Con2025203 PDF

CEFOTAXIME 1G POWDER FOR SOLUTION FOR
INJECTION OR INFUSION
PL 20117/0007
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 30
Labelling Page 34
MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 1

20117/0007
PL 20117/0007
LAY SUMMARY
The Medicines and Healthcare products Regulatory Agency (MHRA) granted

Morningside Healthcare Limited a Marketing Authorisation (licence) for the medicinal
product Cefotaxime 1g Powder for Solution for Injection or Infusion (PL 20117/0007).
This medicine is available by prescription only.
Cefotaxime is an antibiotic that is used to treat a number of bacterial infections. It kills

bacteria by interfereing with the formation of the bacterias cell wall, without this the
bacteria disintegrate and die.
Cefotaxime 1g Powder for Solution for Injection or Infusion raised no clinically

significant safety concerns and it was therefore judged that the benefits of using this
product outweigh the risks; hence a Marketing Authorisation has been granted.

20117/0007
PL 20117/0007
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction Page 4
Pharmaceutical assessment Page 5
Preclinical assessment Page 15
Clinical assessment Page 16
Overall conclusions and risk benefit assessment Page 18

20117/0007
INTRODUCTION
Based on the review of the data on quality, safety and efficacy the UK granted a
marketing authorisation for the medicinal product Cefotaxime 1g Powder for Solution for
Injection or Infusion to Morningside Healthcare Limited on 24 August 2006. This
product is a prescription only medicine.
This is a national application submitted under Article 10.1 of Directive 2001/83, claiming
essential similarity to Claforan 1g Injection (PL 04425/0188) authorised in the UK to
Aventis Pharma Ltd. This product was originally authorised in the UK in March 1981 to
Roussel Laboratories Ltd.
Cefotaxime is a broad-spectrum bactericidal cephalosporin antibiotic. Cefotaxime is

exceptionally active in vitro against gram-negative organisms sensitive or resistant to
first or second generation cephalosporins. It is similar to other cephalosporins in activity
against gram-positive organisms.

20117/0007
PHARMACEUTICAL ASSESSMENT
1. INTRODUCTION
This national standard abridged application is for powder for injection containing 1g of
the cephalosporin antibiotic cefotaxime sodium. The full standard term is powder for
solution for injection or infusion. The product is indicated for the treatment of a number
of infections as described in the SPC, administered by IV bolus, IV infusion or by IM
injection. The application has been made under the first paragraph of Article 10.1,
claiming essential similarity to Claforan 1g Injection (PL 04425/0188) authorised in the
UK to Aventis Pharma Ltd. This product was originally authorised in the UK in March
1981 (PL 00109/0074, Roussel Laboratories Ltd).
No genetically modified organisms are included in the product.
No paediatric development plan exists for this product.
The proposed product has not been authorised to the applicant or to a related company in
any other European Union (EU) Member State, nor is it the subject of any pending
application in any other EU Member State.
2. ACTIVE SUBSTANCE
2.1 General information
2.1.1 Nomenclature
rINN: cefotaxime sodium CAS: 64485-93-4
Chemical name: 5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid, 3-

[(acetyloxyl)methyl]-[[2-amine-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo, [6R-
[6,7(z)]], sodium salt
2.1.2 Structure
C16H16N5Na07S2 MW: 477.46
2.1.3 General properties
White or slightly yellow hygroscopic crystalline powder. It is freely soluble in water,

sparingly soluble in methanol and practically insoluble in ether.
2.2 Manufacture
20117/0007
2.2.1 Manufacturer
A suitable manufacturer is responsible for production of the active substance, cefotaxime

sodium.
2.2.2 Manufacturing process description and process controls
In a letter dated 10 February 2004 the applicant requested that the application was
assessed referring to the Certificate of Suitability issued to the active substance
manufacturer (R0-CEP 1999-033-Rev 00) for Cefotaxime Sodium Sterile, a copy of this
certificate has been provided.
Certificate R0-CEP 1999-033-Rev 00 required some additional tests and limits to

supplement the control measures described in the Ph Eur monograph.
2.2.3 In-process controls for critical stage
Covered by the Certificate of Suitability.
2.2.4 Control of materials
2.3 Control of intermediates
2.4 Characterisation
2.5 Impurities
Details of the impurities that are potentially present in the active substance manufactured
have been provided.

