4.1. Therapeutic indications

Cefotaxime is indicated in the treatment of the following severe infections when known or thought very likely to be caused by bacteria that are susceptible to cefotaxime (see section 4.4 and 5.1):

- Bacterial pneumonia

- Complicated infections of the urinary tract including pyelonephritis

- Severe skin and soft tissue infections

- Genital infections, including gonorrhoea

- Intra-abdominal infections (such as peritonitis)

- Bacterial meningitis

- Endocarditis

- Borreliosis

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Perioperative prophylaxis. For surgical operations with increased risk of infections with anaerobic pathogens, e.g. colorectal surgery, a combination with an appropriate drug with activity against anaerobes is recommended.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Cefotaxime may be administered by intravenous bolus injection or intravenous infusion or by intramuscular injection after reconstitution of the solution.

Dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient's condition.

Therapy may be started before the result of microbiological tests are known.

Adults and adolescents over 12 years

Adults and adolescents usually receive 2 to 6 g cefotaxime daily. The daily dose should be divided in two single doses every 12 hours.

- Common infections in presence (or suspicion) of sensitive bacteria: 1 g every 12 hours.

- Infections in presence (or suspicion) of several sensitive or moderately sensitive bacteria: 1 – 2 g every 12 hours.

- Severe infections or for infections that cannot be localised: 2 – 3 g as a single dose every 6 to 8 hours (maximum daily dose: 12 g).

A combination of cefotaxime and other antibiotics is indicated in severe infections.

Term newborn (0-28 days), infants and children up to 12 years of age

Depending on the severity of the infection: 50 – 100 – 150 mg / kg / day, 12 – 6 hourly.

In life-threatening situations the daily dose may be raised to 200 mg/kg/day under careful attention of the renal function, especially in the newborn period 0 – 7 days due to not fully matured kidney function.

Premature infants

The recommended dosage is 50 mg / kg / day divided into 2 to 4 doses (every 12 to 6 hours). This maximum dose should not be exceeded due to the not yet fully matured kidneys.

Elderly

No dosage adjustment is required, provided that the function of the kidneys and the liver is normal.

Other special recommendations

Gonorrhoea

For gonorrhoea, a single injection (intramuscularly or intravenously) of 500 mg – 1 g cefotaxime. For complicated infections, consideration should be given to available official guidelines. Syphilis should be excluded before initiating treatment.

Bacterial meningitis

Adults: Daily dose of 9 – 12 g cefotaxime divided into equal doses every 6 – 8 hours (3 g 3 – 4 times daily).

Children: 150 – 200 mg / kg / day divided into equal doses every 6 – 8 hours.

Newborns: 0 – 7 days: 50 mg / kg every 12 hours, 7 – 28 days: 50 mg / kg every 8 hours.

Perioperative prophylaxis

1 – 2 g as single dose as close to start of surgery as possible. In those cases where the operation time exceeds 90 minute an additional dose of prophylactic antibiotic should be given.

Intra-abdominal infections

Intra-abdominal infections should be treated with cefotaxime in combination with other antibiotics with coverage for anaerobic bacteria.

Dosage in renal function impairment:

In adult patients with a creatinine clearance of ≤ 5 mL / min, the initial dose equal to the recommended usual dose but the maintenance dose should be reduced by half without change in the frequency of dosing. Blood tests to determine the required dose may be carried out.

Dosage in dialysis or peritoneal dialysis

In patients on haemodialysis and peritoneal dialysis an intravenous injection of 500 mg – 2 g, given at the end of each dialysis session and repeated every 24 hours, is sufficient to treat most infections efficaciously.

Duration of therapy

The duration of therapy with cefotaxime depends on the clinical condition of the patient and varies according to the bacteriological progress. Administration of cefotaxime should be continued until symptoms have subsided or evidence of bacterial eradication has been obtained. Treatment over at least 10 days is necessary in infections caused by Streptococcus pyogenes (parenteral therapy may be switched to an adequate oral therapy before the end of the 10 day period).

Method of administration

Intravenous infusion

In order to avoid any risk of infection, the reconstitution of the solution for infusion should be done in close aseptic conditions. Do not postpone the infusion after the reconstitution of the solution.

For short intravenous infusion: Following reconstitution, the solution should be administered over 20 minutes.

