SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Cefotaxim Eberth 0.5g powder for solution for injection. Cefotaxim Eberth 1 g powder for solution for injection or infusion. Cefotaxim Eberth 2 g powder for solution for injection or infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 500 mg vial contains 500 mg cefotaxime (as cefotaxime sodium). Each 1 g vial contains 1 g cefotaxime (as cefotaxime sodium). Each 2 g vial contains 2 g cefotaxime (as cefotaxime sodium). Excipient(s): Each 500 mg vial contains 24 mg sodium. Each 1 g vial contains 48 mg sodium. Each 2 g vial contains 96 mg sodium. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Cefotaxim Eberth 0,5 g: Powder for solution for injection. Cefotaxim Eberth 1 g: Powder for solution for injection or infusion. Cefotaxim Eberth 2 g: Powder for solution for injection or infusion. Appearance: White to slightly yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Cefotaxime is indicated for the treatment of the following severe infections when known or thought very likely to be due to bacteria that are susceptible to cefotaxime (see section 5.1): • Bacterial pneumonia • Complicated infections of the kidneys and upper urinary tract. • Severe infections of the skin and soft tissue. • Genital infections caused by gonococci, particularly when penicillin has failed or is unsuitable. • Intra-abdominal infections (such as peritonitis • Acute bacterial meningitis • Septicaemic infections originating from the lungs, urinary tract or intestines. Consideration should be given to official guidance on the appropriate use of antibacterial agents 4.2 Posology and method of administration Cefotaxim Eberth may be administered by intravenous bolus injection, by intravenous infusion, or by intramuscular injection, after reconstitution of the solution according to the directions given below. Dosing and mode of administration should be based on the severity of the infection, susceptibility of the causative organism and the patient's condition. Therapy may be started before the results of sensitivity tests are known. Cefotaxim Eberth has synergistic effects with aminoglycosides. Adults and adolescents ( 12 to 18 years): The usual dose in adults and adolescents is 2 to 6 g daily. The daily dosage should be divided in two single doses each 12 hour. However, dosage may be varied according to the severity of the infection, sensitivity of causative organisms and condition of the patient. Common infections in presence (or suspicion) of a sensitive pathogen: 1 g every 12 hours corresponding to a total daily dosage of 2 g. Infections in presence (or suspicion) of several sensitive or moderately sensitive pathogens: 1-2 g every 12 hours corresponding to a total daily dosage of 2-4 g. Severe infection by unidentified pathogens or for infections that cannot be localised: 2-3 g as a single dose every 6 to 8 hours up to a maximum daily dosage of 12 g. Infants and children (from 28 days up to 11 years of age): The usual dosage for infants and children <50 kg is 50-100 mg/kg/day divided into 2 to 4 doses (every 12 to 6 hours). In very severe infections up to 200 mg/kg/day divided into 2-4 doses may be required. In infants and children > 50 kg the usual dose in adults should be given, without exceeding the maximum daily dose of 12 g. Term newborn infants (0 to 27 days): Term newborn 0 to 7 days (any severity): The recommended dosage is 50 mg/kg/day in two divided equal doses ( every 12 hours). Term newborn 8 to 27 days: The recommended dosage is 150 mg/kg/day in 3 divided equal doses (every 8 hour). Please see also special dose recommendations for meningitis below. Preterm newborn 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 and renal function. Elderly: No dosage adjustment is required, provided that the renal and hepatic functions are normal. Other recommendations: Gonorrhoea: For uncomplicated gonorrhoea, a single injection Cefotaxim Eberth 0.5 g is administered (intramuscularly). For complicated infections a dose increase may be necessary. Consideration should be given to available official guidelines. Syphilis should be excluded before initiating the treatment. Bacterial meningitis: In adults daily doses of 6 to 12 g divided into equal doses every 6 to 8 hours are recommended. . Infants and toddlers (28 days to 23 months) and children (2 to 11 years): 150 to 200 mg/kg divided into equal doses every 6 to 8 hours. Term newborn infants: Term newborn infants 0 to 7 days: 50 mg/kg every 12 hours. Term newborn infants 8 to 27 days: 50 mg/kg every 8 hours. Intra-abdominal infections: Cefotaxime should be used in combination with an antibiotic that is active against anaerobes in the treatment of intra-abdominal infections (please refer to section 5.1). Duration of therapy: The duration of therapy with Cefotaxim Eberth depends on the clinical condition of the patient and varies according to the cause of the disease. Administration of Cefotaxim Eberth 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). Impaired renal function: In adult patients with a creatinine clearance of 5 ml/min, the initial dose is similar to the recommended usual dose but the maintenance dose should be reduced by half without change in the frequency of dosing. Dialysis or peritoneal dialysis: In patients on hemodialysis and peritoneal dialysis an i.v. injection of 0.5g- 2g, administered at the end of each dialysis session and repeated every 24 hours, is sufficient to treat most infections effectively. Septicemic infections: In case of gram-negative pathogens a combination with another suitable antibiotic should be considered (please refer to section 5.1). Method of administration: The intramuscular method of administration is reserved to exceptional clinical situations and should undergo a risk-benefit assessment! It is recommended that no more than 4 ml is injected unilaterally. If the daily