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2.6 Control of active substance
2.6.1 Specification
An appropriate specification is provided, with all proposed limits being

acceptable.
It is stated that N,N-dimethylaniline is not used in the manufacturing process,

hence it is acceptable that a test for this residual solvent (included in the Ph Eur
monograph) is not performed. It is also stated that no ICH Class I solvents are
used.
2.6.2 Analytical procedures / validation
The manufacturer of the finished product uses the Ph Eur methods for assay and
related substances for the active substance and finished product. Validation data
has been included in the dossier.
2.6.3 Batch analyses
Satisfactory batch data have been provided for three batches (CFTS020060,
CFTS020061 and CFTS020062) manufactured in 2002. The levels of impurities
found have been summarised.
In addition, three Certificates of Analysis from the active substance manufacturer

and from the manufacturer of the finished product have been provided. The results
from the two analyses are similar and demonstrate compliance with the proposed
active substance specification.
Satisfactory Certificates of Analysis have also been provided for four batches of
active substance manufactured by an additional manufacturer that was used in
manufacture of the stability batches.
2.7 Reference standards or materials
2.8 Container closure system
Bulk substance is stored in an appropriate container.
2.9 Stability
Stability data have been generated by the active substance manufacturer. Data
have been provided for three commercial scale batches manufactured in April
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2002. These batches have been stored for up to 6 months at 40C/75% and for up
to 9 months at 25C/60%.
Batches were tested for appearance, loss on drying, assay, related substances, pH,
specific optical rotation and specific absorbance. All batches remained within
specification under the above conditions. A retest period of 24 months was
proposed and data have been provided that support this re-test period.
A commitment has been provided that the stability studies on the current batches
will be continued to 48 months.
In addition, stress studies have been conducted exposing the active substance to
acid, alkali, thermal, UV and oxidative stress. The substance was sensitive to all
conditions except exposure to UV light. Specificity of the method has been
demonstrated.
3. MEDICINAL PRODUCT
3.1 Composition
Composition and function of ingredients
Ingredient Quantity Function Reference

(g) Standard
Cefotaxime sodium (1.0) Active ingredient Ph Eur
(equivalent to cefotaxime)
No overages are included. Nominal content of each vial is based on assay and
moisture content of the batch of active substance.
3.2 TSE Risk Materials
Declarations have been provided that the only materials of animal origin used in
the fermentation stage or other stages are milk-derived materials. The risk of TSE
may be considered to be minimised. A TSE declaration referring to
EMEA/410/01
rev 02 has been provided and is satisfactory.
The media used for media fill studies (CASO broth) uses casein that is derived
from milk fit for human consumption and peptone that is derived from casein
(bovine source). The milk-derived substances are excluded from the scope of the
guidance note. A TSE Certificate of Suitability has been issued to the supplier of
Casein-Meat Peptone E2 Ref. 19501 (R1-CEP 2000-120-Rev 00), a copy of
which has been provided.

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3.3 Pharmaceutical Development
Brief but satisfactory information has been provided.
The SPC for the reference product states that the product is compatible with water
for injections, sodium chloride injection, 5% dextrose injection, dextrose and
sodium chloride injection and compound sodium lactate injection (Ringer-lactate
injection). It is proposed that once the product is opened it should be used
immediately or within 24 hours if stored in a refrigerator. The SPC of the
reference product also states that the product may be reconstituted with 1%
lidocaine but must be used immediately. It is also compatible with metronidazole
infusion 500mg/100ml, with both products being chemically stable if stored at 2-
8C for up to 24 hours.
The product may be administered intravenously, by bolus injection, by infusion or

intramuscularly. For intravenous and intramuscular use it is recommended that the
product is reconstituted with water for injections. The SPC for the reference
product gives the following dilutions, that should also apply to this product: 1g
plus 4ml; 2g plus 10ml. In addition, the reference SPC states that for intravenous
infusion 1-2 g are dissolved in 40-100ml water for injections or in the infusion
fluids listed above. The prepared infusion may be administered over 20-60
minutes.
3.4 Manufacture
3.4.1 Manufacturer
A copy of the manufacturing authorisation for the site intended for manufacture
and assembly has been provided issued by the relevant authorities, dated October
2003.
3.4.2 Batch formula
The filling process is considered as a continuous process, whereby a specific

batch is produced using raw materials from only a single batch of active substance
and is produced over not more than 5 days of continuous operation.
3.4.3 Manufacturing process and process controls
A flow chart of the manufacturing process has been provided. The manufacturing
process consists of aseptic filling (Grade A area) of a single batch of active
substance into washed, sterilised and depyrogenated vials. After filling, the vials
are sealed with sterilised rubber stoppers and an aluminium overcap is applied.

