SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Claforan™ Injection 250mg, 500mg, 1g and 2g

QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains Cefotaxime Sodium equivalent to 250mg cefotaxime base

Contains Cefotaxime Sodium equivalent to 500mg cefotaxime base

Contains Cefotaxime Sodium equivalent to 1g cefotaxime base Contains Cefotaxime Sodium equivalent to 2g cefotaxime base

Each gram of Claforan contains approximately 48mg (2.09mmol) of sodium

3 PHARMACEUTICAL FORM

Vials containing powder to be dissolved in Water for injections EP

Claforan is supplied as a white to slightly creamy powder, 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.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Properties: Claforan is a broad-spectrum bactericidal cephalosporin antibiotic. Claforan 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.

Indication: Claforan 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 bronchietasis, 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

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 Claforan 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. Claforan 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 Claforan.

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) pneumonia.

Clostridium spp.

GRAM NEGATIVE:

Escherichia coli.

Haemophilus influenzae including ampicillin resistant strains.

Klebsiella spp.

Proteus spp. (both indole positive and indole negative).

Enterobacter spp.

Neisseria spp. (including B-lactamase producing strains of N. gonorrhoea). Salmonella spp. (including Sal. typhi).

Shigella spp.

Providencia spp.

Serratia spp.

Citrobacter spp.

Claforan 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 Claforan 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 aminoglucoside antibiotic may be indicated.

4.2 Posology and method of administration

Claforan may be administered intravenously, by bolus injection, by 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 spp. 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 infections doses of up to 200mg/kg/day may be required.

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 Claforan in severe renal failure (GFR < 5ml/min = serum creatinine approximately 751 micromol/l). After an initial loading dose of 1g, daily dose should be halved without change in the frequency of dosing, i.e. 1g in 12 hourly becomes 0.5g 12 hourly, 1g 8 hourly becomes 0.5g 8 hourly, 2g 8 hourly becomes 1g 8 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.

ADMINISTRATION:

Cefotaxime and aminoglycosides should not be mixed in the same syringe or perfusion fluid.

Intravenous and Intramuscular Administration: Reconstitute Claforan with Water for Injection as given in the Dilution Table. Shake well until dissolved and then withdraw the entire contents of the vial into the syringe and use immediately.

Dilution Table:

Vial Size	Diluent to be added
250mg	2ml
500mg	2ml
1g	4ml
2g	10ml

Intravenous Infusion: Claforan may be administered by intravenous infusion. 1-2g are dissolved in 40-100ml of Water for Injection or in the infusion fluids listed under “Pharmaceutical Particulars”. 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.

Intravenous administration (injection or infusion):

For intermittent I.V. injections, the solution must be injected over a period of 3 to 5 minutes. During post-marketing surveillance, potentially life-threatening arrhythmia has been reported in a very few patients who received rapid intravenous administration of cefotaxime through a central venous catheter.

4.3 Contraindications

-    Hypersensitivity to cephalosporins.

-    In patients with a history of hypersensitivity to Cefotaxime and/or to any component of Claforan.

Allergic cross reactions can exist between penicillins and cephalosporins (see section 4.4)

For pharmaceutical forms containing lidocaine:

-    known history of hypersensitivity to lidocaine or other local anesthetics of the amide type

-    non-paced heart block

-    severe heart failure

-    administration by the intravenous route

-    infants aged less than 30 months of age

4.4 Special Warnings and Special Precautions for Use

As with other antibiotics, the use of cefotaxime, especially if prolonged, may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

- Anaphalactic reactions

Serious, including fatal hypersensitivity reactions have been reported in patients receiving cefotaxime (see sections 4.3 and 4.8).

If a hypersensitivity reaction occurs, treatment must be stopped.

The use of cefotaxime is strictly contra-indicated in subjects with a previous history of immediate-type hypersensitivity to cephalosporins.

Since cross allergy exists between penicillins and cephalosporins, use of the latter should be undertaken with extreme caution in penicillin sensitive subjects.

-    Serious bullous reactions

Cases of serious bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with cefotaxime (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

-    Clostridium difficile associated disease (e.g. pseudomembranous colitis)

Diarrhea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment, may be symptomatic of Clostridium difficile associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudo-membranous colitis.

The diagnosis of this rare but possibly fatal condition can be confirmed by endoscopy and/or histology.

It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of cefotaxime.

If a diagnosis of pseudomembranous colitis is suspected, cefotaxime should be stopped immediately and appropriate specific antibiotic therapy should be started without delay.