dose exceeds 2 g cefotaxime, or if cefotaxime is injected more frequently than twice per day, the i.v. route is recommended. Intramuscular administration of cefotaxime reconstituted with lidocaine should not be administrated to children in the first year of age. The product information of the chosen lidocaine-containing medicinal product must be regarded. In order to avoid any risk of infection, the reconstitution of the infusion should be done in close aseptic conditions. Do not postpone the infusion after the reconstitution of the solution. Intravenous infusion: For short intravenous infusion: Following reconstitution the solution should be administered as a 20 minute intravenous infusion. For long lasting intravenous infusion: Following reconstitution, the solution should be administered as a 50-60 minutes intravenous infusion. Intravenous injection: For intravenous injection: Following reconstitution, the injection time should be 3-5 minutes. Intramuscular injection: The solution should be administered by deep intramuscular injection. Solutions with lidocaine must not be administered intravenously. If the total daily dose is more than 2 g, the intravenous administration should be chosen. In case of severe infections, intramuscular injection is not recommended. The following table shows the volume of dissolution for each vial size. Mode of administration
For instructions on reconstitution of the product before administration, see section 6.6. 4.3 Contraindications Cefotaxim Eberth should not be used in patients - with hypersensitivity to the active substance cefotaxime, to other cephalosporins or to any of the excipients. - previous, immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam antibiotic. 4.4 Special warnings and precautions for use • Special care is indicated in patients who have experienced any allergic reaction to penicillins or any other beta-lactam antibiotics as cross-reactions may occur (for contraindications due to known hypersensitivity reactions see section 4.3). If anaphylactic reactions occur, the treatment must be withdrawn and appropriate emergency treatment measure must be initiated. • Patients with severe renal dysfunction may need dosage adjustment (see section 4.2.). • Cefotaxim Eberth should be used with caution in patients with allergic diathesis and asthma. • As with other broad-spectrum antibiotics, prolonged use may result in the overgrowth of non susceptible organisms, which may require interruption of treatment. If super-infection occurs during treatment, specific anti-microbial therapy should be instituted if considered clinically necessary. • Pseudomembranous colitis has been reported with the use of broad-spectrum antibiotics. Therefore, it is important to consider its diagnosis in patients who develop severe diarrhoea during or after antibiotic use. The presence of C. difficile toxin should be investigated and treatment with cefotaxime stopped in cases of suspected colitis. The diagnosis can be confirmed by toxin detection and 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. • 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. • Do not mix aminoglycosides and cefotaxim in the same syringe or liquids for perfusion. • Fast infusion in a central vein can cause arrhythmia. • The sodium content of cefotaxime (2.09mmol/g) should be taken into account when prescribing to patients requiring sodium retention. • In case of intramuscular administration of Cefotaxim Eberth with lidocaine the summary of product characteristics of the lidocaine containing product should be regarded. Sodium The sodium content is 2.09 mmol pr. gr.; caution in patients with cardiac insufficiency/patients requiring sodium retention. 4.5 Interaction with other medicinal products and other forms of interaction Probenecid: Concomitant administration of probenecid results in an increase and a prolongation of serum concentrations of cefotaxime by inhibition of renal elimination of cefotaxime. Oral contraceptives: The efficacy of oral contraceptives may be decreased by concomitant use of cefotaxime. Therefore during therapy with Cefotaxim Eberth additional contraceptive methods should be used. Aminoglycocides, diuretics: Concurrent treatment with high doses of cephalosporins and nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Monitoring of the renal function is strongly recommended. Bacteriostatic antibiotics: Cefotaxim Eberth should not be combined with bacteriostatic antibiotics (e.g. tetracyclines, erythromycin and chloramphenicol) because an antagonistic effect is possible. Other forms of interactions: 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 (Benedict's or Fehling's solution, or with Clinitest tablets) but not with the use of specific enzyme-based tests (glucose oxidase methods). 4.6 Pregnancy and lactation Pregnancy: Cefotaxim Eberth should only be used during pregnancy if mandatorily indicated, when the benefit outweighs the possible risk for the foetus. Experience with the use of Cefotaxim Eberth in pregnant women is poor. Cefotaxime crosses the placenta. Animal trials do not indicate any direct or indirect harmful affect on pregnancy, the embryonic development, delivery or postnatal development (see section 5.3). Lactation: Cefotaxim Eberth should not be used during lactation. If treatment is necessary, lactation must be stopped. Cefotaxime is excreted in human milk in low concentrations. Use during lactation can in infants lead to an effect on the physiological intestinal flora with diarrhoea, to Saccharomyces colonisation, and may also result in sensitisation. 4.7 Effects on abilitity to drive and use machines Cefotaxim Eberth has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Approximately 5% of all treated patients may expect side effects. These side effects are mostly dose-dependent and due to pharmacological effects of the medicinal product.