20117/0007
Manufacture is in a facility dedicated to the manufacture of injectable
cephalosporin products involving aseptic filling.
The conditions for sterilisation of the vials (and depyrogenisation), stoppers and
removable parts of the filling machine are suitable.
3.4.4 In-process controls for critical stages
Fill weight is checked on 12 vials every 30 minutes.
After capping and labelling periodic checks are made of the legibility of the
labelling and seal integrity.
Filled and capped vials are subject to a 100% visual inspection.
Studies on seal force have been presented. and a suitable operating range has been
established.
3.4.5 Control of intermediates
There are no intermediate products.
3.4.6 Process validation or evaluation
The manufacturing process has been validated through the successful manufacture
of four 1g production batches (9,372 to 28,116 vials) between July 2001 and July
2002 using batches of active substance provided by the manufacturer of the
stability batches. The batches comply with the proposed finished product
specification and confirm the consistency of the manufacturing process.
Satisfactory validation reports have been provided for the autoclave (solid load,
porous load, media fill load and rubber stoppers), vial washer,
depyrogenation
tunnel and filling/stoppering machine.
A satisfactory report has been provided covering seven consecutive media fill
studies (13,150 vials of 10ml, 15ml or 20ml, filled over 3-4 days) with sterilised
anhydrous lactose followed by a growth promotion medium. Two of the filling
runs showed contamination; one vial out of 13,338 (0.008%) and two vials out of
13,228 vials (0.015%). Overall, the contamination rate was three vials out of
92,710 vials (0.003%). Revalidation is every 6 months using a single vial size;
this is acceptable. Results of a revalidation media fill study (two runs) have been
presented. No contamination was observed in either of the runs in which 13,150
vials were filled.
3.5 Control of excipients

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3.5.1 Specification
There are no excipients in this product.
3.6 Control of drug product
3.6.1 Specification
The finished product specification has been described and is based on the
specification for the active substance. It complies with the BP monograph for
Cefotaxime Sodium for Injection.
Absence of a limit for average weight is accepted, given that the fill weight is
highly dependent on potency. A suitable measure of uniformity is included.
3.6.2 Analytical procedures / validation
The analytical methods have been suitably described.
A reverse phase HPLC method is used as the assay method and for determination
of levels of related substances. The method is based on the method described in
the Ph Eur monograph for cefotaxime sodium but with some changes made. The
method has been validated in accordance with ICH and with respect to cefotaxime
and impurities A and B (based on the available reference standards. System
suitability parameters are included in the method). Forced degradation studies
have been included. The method can detect impurities A, B and E as described in
the Ph Eur.
The tests for sterility and bacterial endotoxins performed on the finished product
are conducted and validated in accordance with the methods described in the
European Pharmacopoeia.
Cefotaxime working standard used in the validation of the assay method was a
standard production batch. A satisfactory Certificate of Analysis has been
provided for this batch.
3.6.3 Batch analyses
Satisfactory batch analysis data have been provided for four 1g production
batches (9,372-2,8116 vials) between July 2001 and July 2002. The batches
comply with the proposed finished product specification and with the Ph Eur
limits for sub-
visible particles.

20117/0007
3.6.4 Justification
A comparison of monograph and proposed specification requirements has been

provided. This can be considered as a justification for the finished product
specifications.
3.7 Container closure system
The product is presented in clear borosilicate Type I glass vials (10 ml nominal
capacity) with grey chlorobutyl stoppers (complying with the Ph Eur monograph
for rubber closures, Type I) with an aluminium overcap. Packs contain 10 vials.
Satisfactory specifications have been provided for the vials and stoppers.
Satisfactory batch data/Quality Certificates have been provided for batches of the
vials and stoppers.
Satisfactory baseline microbial and endotoxin data have been provided for the
vials and stoppers. Validation data have been provided for the methods used.
3.8 Stability
Stability data were provided for eight 1 g production batches (8,000-62,333 vials)
manufactured between March 1997 and June 2000. Five batches were
manufactured with active substance from the manufacturer that produced the
active substance used in process validation, and the other three batches used
active substance from the intended commercial supplier. All batches were
manufactured at a manufacturing facility that has now been decommissioned and
filled into containers/closures that are identical to those intended for
commercialisation.
The analytical methods were as described for routine batch release.
Stability data provided: 25C/60% (2 x 36, 6 x 24 months)
Test parameters: appearance of powder and constituted solution, pH, loss

on drying or water content, assay, related substances, UV
absorbance, visible particles, sterility, bacterial
endotoxins
Only minor changes were seen in most of the test parameters. All batches comply
with the specification throughout the test period. Limits for individual and total
related substances were introduced part way through the stability studies and,
therefore, are not available for all inspection points. The highest levels of
individual and total impurities found over 24 months storage at 25C/60% were
1.0% and 3.1%, respectively. Some batches showed an apparent fall in assay