For long lasting intravenous infusion: Following reconstitution, the solution should be administered over 50 – 60 minutes.

Intravenous injection

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.

Intramuscular injection

The intramuscular method of administration is restricted to exceptional clinical situations (e.g. gonorrhoea). It is not indicated in severe infections and should undergo a risk-benefit assessment. It is recommended that no more than 4 ml are injected unilaterally. If the daily dose exceeds 2 g cefotaxime or if cefotaxime is injected more frequently than twice per day, the intravenous route is recommended. In case of severe infections, intramuscular injection is not recommended.

The solution should be administered by deep intramuscular injection. Solutions with lidocaine must not be administered intravenously. Cefotaxime reconstituted with lidocaine should not be administrated to children in the first year of age. The product information of the chosen lidocain containing medicinal product must be regarded.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

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

4.3. Contraindications

- Hypersensitivity to the active substance, to other cephalosporins or any of the excipients listed in section 6.1.

- Previous, immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam antibiotic.

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 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.

- Anaphylactic 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.

- Severe skin reactions

Severe cutaneous adverse reactions (SCARs) including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with cefotaxime treatment.

At the time of prescription patients should be advised of the signs and symptoms for skin reactions.

If signs and symptoms suggestive of these reactions appear, cefotaxime should be withdrawn immediately. If the patient has developed AGEP, SJS, TEN or DRESS with the use of cefotaxime, treatment with cefotaxime must not be restarted and should be permanently discontinued.

In children, the presentation of a rash can be mistaken for the underlying infection or an alternative infectious process, and physicians should consider the possibility of a reaction to cefotaxime in children that develop symptoms of rash and fever during therapy with cefotaxime.

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 diarrhea 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

Leucopenia, neutropenia and, more rarely, bone marrow failure, pancytopenia or agranulocytosis may develop during treatment with cefotaxime (see Section 4.8.). 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

For patients with impaired renal function, 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 preexisting 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.

- The use of cefotaxime for treatment of endocarditis should be restricted to patients known to have penicillin allergy (not type 1). Cefotaxime should be used in combination with other appropriate antibacterial agents, considering its limited antibacterial spectrum.

- 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 false-positive results. This phenomenon is not seen when a glucose-oxydase specific method is used.

- Sodium intake

This medicinal product contains 48 mg (2.09 mmol) sodium per 1 of powder, equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Cefotaxime is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

This medicinal product is administered only after reconstitution - see section 6.6.

The sodium content of the diluent should be taken into account when calculating the total sodium content of the prepared dilution of the product. For detailed information on the sodium content of the solution used to dilute the product, please refer to the product characteristics of the diluent used.

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).

Bacteriostatic antibiotics: Cefotaxime should not be combined with bacteriostatic antibiotics (e.g. tetracyclines, erythromycin and chloramphenicol) because an antagonistic effect is possible.

Interference with Laboratory Tests: As with other cephalosporins, a positive Coombs' test has been seen in some patients treated with cefotaxime. This phenomenon can interfere with the cross-matching of blood.

A false positive reaction to glucose may occur with reducing substances (e.g. Fehling's solution) but not with the use of specific glucose oxidase methods.

4.6. Fertility, 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. There 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.

Breastfeeding

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).

In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may be impaired. In such cases patients should refrain from driving cars and using machines.

4.8. Undesirable effects

System organ class

Very Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Very rare

(<1/10,000)

Not known (cannot be estimated from available data)*

Infections and infestations

Superinfection (see section 4.9)

Blood and the lymphatic system disorders

Leukopenia

Eosinophilia

Thrombocytopenia

Bone marrow failure

Pancytopenia

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.

Palpitations

Gastrointestinal disorders

Diarrhea

Nausea

Vomiting

Abdominal pain

Pseudomembranous 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 subcutaneous tissue disorders

Rash

Pruritus

Urticaria

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis (see section 4.4)

Acute generalised exanthematous pustulosis (AGEP)

Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4)

Renal and urinary disorders

Decrease in renal function/increase of creatinine (particularly when coprescribed with aminoglycosides)

Acute renal failure (see section 4.4)

Interstititial nephritis

General disorders and administration site conditions

For IM formulations: Pain at the injection site

Fever

Inflammatory reactions at the injection site, including phlebitis/ thrombophlebitis, Malaise, Fatigue

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 authorization 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, Website: (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 ß-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.