4.9 Overdose Symptoms: Cases of acute intoxication with cefotaxime have not been published. Symptoms of overdose may largely correspond to the profile of side effects. In cases of overdosage (particularly in renal insufficiency) there is a risk of reversible encephalopathy. Treatment: Symptomatic treatment. Maintain good diuresis. Possibly haemodialysis or peritoneal dialysis in case of toxic reactions or renal impairment. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Cefotaxime is a parenteral betalactam-antibiotic of the group of cephalosporins. Third-generation cephalosporins. ATC Code: J01DD01 Mode of action The bactericidal activity of cefotaxime results from the inhibition of bacterial cell wall synthesis (during the period of growth) caused by an inhibition of penicillin-binding proteins (PBPs) like transpeptidases. Pharmacokinetics and pharmacodynamics relationship The extent of the bactericidal activity depends on the period of time when the serum level exceeds the minimal inhibitory concentration (MIC) of the pathogen. Mechanism of resistance A resistance to cefotaxime may be caused by following mechanisms: - inactivation by beta-lactamases. Cefotaxime can be hydrolysed by certain beta-lactamases, especially by extended-spectrum beta-lactamases (ESBLs) which can be found in strains of Escherichia coli or Klebsiella pneumoniae, or by chromosomal encoded inducible or constitutive beta-lactamases of the AmpC type which can be detected in Enterobacter cloacae. Therefore infections caused by pathogens with inducible, chromosomal encoded AmpC- beta-lactamases should not be treated with cefotaxime even in case of proven in-vitro-susceptibility because of the risk of the selection of mutants with constitutive, derepressed AmpC- beta-lactamases-expression. - reduced affinity of PBPs against cefotaxime. The acquired resistance of Pneumococci and other Streptococci is caused by modifications of already existing PBPs as a consequence of a mutation process. In contrast to this concerning the methicillin-(oxacillin-) resistant Staphylococcus, the creation of an additional PBP with reduced affinity against cefotaxime is responsible for resistance. - inadequate penetration of cefotaxime through the outer cell membrane of gram-negative bacteria so that the inhibition of the PBPs is insufficient. - the presence of transport mechanism (efflux pumps) being able to actively transport cefotaxime out of the cell. A complete cross resistance of cefotaxime occurs with ceftriaxone and partially with other penicillins and cephalosporins. Breakpoints: The following minimal inhibitory concentrations were defined for sensitive and resistant germs: EUCAST (European Committee on Antimicrobial Susceptibility Testing) break points (dated: Version 1.1, April 2010) December 2009):
*For Staphylococcus spp. the test results of oxacillin is used. Oxacillin-resistant Staphylococcus is assessed as resistant against cephalosporins. ** For Streptococcus spp. (groups A, B, C and G) the test results of penicillin G is used. *** Generally based on serum pharmacokinetics Susceptibility The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. If the efficacy of cefotaxime is questionable due to the local prevalence of resistance, expert opinion should be sought regarding the choice of therapy. In particular in the case of severe infections or failure of therapy a microbiological diagnosis including a verification of the germ and its susceptibility should be aspired. The prevalence of acquired resistance in Germany based on Version 1.1, April 2010 data of the last 5 years (December 2009):
Literature data, reference books and therapy guidelines support susceptibility. ° No current surveillance data available. Susceptibility is anticipated according to the current scientific knowledge. + In at least one region the resistance rate is > 50%. # In Intensive Care Units the resistance rate is ≥10%. % Extended Spectrum Beta-Lactamase (ESBL) producing strains are always resistant. $In the community areaaquired infections the resistance rate is < 10%. 