20117/0007
values, although this was not reflected in a corresponding increase in the levels of
related substances.
The applicant has confirmed that stability studies have been initiated with batches
of 1g and 500mg product manufactured at the new proposed commercial
facilities. Satisfactory results are available following 3-18 months storage at
25C/60% and after 3-12 months storage at 40C/75%.
Stability studies have been conducted following reconstitution of the powder with
water for injections, 50ml 5% dextrose, 0.9% NaCl, 0.9% NaCl/5% dextrose and
Lactated Ringers Solution.
Stability data provided: room temperature (initial, 5 and 24 hours)

refrigerated (initial, 6, 27 and 48 hours)
Test parameters: pH, assay, related substances, sterility, absorbance
The vials retained their physical, chemical and microbiological quality over less
than 5 hours.
The applicant has proposed a shelf life of 24 months for product stored below
25C. This proposal is accepted. The reconstituted product must be used within 4
hours. This is acceptable.
The licence holder also commits to carry out stability studies on a batch of
reconstituted solution stored in an inverted position this year and to immediately
notify the MHRA if any any out of specification results are observed. This is
acceptable
3.9 Other information
3.9.1 Bioavailability, bioequivalence
Not relevant.
3.9.3 Essential similarity
The requirements for essential similarity are met.
3.10 Product Literature
3.10.1 SPC
The SPC is satisfactory.
3.10.2 PIL
20117/0007
The leaflet is satisfactory.
3.10.3 Labelling
The labelling is satisfactory.
3.11 Administrative
3.11.1 Comment on Expert Report
The Pharmaceutical Expert has suitable experience and the report is satisfactory.
3.11.2 MAA form
The MAA form is satisfactory.
3.11.3 GMP
The site for manufacture of the active substance has been inspected as part of the
EDQM Certification scheme and documentation has been provided to support the
satisfactory outcome of inspection of the manufacturing facilities.
A copy of the Manufacturing Authorisation for the manufacturing, assembly and

release site has been provided. Manufacture is in accordance with the principles
of Good Manufacturing Practice.
It is proposed that batch release will be performed at Medochemie Ltd, Iapetou

St, V.I.P.E., Agios, Athanasios, Limassol, Cyprus. A copy of the relevant licence
has been provided.
3.11.4 Guideline Compliance
This application generally complies with the requirements of the Notice to

Applicants and relevant Notes for Guidance.
4. CONCLUSIONS
A Marketing Authorisation may be granted.

20117/0007
PRECLINICAL ASSESSMENT
No new preclinical data have been supplied with this application and none is
required for an application of this type.
MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 20117/0007 15
CLINICAL ASSESSMENT
1. Introduction
Cefotaxime is a broad-spectrum bactericidal cephalosporin antibiotic. Cefotaxime is

exceptionally active in vitro against gram-negative organisms sensitive or resistant to first or
second-generation cephalosporins. It is similar to other cephalosporins in activity against
gram-positive organisms.
This application is made under Article 10.1, first paragraph, claiming essential similarity to
the innovator's product Claforan 1g Injection, authorised to Aventis Pharma Ltd in the UK
(PL 04425/0188), the applicant has now submitted this application for a generic intravenous
or intramuscular product.
2. Assessment
The following is the comparison of the Summaries of Product Characteristics of the index
product under assessment and of the corresponding innovator product (Claforan 1g Injection)
from Aventis Pharma Ltd (PL 04425/0188) in the UK:
2.1 Indications
Virtually identical
2.2 Posology
Virtually identical
2.3 Contraindications
Virtually identical
2.4 Special warnings and precautions for use
Virtually identical
2.5 Interactions
Virtually identical
2.6 Use during pregnancy and lactation
Virtually identical
2.7 Effect on the ability to drive and use machines
Virtually identical
2.8 Undesirable effects
Virtually identical
2.9 Overdose
Virtually identical
2.10 Pharmacodynamic properties
Virtually identical
2.11 Pharmacokinetic properties
Virtually identical
3. Discussion
The Summaries of Product Characteristics of the index products are virtually identical.
For this parenteral formulation, there are no bioequivalence issues.
4. Patient Information Leaflet
This is in compliance with Directive 92/27/EEC and is satisfactory.
5. Recommendations
There are no major clinical public health issues and the recommendation is to grant a
marketing authorisation for this preparation.
OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Cefotaxime 1g Powder for Solution for Injection or
Infusion are well defined and controlled. The specifications and batch analytical results
indicate consistency from batch to batch. There are no outstanding quality issues that would
have a negative impact on the benefit/risk balance.
PRECLINICAL
No new preclinical data were submitted and none are required for applications of this type.
EFFICACY
No new or unexpected safety concerns arise from this application.
The SPC, PIL and labelling are satisfactory and consistent with that for the cross-reference
product.
RISK BENEFIT ASSESSMENT

The quality of the product is acceptable, no significant preclinical or clinical safety concerns
were identified, and some benefit has been shown to be associated with Cefotaxime 1g
Powder for Solution for Injection or Infusion. The risk benefit is therefore considered to be
positive.
PL 20117/0007
STEPS TAKEN FOR ASSESSMENT
1 The MHRA received the marketing authorisation application on 31 October