Clostridium difficile associated disease can be favoured by faecal stasis. Medicinal products that inhibit peristalsis should not be given.

-    Haematological reactions

Leukopenia, neutropenia and, more rarely, agranulocytosis may develop during treatment with cefotaxime, particularly if given over long periods. For treatment courses lasting longer than 7-10 days, the blood white cell count should be monitored and treatment stopped in the event of neutropenia.

Some cases of eosinophilia and thrombocytopenia, rapidly reversible on stopping treatment, have been reported. Cases of haemolytic anemia have also been reported. (see section 4.8)

-    Patients with renal insufficiency

The dosage should be modified according to the creatinine clearance calculated (see section 4.2).

Caution should be exercised if cefotaxime is administered together with aminoglycosides; probenecid or other nephrotoxic drugs (see section 4.5). Renal function must be monitored in these patients, the elderly, and those with pre-existing renal impairment.

-    Neurotoxicity

High doses of beta-lactam antibiotics, including cefotaxime, particularly in patients with renal insufficiency, may result in encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions) (see section 4.8).

Patients should be advised to contact their doctor immediately prior to continuing treatment if such reactions occur.

-    Precautions for administration

During post-marketing surveillance, potentially life-threatening arrhythmia has been reported in a very few patients who received rapid intravenous administration of cefotaxime through a central venous catheter. The recommended time for injection or infusion should be followed (see section 4.2).

See section 4.3 for contraindications for formulations containing lidocaine.

-    Effects on Laboratory Tests

As with other cephalosporins a positive Coombs' test has been found in some patients treated with cefotaxime. This phenomenon can interfere with the cross-matching of blood.

Urinary glucose testing with non-specific reducing agents may yield falsepositive results. This phenomenon is not seen when a glucose-oxydase specific method is used.

-    Sodium intake

The sodium content of cefotaxime sodium (48.2 mg/g) should be taken into account.

4.5 Interaction with other medicinal products and other forms of interaction

Uricosurics: Probenecid interferes with the renal tubular transfer of cefotaxime, thereby increasing cefotaxime exposure about 2-fold and reducing renal clearance to about half at therapeutic doses. Due to the large therapeutic index of cefotaxime, no dosage adjustment is needed in patients with normal renal function. Dosage adjustment may be needed in patients with renal impairment (see sections 4.4 and 4.2).

Aminoglycoside antibiotics and diuretics: As with other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide). Renal function must be monitored in these patients (see section 4.4).

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:

The safety of cefotaxime has not been established in human pregnancy.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. They are, however, no adequate and well controlled studies in pregnant women.

Cefotaxime crosses the placental barrier. Therefore, cefotaxime should not be used during pregnancy unless the anticipated benefit outweighs any potential risks.

Lactation:

Cefotaxime passes into human breast milk.

Effects on the physiological intestinal flora of the breast-fed infant leading to diarrhoea, colonisation by yeast-like fungi, and sensitisation of the infant cannot be excluded.

Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7    Effects on ability to drive and use machines

There is no evidence that cefotaxime directly impairs the ability to drive or to operate machines. High doses of cefotaxime, particularly in patients with renal insufficiency, may cause encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions) (see section 4.8). Patients should be advised not to drive or operate machinery if any such symptoms occur.

4.8 Undesirable Effects

System	Very	Common	Uncommon	Rare	Very rare	Not known
organ class	Common ( 1/10)	( 1/100 to <1/10)	( 1/1,000 to <1/100)	(>1/10,000 to <1/1,000)	(<1/10,000)	(cannot be estimated from available data)*

Infections and infestations						Superinfection (see section 4.4)
Blood and the lymphatic system disorders			Leukopenia Eosinophilia Thrombo cytopenia			Neutropenia Agranulocytosis (see section 4.4) Haemolytic anaemia
Immune system disorders			Jarisch- Herxheimer reaction			Anaphylactic reactions Angioedema Bronchospasm Anaphylactic shock
Nervous system disorders			Convulsions (see section 4.4)			Headache Dizziness Encephalopathy (e.g. impairment of consciousness, abnormal movements) (see section 4.4)
Cardiac disorders						Arrhythmia following rapid bolus infusion through central venous catheter
Gastro intestinal disorders			Diarrhea			Nausea Vomiting Abdominal pain Pseudomembrano us colitis (see section 4.4) Candidiasis
Hepato- bilary disorders			Increase in liver enzymes (ALAT, ASAT, LDH, gamma- GT and/or alkaline phosphatase) and/or bilirubin			Hepatitis* (sometimes with jaundice)
Skin and subcutaneou s tissue disorders			Rash Pruritus Urticaria			Erythema multiforme Stevens-Johnson syndrome

