Cefotaxime 2g Powder for solution for injection or infusion

Each vial contains cefotaxime sodium equivalent to 2g of cefotaxime.

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

For a full list of excipients, see section 6.1.

Powder for solution for injection or infusion (Powder for injection or infusion).

White to slightly yellow powder.

1. Cefotaxime is indicated in the treatment of serious infections, either before the infecting organism has been identified or when caused by bacteria of established sensitivity, including

osteomyelitis,

septicaemia,

bacterial endocarditis,

meningitis, and

peritonitis.

and other serious bacterial infections suitable for parenteral antibiotic therapy.

2. Cefotaxime may be used for pre-operative prophylaxis in patients undergoing surgical procedures, that may be classified as contaminated or potentially so.

Cefotaxime may be administered intravenously, by bolus injection or by infusion, or by intramuscular injection. 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 three or four 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 two to four divided doses. However, in very severe infection doses of up to 200mg/kg/day may be required.

Neonates: The recommended dosage is 50mg/kg/day in two to four divided doses. In severe infections 150-200mg/kg/day, in divided doses, have been given.

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.

Dosage in hepatic impairment: No dosage adjustment is required.

Intravenous and Intramuscular Administration: Reconstitute cefotaxime with Water for Injections PhEur 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.

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.

Known or suspected allergy to cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug.

Cefotaxime constituted with Lidocaine Injection BP must never be used:

- by the intravenous route

- in infants under 30 months

- in subjects with a previous history of hypersensitivity to Lidocaine Injection BP

- in patients who have an unpaced heart block

- in patients with severe heart failure.

Preliminary enquiry about hypersensitivity to penicillin and other β-Lactam antibiotics is necessary before prescribing cephalosporins since cross allergy occurs in 5–10% of cases. Cefotaxime is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other betalactam drug (see section 4.3, Contraindications). Cefotaxime should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other betalactam drug. 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”.

Since haematological abnormalities may develop during treatment with cefotaxime, blood count should be monitored if treatment lasts for longer than 7 days. In case of neutropenia (<1400 neutrophils/mm³), treatment should be interrupted.

As with other antibiotics, the use of cefotaxime, especially if prolonged, may result in overgrowth of non susceptible organisms, such as Enterococcus spp, candida, Pseudomonas aeruginosa. 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.

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.

Aminoglycoside antibiotics and diuretics: Cephalosporin antibiotics at high dosage should be given with caution to patients receiving aminoglycoside antibiotics or potent diuretics such as frusemide 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.

Uricosurics: Probenecid interferes with renal tubular transfer of cefotaxime delaying its excretion and increasing the plasma concentration.

Interference with Laboratory Tests:

A false positive Coombs test may be seen during treatment with cephalosporins. This phenomenon may occur during treatment with cefotaxime and can interfere with blood cross-matching.

A false positive reaction to urinary glucose may occur with copper reduction methods (Benedict's, Fehling's or Clinitest) but not with the use of specific glucose oxidase methods.

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 in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Consequently caution should be exercised when cefotaxime is administered to a nursing woman.

.

Cefotaxime has been associated with dizziness, which may affect the ability to drive or operate machinery.

Adverse reactions to cefotaxime have occurred relatively infrequently and have generally been mild and transient. Effects reported include the following;

Genitourinary: Candidiasis.

Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhoea (diarrhoea may sometimes be a symptom of pseudomembranous colitis see 4.4, Special Warnings and precautions for use).

Hepatobiliary: Transient rises in liver transaminases, alkaline phosphatase and/or bilirubin, transient hepatitis and cholestatic jaundice.

Renal: 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.

Nervous system: Headache, dizziness. 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: 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.

Blood and lymphatic system: 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.

Cardiac: Avery small number of cases of arrhythmias have occurred following rapid bolus infusion through a central venous catheter.

Local effects: 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.

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.

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.

General Properties

ATC Classification

Pharmacotherapeutic group: Beta-lactam antibiotics, cephalosporins.

ATC Code: J01D A10

Mode of action

Cefotaxime is a third generation broad spectrum bactericidal cephalosporin antibiotic. The bactericidal properties are due to the inhibitory effect of cefotaxime on bacterial cell wall synthesis.

Mechanisms of resistance

Resistance to Cefotaxime may be due to production of extended-spectrum beta-lactamases that can efficiently hydrolyse the drug, to the induction and/or constitutive expression of AmpC enzymes, to impermeability or to efflux pump mechanisms. More than one of these possible mechanisms may co-exist in a single bacterium.

Breakpoints:

Current MIC breakpoints used to interpret cefotaxime susceptibility data are shown below.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)

1. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).

2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.

3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).

4. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.

RD = rationale document listing data used by EUCAST for determining breakpoints.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on the probabilities whether micro-organisms will be susceptible to cefotaxime or not.

^*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

Methicillin-(oxacillin) resistant staphylococci (MRSA) are resistant to all currently available β-lactam antibiotics including cefotaxime.

Penicillin-resistant Streptococcus pneumoniae show a variable degree of cross-resistance to cephalosporins such as cefotaxime.

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 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 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.

There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.

None.

Cefotaxime sodium should not be mixed with alkaline solutions such as sodium bicarbonate injection or solutions containing aminophylline.

Cefotaxime should not be admixed with aminoglycosides. If they are used concurrently they should be administered in separate sites.

Cefotaxime should not be mixed with other medicinal products except those listed in section 6.6.

Unopened: 2 years.

For the reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Unopened: Do not store above 25°C. Keep the vials in the outer carton.

For storage times following reconstitution, see section 6.3.

Cefotaxime is supplied in Type III 10ml glass vials, closed with a Type I rubber stopper coated in Omniflex and sealed with an aluminium cap fitted with a detachable flip top.

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

Not all pack sizes may be marketed.

For single use only. Discard any unused contents.

When dissolved in Water for Injections PhEur, cefotaxime forms a straw-coloured solution suitable for intravenous and intramuscular injection. Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety.

Dilution table (Intramuscular and Intravenous administration):

Reconstituted solution: Whilst it is preferable to use only freshly prepared solutions for both intravenous and intramuscular injection, cefotaxime is compatible with several commonly used intravenous infusion fluids and will retain satisfactory potency for up to 24 hours refrigerated in the following:

Water for Injections Ph Eur

Sodium Chloride Intravenous Infusion BP

5% Glucose Intravenous Infusion BP

Sodium Chloride and Glucose Intravenous Infusion BP

Compound Sodium Lactate Intravenous Infusion BP (Ringer-lactate solution for injection)

Intravenous Infusion:

1-2g cefotaxime are dissolved in 40-100ml of infusion fluid.

After 24 hours any unused solution should be discarded.

Cefotaxime is compatible with 1% lidocaine; however freshly prepared solutions should be used.

Cefotaxime is also compatible with metronidazole infusion (500mg/100ml) and both will maintain potency when refrigerated (2º-8ºC) 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.

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

PL 29831/0029

PA 1339/2/3

Date of first authorisation: 13 October 2007 (UK)

19 December 2007 (Ireland)