2003
2 Following initial assessment of the application the MHRA requested further
information relating to the quality dossier on 24 November 2004
3 The applicant responded to the MHRAs request, providing further information
on the quality dossier in June 2005
4 Following assessment of the response the MHRA requested further information
relating to the quality dossier on 23 December 2005
on the quality dossier on 5 April 2006 and 9 June 2006
6 Following assessment of the response the MHRA requested further information
relating to the quality dossier on 26 June 2006
on 10 July 2006
8 Following assessment of the response the MHRA requested further additional
information relating to the quality dossier on 13 July 2006
on 28 July 2006
10 The application was determined on 24 August 2006
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Cefotaxime 1g Powder for Solution for Injection or Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Cefotaxime sodium equivalent to 1g of cefotaxime.
3. PHARMACEUTICAL FORM
Powder for solution for injection or infusion. A white to slightly creamy

powder.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Properties:
Cefotaxime is a broad-spectrum bactericidal cephalosporin antibiotic.

Cefotaxime is exceptionally active in vitro against Gram-negative organisms
sensitive or resistant to first or second generation cephalosporins. It is similar
to other cephalosporins in activity against Gram-positive organisms.
Indications:
Cefotaxime is indicated in the treatment of the following infections either

before the infecting organism has been identified or when caused by bacteria
of established sensitivity.
Septicaemias
Respiratory Tract Infections such as acute and chronic bronchitis, bacterial
pneumonia, infected bronchiectasis, lung abscess and post-operative chest
infections.
Urinary Tract Infections such as acute and chronic pyelonephritis, cystitis

and asymptomatic bacteriuria.
Soft-Tissue Infections such as cellulitis, peritonitis and wound infections.
Bone and Joint Infections such as osteomyelitis, septic arthritis.

20117/0007
Obstetric and Gynaecological Infections such as pelvic inflammatory
disease.
Gonorrhoea particularly when penicillin has failed or is unsuitable.
Other Bacterial Infections meningitis and other sensitive infections suitable

for parenteral antibiotic therapy.
Prophylaxis:
The administration of Cefotaxime prophylactically may reduce the incidence

of certain post-operative infections in patients undergoing surgical procedures
that are classified as contaminated or potentially contaminated or in clean
operations where infection would have serious effects.
Protection is best ensured by achieving adequate local tissue concentrations at

the time contamination is likely to occur. Cefotaxime should therefore be
administered immediately prior to surgery and if necessary continued in the
immediate post-operative period.
Administration should usually be stopped within 24 hours since continuing

use of any antibiotic in the majority of surgical procedures does not reduce the
incidence of subsequent infection.
Bacteriology:
The following organisms have shown in vitro sensitivity to Cefotaxime.
Gram-positive:
Staphylococci, including coagulase-positive, coagulase-negative and

penicillinase-producing strains.
Beta-haemolytic and other streptococci such as Streptococcus mitis (viridans)

(many strains of enterococci, e.g. Streptococcus faecalis, are relatively
resistant).
Streptococcus (Diplococcus) pneumoniae
Clostridium spp.
Gram-negative:
Escherichia coli.
Haemophilus influenzae including ampicillin resistant strains.
Klebsiella spp.
Proteus spp. (both indole positive and indole negative).

20117/0007
Enterobacter spp.
Neisseria spp. (including -lactamase producing strains of N. gonorrhoea).
Salmonella spp. (including Sal. typhi).
Shigella spp.
Providencia spp.
Serratia spp.
Citrobacter spp.
Cefotaxime has frequently exhibited useful in vitro activity against

Pseudomonas and Bacteroides species although some strains of Bacteroides
fragilis are resistant.
There is in vitro evidence of synergy between Cefotaxime and aminoglycoside

antibiotics such as gentamicin against some species of Gram-negative bacteria
including some strains of Pseudomonas. No in vitro antagonism has been
noted. In severe infections caused by Pseudomonas spp. the addition of an
aminoglycoside antibiotic may be indicated.
4.2. Posology and method of administration
Cefotaxime may be administered intravenously or by bolus injection or

infusion or intramuscularly. The dosage, route and frequency of administration
should be determined by the severity of infection, the sensitivity of causative
organisms and condition of the patient. Therapy may be initiated before the
results of sensitivity tests are known.
Adults:
The recommended dosage for mild to moderate infections is 1g 12 hourly.
However, dosage may be varied according to the severity of the infection,
sensitivity of causative organisms and condition of the patient. Therapy may
be initiated before the results of sensitivity tests are known.
In severe infections dosage may be increased up to 12g daily given in 3 or 4
divided doses. For infections caused by sensitive Pseudomonas species daily
doses of greater than 6g will usually be required.
Children:
The usual dosage range is 100-150mg/kg/day in 2 to 4 divided doses.

However, in very severe infection doses of up to 200mg/kg/day may be
required.