5.2 Pharmacokinetic properties Absorption: Cefotaxim Eberth is for parenteral application. Mean peak concentrations 5 minutes after intravenous administration are about 81-102 mg/l following a 1 g dose of cefotaxime and about 167-214 mg/l 8 minutes after a 2 g dose. Intramuscular injection produces mean peak plasma concentrations of 20 mg/l within 30 minutes following a 1 g dose. Distribution: Cefotaxime has good penetration into different compartments. Therapeutic drug levels exceeding the minimum inhibitory levels for common pathogens can rapidly be achieved. Cerebrospinal fluid concentrations are low when the meninges are not inflamed but cefotaxime usually passes the blood-brain barrier in levels above the MIC of the sensitive pathogens when the meninges are inflamed (3-30 µg/ml). Cefotaxime concentrations (0.2-5.4 µg/ml), inhibitory for most gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1or 2 g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, peritoneal fluid and gall bladder wall, after therapeutic doses. High concentrations of cefotaxime and O-desacetyl-cefotaxime are achieved in bile. Cefotaxime passes the placenta and attains high concentrations in foetal fluid and tissues (up to 6 mg/kg). Small amounts of cefotaxime diffuse into the breast milk. Protein binding for cefotaxime is approximately 25-40%. The apparent distribution volume for cefotaxime is 21-37 l after 1 g intravenous infusion over 30 minutes. Biotransformation: Cefotaxime is partly metabolised in humans. Approximately 15-25% of a parenteral dose are metabolised to the O-desacetyl-cefotaxime metabolite, which also has antibiotic properties. Elimination: The main route of excretion of cefotaxime and O-desacetyl-cefotaxime is through the kidneys. Only a small amount (2%) of cefotaxime is excreted in the bile. In the urine collected within 6 hours 40-60% of the administered dose of cefotaxime is recovered as unchanged cefotaxime and 20% is found as O-desacetylcefotaxime. After admini-stration of radioactive labelled cefotaxime more than 80% can be recovered in the urine; 50-60% of this fraction is unchanged cefotaxime and the rest contains metabolites. The total clearance of cefotaxime is 240-390 ml/min and the renal clearance is 130-150 ml/min. The serum half-lives of cefotaxime and O-desacetyl-cefotaxime are normally about 50-80 and 90 minutes, respectively. In elderly, the serum half-life of cefotaxime is 120-150 min. In patients with severely impaired renal function (creatinine clearance 3-10 ml/min) the serum half-life of cefotaxime can be increased to 2.5-3.6 hours. There is no accumulation following administration of 1000 mg intravenously or 500 mg intramuscularly for 10 or 14 days. In term newborn infants the pharmacokinetics are influenced by gestation and chronological age, the half-life being prolonged in preterm and low birth weight term newborn infants of the same age. 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction. Cefotaxime passes through the placenta. After intravenous administration of 1 g cefotaxime during the birth values of 14 µg/ml were measured in the umbilical cord serum in the first 90 minutes after administration, which dropped to approximately 2.5 µg/ml by the end of the second hour after application. In the amniotic fluid, the highest concentration of 6.9 µg/ml was measured after 3-4 hours. This value exceeds the MIC for most gram-negative bacteria 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients None. 6.2 Incompatibilities Cefotaxim Eberth should not be mixed with other antibiotics in the same syringe or solution for infusion. This applies in particular for aminoglycosides. If both Cefotaxim Eberth and aminoglycosides shall be administered these medicinal products should be administered separately at different sites. Cefotaxim Eberth should not be dissolved in solutions having a pH-value of more than 7.5 e.g. sodium bicarbonate. 6.3 Shelf life 0.5 g powder for solution for injection: 3 years 1 g powder for solution for injection or infusion: 3 years 2 g powder for solution for injection or infusion: 3 years Chemical and physical in-use stability has been demonstrated for 24 hours at 4°C and 12 hours at 25°C. From a microbiological point of view 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 to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions. 6.4 Special precautions for storage Powder for solution for injection and powder for solution for injection or infusion: Do not store above 25°C. Store in the original package in order to protect from light. For storage of reconstituted solution, please refer to section 6.3. 