						Toxic epidermal necrolysis (see section 4.4)
Renal and Urinary disorders			Decrease in renal function/ increase of creatinine (particularly when coprescribed with aminoglycosi des)			Interstititial nephritis
General disorders and administrati on site conditions	For IM formulati ons: Pain at the injection site		Fever Inflammatory reactions at the injection site, including phlebitis/ thrombophleb itis			For IM formulations (since the solvent contains lidocaine): Systemic reactions to lidocaine

postmarketing experience

Jarisch-Herxheimer reaction

For the treatment of borreliosis (Lyme’s Disease), a Jarisch-Herxheimer reaction may develop during the first days of treatment.

The occurrence of one or more of the following symptoms has been reported after several week's treatment of borreliosis: skin rash, itching, fever, leucopenia, increase in liver enzymes, difficulty of breathing, joint discomfort.

Hepatobiliary disorders

Increase in liver enzymes (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) and/or bilirubin have been observed. These laboratory abnormalities may rarely exceed twice the upper limit of the normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms of overdose may largely correspond to the profile of side effects.

There is a risk of reversible encephalopathy in cases of administration of high doses of B-lactam antibiotics including cefotaxime.

In case of overdose, cefotaxime must be discontinued, and supportive treatment initiated, which includes measures to accelerate elimination, and symptomatic treatment of adverse reactions (e.g. convulsions).

No specific antidote exists. Serum levels of cefotaxime can be reduced by haemodialysis or peritoneal dialysis.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Claforan is a broad spectrum bactericidal cephalosporin antibiotic. Claforan 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

Table 1

Pharmacokinetics in adults

1.

2.

3.

4.

	Healthy Adults	Healthy Adults
	i.v. (5 min)	i.m.
Dose Absorbtion	1g	1g
Bioavailability in % Kinetic parameters	100	90-95
Tmax (h)		0.5
Cmax (pg/ml)	100	20-30
Terminal half-life (h)	0.9 - 1.1	1.
Volume of distribution (liters/kg) Protein binding	0.30
- Type	Albumin
- % Metabolism	25-40
Liver Kidney Other tissues % -    Product -    Metabolites	+
M1	Desacetyl CTX*
M2	Lactamine form
M3 Excretion	Lactamine form

Urine	90% CTX: 50% desacetyl CTX: 1525% M2 + M3: 15-30%
Faeces %	10%

*The half-life of desacetylcefotaxime in healthy subjects is approximatively 2h. Its antibacterial activity is synergistic with that of cefotaxime.

After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102^g/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200^,g/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 21.6L/1.73m2 after 1g intravenous 30 minute infusion.

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^g/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the MIC of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4^g/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 217ml/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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

None

6.2    Incompatibilities

None stated

6.3    Shelf life

Finished Product: 24 months Reconstituted Solution: 24 hours

6.4    Special precautions for storage

Finished Product: Store below 25°C. Protect from light.

Reconstituted Solution: Whilst it is preferable to use only freshly prepared solutions for both intravenous and intra muscular injection, Claforan is compatible with several commonly used intravenous infusion fluids and will retain satisfactory potency for up to 24 hours refrigerated (2-8°C) in the following:

Water for Injections

Sodium Chloride Injection

5% Dextrose Injection

Dextrose and Sodium Chloride Injection

Compound Sodium Lactate Injection (Ringer-lactate Injection)

After 24 hours any unused solution should be discarded.

Claforan is also compatible with 1% lidocaine, however freshly prepared solutions should be used.

Claforan is also compatible with metronidazole infusion (500mg, 100ml) and both will maintain potency when refrigerated (2-8°C) for up to 24 hours. Some increase in colour of prepared solutions may occur on storage. However, provided the recommended storage conditions are observed, this does not indicate change in potency or safety.

6.5    Nature and contents of container

Claforan is supplied in tubular or moulded glass vials, closed with a grey elastomer stopper and sealed with either an aluminium cap fitted with a detachable flip top, or an infusion connector closure.

The bottles are boxed individually and in packs of 10, 25 or 50.

7 MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

or Trading as Sanofi-aventis or Sanofi Winthrop

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8    MARKETING AUTHORISATION NUMBER

PL 04425/0188

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/03/1981 / 26/02/2009

10 DATE OF REVISION OF THE TEXT

11/03/2014