20117/0007
Neonates:
The recommended dosage is 50mg/kg/day in 2 to 4 divided doses. In severe

infections 150-200mg/kg/day, in divided doses, have been given.
Dosage in Gonorrhoea:
A single injection of 1g may be administered intramuscularly or intravenously.
Dosage in renal impairment:
Because of extra-renal elimination, it is only necessary to reduce the dosage of

cefotaxime in severe renal failure (GFR <5ml/min = serum creatinine
approximately 751 micromol/litre). After an initial loading dose of 1g, daily
dose should be halved without change in the frequency of dosing, i.e. 1g
twelve hourly becomes 0.5g twelve hourly, 1g eight hourly becomes 0.5g
eight hourly, 2g eight hourly becomes 1g eight hourly etc. As in all other
patients, dosage may require further adjustment according to the course of the
infection and the general condition of the patient.
Intravenous and Intramuscular Administration:
Reconstitute cefotaxime with 4.0mL of Water for Injections as directed in

Section 6.6 (Instructions for use/handling). Shake well until dissolved and
then withdraw the entire contents of the vial into the syringe and use
immediately.
Intravenous Infusion:
Cefotaxime may be administered by intravenous infusion using the fluids

stated in Section 6.6 (Instructions for use/handling). The prepared infusion
may be administered over 20-60 minutes. To produce an infusion using vials
with an infusion connector, remove the safety cap and directly connect the
infusion bag. The needle in the closure will automatically pierce the vial
stopper. Pressing the infusion bag will transfer solvent into the vial.
Reconstitute by shaking the vial and finally, transfer the reconstituted solution
back to the infusion bag ready for use.
4.3. Contraindications
Known or suspected allergy to cephalosporins.
4.4. Special warnings and precautions for use
Preliminary enquiry about hypersensitivity to penicillin and other -Lactam

antibiotics is necessary before prescribing cephalosporins since cross allergy
occurs in 510% of cases.

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Hypersensitivity reactions (anaphylaxis) occurring with the two types of
antibiotics can be serious and occasionally fatal. Hypersensitivity requires that
treatment be stopped.
Patients with severe renal dysfunction should be placed on the dosage

schedule recommended under Posology and Method of Administration.
As with other antibiotics, the use of cefotaxime, especially if prolonged, may

result in overgrowth of non susceptible organisms, such as Enterococcus spp.
Repeated evaluation of the condition of the patient is essential. If
superinfection occurs during treatment with cefotaxime, specific anti-
microbial therapy should be instituted if considered clinically necessary.
Cefotaxime reconstituted with lidocaine must never be used in the following:
- by the intravenous route
- in infants under 30 months
- in subjects with a previous history of hypersensitivity to this product
- in patients who have an unpaced heart block
- in patients with severe heart failure.
The sodium content of cefotaxime (2.09mmol/g) should be taken into account

when prescribing to patients requiring sodium restriction.
Cefotaxime may predispose patients to pseudomembranous colitis. Although

any antibiotic may predispose to pseudomembranous colitis, the risk is higher
with broad spectrum drugs, such as cephalosporins. This side effect, which
may occur more frequently in patients receiving higher doses for prolonged
periods, should be considered as potentially serious. The presence of C.
difficile toxin should be investigated, and treatment with cefotaxime stopped
in cases of suspected colitis. Diagnosis can be confirmed by toxin detection
and specific antibiotic therapy (e.g. oral vancomycin or metronidazole) should
be initiated if considered clinically necessary. The administration of products
which cause faecal stasis should be avoided.
4.5. Interactions with other medicinal products and other forms of interaction
Cephalosporin antibiotics at high dosage should be given with caution to

patients receiving aminoglycoside antibiotics or potent diuretics such as
furosemide as these combinations are suspected to adversely affect renal
function. However, at the recommended doses, enhancement of nephrotoxicity
is unlikely to be a problem with cefotaxime.
Probenecid interferes with renal tubular transfer of cefotaxime delaying its

excretion and increasing the plasma concentration.

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Interference with Laboratory Tests:
A positive Coombs test may be seen during treatment with cephalosporins.

This phenomenon may occur during treatment with cefotaxime.
A false positive reaction to glucose may occur with reducing substances but
not with the use of specific glucose oxidase methods.
4.6. Pregnancy and lactation
Pregnancy: It is known that cefotaxime crosses the placental barrier. Although

studies in animals have not shown an adverse effect on the developing foetus,
the safety of cefotaxime in human pregnancy has not been established.
Consequently, cefotaxime should not be administered during pregnancy
especially during the first trimester, without carefully weighing the expected
benefit against possible risks.
Lactation: Cefotaxime is excreted in the milk.
4.7. Effects on ability to drive and use machines
None known.
4.8. Undesirable effects
Adverse reactions to cefotaxime have occurred relatively infrequently and