6.5 Nature and contents of container 0.5 g: Glass vials (type II, nominal volume 15 ml) with chlorobutyl rubber stopper sealed with a yellow aluminium cap. 1 g: Glass vials (type II, nominal volume 15 ml) with chlorobutyl rubber stopper sealed with a blue aluminium cap. 2 g: Glass vials (type II, nominal volume 50 ml) with chlorobutyl rubber stopper sealed with a red aluminium cap. Pack sizes: 0.5 g: 1, 5, 10 and 50 vials 1 g: 1, 5, 10 and 50 vials 2 g: 1, 5, 10 and 50 vials Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling (For necessary dose recommendations – see section 4.2). Compatibility: Cefotaxim Eberth is compatible with: Sodium chloride 0.9%; dextrose 5% or 10% Ringer-lactate; lidocaine solution 1.0%. - Aseptic techniques should be used to reconstitute the solution. - The reconstituted solution should be administered immediately. - Any unused solution should be discarded. Intravenous infusion: Cefotaxim Eberth 1 g or 2 g: Preparation of a short term intravenous infusion For short term intravenous infusion 1 g or 2 g Cefotaxim Eberth should be dissolved in 40-50 ml water for injections or in another compatible solution for infusion as mentioned above (e.g. glucose 10%). Step 1: 15 ml of sodium chloride 9 mg/ml (0.9%) solution or another compatible solution for infusion is added to one vial of Cefotaxim Eberth 1 g giving a concentration of 66.7 mg/ml. Step 2: Shake the vial until all of the powder is dissolved. Step 3: Withdraw the calculated amount (see section 4.2) with a syringe and needle and dilute further to 40-50 ml with sodium chloride 9 mg/ml (0.9%) solution or another compatible solution for infusion, giving a concentration of 25 mg-20 mg/ml) Cefotaxim Eberth 2 g: Preparation of an long lasting intravenous infusion For long lasting intravenous infusion 2 g Cefotaxim Eberth 2 g should be dissolved in 100 ml of a suitable solution e.g. 0.9 % sodium chloride or isotonic glucose solution or other compatible solutions for infusions as mentioned above (see “Compatibility”)... Preparation of an intravenous solution for infusion: For the preparation of 2 g cefotaxime solution for infusion 1 vial of 50 ml Cefotaxim Eberth 2 g, a bottle of 100 ml sodium chloride 9 mg/ml (0.9%) solution for infusion and a sterile transfer device are needed. The transfer device will transfer or mix sterile liquids in closed system. Step 1: Connect the transfer device with the bottle of sterile sodium chloride 9 mg/ml (0.9%) solution for infusion or other approved dilution system by spiking the device through the plastic cap of the bottle. Step 2: Connect the other side of the device through the cap of the bottle with cefotaxime 2g powder for solution for infusion. Step 3: Mix the isotonic solution with the powder of cefotaxime by shaking the vial system until all the powder is dissolved. Step 4: Transfer all the solution into the 100 ml vial and disconnect the vial of cefotaxime from the transfer device. Step 5: Connect a device for infusion to the spike on top of the 100 ml vial filled with dissolved cefotaxime and start infusion. Use in the paediatric population (intravenous infusion): Reconstitution of an intravenous solution for infusion 1) 15 ml of sodium chloride 9 mg/ml (0.9%) solution or another compatible solution for infusion is added to one vial of Cefotaxim Eberth 1 g giving a concentration of 66.7 mg/ml. 2) Shake the vial until all of the powder is dissolved. 3) Withdraw the calculated amount (see section 4.2) with a syringe and needle and dilute further up to 40-50 ml with sodium chloride 9 mg/ml (0.9%) solution or another compatible solution for infusion. For shelf life and storage conditions following reconstitution, see section 6.3. Intravenous injection: Cefotaxim Eberth 0.5 g is dissolved in 2 ml water for injections or Cefotaxim Eberth, 1 g is dissolved in 4 ml water for injections and Cefotaxim Eberth 2 g is dissolved in 10 ml water for injections.. Intramuscular injection: Cefotaxim Eberth 0.5 g is dissolved in 2 ml water for injections or Cefotaxim Eberth 1.0 g is dissolved in 4 ml water for injections In order to prevent pain caused by the injection, Cefotaxim Eberth 0.5 g may be dissolved in 2 ml 1% lidocaine hydrochloride or Cefotaxim Eberth 1 g may be dissolved in 4 ml 1% lidocaine hydrochloride (only for adults). Following reconstitution the solution should be clear and pale yellow to brownish yellow. Do not use if any particulate matter is visible. Only for single use. 7. MARKETING AUTHORISATION HOLDER Dr. Friedrich Eberth Arzneimittel GmbH Werksweg 2 D-92551 Stulln Germany 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT [To be completed nationally] |
Antibiotics >
