test less valuable. The additional
bolding was undone as required.
Overall, the success criteria were met and the readability test has been sufficiently performed.
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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
Cefixim Schluttig 200 mg and 400 mg, film-coated tablets, and Cefixim Schluttig 100 mg/5 ml, power for
oral suspension have a proven chemical-pharmaceutical quality and are generic forms of Suprax. Suprax
200 mg and 400 mg film-coated tablets and 100 mg/5 ml powder for oral suspension are well-known
medicinal products with an established favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations.
The SPC, package leaflet and labelling are in the agreed templates and are in agreement with other the
reference product.
The Board followed the advice of the assessors.
There was no discussion in the CMD(h). Agreement between member states was reached during a written
procedure. The member states, on the basis of the data submitted, considered that essential similarity has
been demonstrated for Cefixim Schluttig 200 mg and 400 mg, film-coated tablets, and Cefixim Schluttig
100 mg/5 ml, power for oral suspension with the reference product, and have therefore granted a
marketing authorisation. The decentralised procedure was finished on 3 August 2011. Cefixim Schluttig
200 mg, 400 mg and 100 mg/5 ml were authorised in the Netherlands on 7 September 2011.
The date for the first renewal will be: 3 May 2016.
The following post-approval commitments have been made during the procedure:
Quality - medicinal product
- The MAH committed to perform process validation on full-scale batches of cefixime 400 mg filmcoated tablets and the 100 mg/5 mL suspension.
- The MAH committed to provide batch analysis results of three full-scale batches of cefixime 400 mg
film-coated tablets and of 100 mg/5 mL suspension.
- The MAH committed to place the first three commercial batches of all three cefixime formulations on
long-term and accelerated stability.
Non-clinical – ERA
- The MAH committed to submit an Environmental Risk Assessment (ERA) in accordance with EMA
guidance should before marketing in the Netherlands.
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List of abbreviations
AE
AOM
ASMF
ATC
AUC
BP
CEP
CHMP
CI
Cmax
CMD(h)
CV
EDMF
EDQM
EMA
EU
GCP
GLP
GMP
ICH
MAH
MEB
OTC
PAR
Ph.Eur.
PIL
PSUR
SD
SPC
t½
tmax
TSE
USP
Adverse Event
Acute Otitis Media
Active Substance Master File
Anatomical Therapeutic Chemical classification
Area Under the Curve
British Pharmacopoeia
Certificate of Suitability to the monographs of the European Pharmacopoeia
Committee for Medicinal Products for Human Use
Confidence Interval
Maximum plasma concentration
Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
Coefficient of Variation
European Drug Master File
European Directorate for the Quality of Medicines
European Medicines Agency
European Union
Good Clinical Practice
Good Laboratory Practice
Good Manufacturing Practice
International Conference of Harmonisation
Marketing Authorisation Holder
Medicines Evaluation Board in the Netherlands
Over The Counter (to be supplied without prescription)
Public Assessment Report
European Pharmacopoeia
Package Leaflet
Periodic Safety Update Report
Standard Deviation
Summary of Product Characteristics
Half-life
Time for maximum concentration
Transmissible Spongiform Encephalopathy
Pharmacopoeia in the United States
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Procedure
number
Type of
modification
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Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached
B