have generally been mild and transient. Effects reported include candidiasis,
nausea, vomiting, abdominal pain, diarrhoea (diarrhoea may sometimes be a
symptom of pseudomembranous colitis (see warnings)), transient rises in liver
transaminases, alkaline phosphatase and/or bilirubin.
As with other cephalosporins, changes in renal function have been rarely

observed with high doses of cefotaxime, particularly when co-prescribed with
aminoglycosides. Rare cases of interstitial nephritis have been reported in
patients treated with cefotaxime. Administration of high doses of
cephalosporins, particularly in patients with renal insufficiency, may result in
encephalopathy (e.g. impairment of consciousness, abnormal movements and
convulsions).
Hypersensitivity reactions have been reported. These include skin rashes,

pruritus and less frequently urticaria, drug fever and very rarely anaphylaxis
(e.g. angioedema and bronchospasm possibly culminating in shock).
As with other cephalosporins, occasional cases of bullous reactions such as

Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema
multiforme have also been reported.

20117/0007
As with other beta-lactam antibiotics, granulocytopenia and more rarely
agranulocytosis may develop during treatment with cefotaxime, particularly if
given over long periods. A few cases of eosinophilia and neutropenia have
been observed, reversible when treatment is ceased. Some cases of rapidly
reversible eosinophilia and thrombocytopenia on stopping treatment have been
reported. Rare cases of haemolytic anaemia have been reported. For cases of
treatment lasting longer than 10 days, blood count should therefore be
monitored.
Transient pain may be experienced at the site of injection. This is more likely
to occur with higher doses. Occasionally, phlebitis has been reported in
patients receiving intravenous cefotaxime. However, this has rarely been a
cause for discontinuation of treatment.
A very small number of cases of arrhythmias have occurred following rapid

bolus infusion through a central venous catheter.
The following symptoms have occurred after several weeks of treatment for
borreliosis (Lyme's Disease): skin rash, itching, fever, leucopenia, increases in
liver enzymes, difficulty of breathing, joint discomfort. To some extent these
manifestations are consistent with the symptoms of the underlying disease, for
which the patient is being treated.
4.9. Overdose
Serum levels of cefotaxime may be reduced by peritoneal dialysis or

haemodialysis. In the case of overdosage, particularly in renal insufficiency,
there is a risk of reversible encephalopathy.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Cefotaxime is a broad spectrum bactericidal cephalosporin antibiotic.

Cefotaxime is exceptionally active in vitro against Gram-negative organisms
sensitive or resistant to first or second generation cephalosporins. It is similar
to other cephalosporins in activity against Gram-positive bacteria.
5.2. Pharmacokinetic properties
After a 1000mg intravenous bolus, mean peak plasma concentrations of

cefotaxime usually range between 81 and 102 microgram/ml. Doses of 500mg
and 2000mg produce plasma concentrations of 38 and 200 microgram/ml,
respectively. There is no accumulation following administration of 1000mg
intravenously or 500mg intramuscularly for 10 or 14 days. The apparent
volume of distribution at steady-state of cefotaxime is 21.6 litres/1.73m2 after
a 1g intravenous 30 minute infusion.

20117/0007
Concentrations of cefotaxime (usually determined by non-selective assay)
have been studied in a wide range of human body tissues and fluids.
Cerebrospinal fluid concentrations are low when the meninges are not
inflamed, but are between 3 and 30 microgram/ml in children with meningitis.
Cefotaxime usually passes the blood-brain barrier in levels above the
minimum inhibitory concentration of common sensitive pathogens when the
meninges are inflamed. Concentrations (0.2-5.4 microgram/ml), inhibitory for
most Gram-negative bacteria, are attained in purulent sputum, bronchial
secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be
effective against most sensitive organisms are similarly attained in female
reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid,
renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic
doses. High concentrations of cefotaxime and desacetyl-cefotaxime are
attained in bile.
Cefotaxime is partially metabolised prior to excretion. The principal

metabolite is the microbiologically active product, desacetyl-cefotaxime. Most
of a dose of cefotaxime is excreted in the urine - about 60% as unchanged
drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported
to be between 260 and 390ml/minute and renal clearance 145 to 217
ml/minute.
After intravenous administration of cefotaxime to healthy adults, the

elimination half-life of the parent compound is 0.9 to 1.14 hours and that of
the desacetyl metabolite, about 1.3 hours.
In neonates the pharmacokinetics are influenced by gestational and

chronological age, the half-life being prolonged in premature and low birth
weight neonates of the same age.
In severe renal dysfunction the elimination half-life of cefotaxime itself is

increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime
is increased to about 10 hours. Total urinary recovery of cefotaxime and its
principal metabolite decreases with reduction in renal function.
5.3. Preclinical safety data
Not applicable.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
None
6.2. Incompatibilities
Not applicable

20117/0007
6.3. Shelf life
Unopened: 2 years
After reconstitution: Use immediately.
The product has shown chemical stability for up to 4 hours if stored between
2-8C in the following infusion fluids:-
-Water for Injections.

- Sodium Chloride Injection.
- 5% Dextrose Injection.
- Dextrose and Sodium Chloride Injection.
6.4. Special precautions for storage
Unreconstituted solution: Do not store above 25C. Keep the container in the
outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3
6.5. Nature and contents of container
Cefotaxime is supplied in clear 10ml Type I glass vials with chlorobutyl

rubber stoppers and an aluminium overseal. The vials are boxed individually
and in packs of 10.
6.6 Special precautions for disposal of used medicinal product or waste

materials derived from such medicinal product and other handling of the
product
Cefotaxime is supplied as a white to slightly creamy Powder for Solution for

Injection or Infusion, which when dissolved in Water for Injections forms a
straw-coloured solution suitable for IV or IM injection. Variations in the
intensity of colour of the freshly prepared solution do not indicate a change in
potency or safety.
Reconstituted Solutions should be used immediately
Cefotaxime is compatible with several commonly used intravenous infusion

fluids as follows:
- Water for Injections

- Sodium Chloride Injection
- 5% Dextrose Injection
- Dextrose and Sodium Chloride Injection
- Cefotaxime is also compatible with 1% lidocaine, however only freshly
prepared solutions should be used (see section 4.4).

20117/0007
Cefotaxime is also compatible with metronidazole infusion (500mg/100ml)
some increase in colour of prepared solutions may occur on storage. However,
this does not indicate change in potency or safety.
Any unused product or waste material should be disposed of in accordance

with local requirements
7. MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd

115 Narborough Road
Leicester
LE3 0PA
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 20117/0007
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION
24/08/2006
10. DATE OF REVISION OF THE TEXT
24/08/2006

20117/0007
PATIENT INFORMATION LEAFLET

20117/0007
20117/0007
TECHNICAL LEAFLET FOR PROFESSIONALS ADMINISTERING
CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR
INFUSION

20117/0007
20117/0007
PACKAGING
Vial label:

20117/0007
Small pack carton:

20117/0007
Large pack carton:

20117/0007

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CEFOTAXIME 1G POWDER FOR SOLUTION FOR

Lay summary Page 2

Scientific discussion Page 3

Steps taken for assessment Page 19

Summary of product characteristics

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 1

The Medicines and Healthcare products Regulatory Agency (MHRA) granted

Cefotaxime is an antibiotic that is used to treat a number of bacterial infections. It kills

Cefotaxime 1g Powder for Solution for Injection or Infusion raised no clinically

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 2

Pharmaceutical assessment Page 5

Preclinical assessment Page 15

Clinical assessment Page 16

Overall conclusions and risk benefit assessment Page 18

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 3

Cefotaxime is a broad-spectrum bactericidal cephalosporin antibiotic. Cefotaxime is

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 4

No genetically modified organisms are included in the product.

No paediatric development plan exists for this product.

2.1 General information

rINN: cefotaxime sodium CAS: 64485-93-4

Chemical name: 5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid, 3-

C16H16N5Na07S2 MW: 477.46

2.1.3 General properties

White or slightly yellow hygroscopic crystalline powder. It is freely soluble in water,

A suitable manufacturer is responsible for production of the active substance, cefotaxime

2.2.2 Manufacturing process description and process controls

Certificate R0-CEP 1999-033-Rev 00 required some additional tests and limits to

2.2.3 In-process controls for critical stage

Covered by the Certificate of Suitability.

2.2.4 Control of materials

Covered by the Certificate of Suitability.

2.3 Control of intermediates

Covered by the Certificate of Suitability.

Covered by the Certificate of Suitability.

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 6

An appropriate specification is provided, with all proposed limits being

It is stated that N,N-dimethylaniline is not used in the manufacturing process,

2.6.2 Analytical procedures / validation

2.6.3 Batch analyses

In addition, three Certificates of Analysis from the active substance manufacturer

2.7 Reference standards or materials

Covered by the Certificate of Suitability.

2.8 Container closure system

Bulk substance is stored in an appropriate container.

Composition and function of ingredients

Ingredient Quantity Function Reference

3.2 TSE Risk Materials

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 8

Brief but satisfactory information has been provided.

The product may be administered intravenously, by bolus injection, by infusion or

3.4.2 Batch formula

The filling process is considered as a continuous process, whereby a specific

3.4.3 Manufacturing process and process controls

MHRA PAR CEFOTAXIME 1G POWDER FOR SOLUTION FOR INJECTION OR INFUSION, PL 9

3.4.4 In-process controls for critical stages

Fill weight is checked on 12 vials every 30 minutes.

Filled and capped vials are subject to a 100% visual inspection.

3.4.5 Control of intermediates