Cladex

Cefotaxime sodium.

Each vial contains: Cefotaxime (as sodium) 1 g.

Pharmacology: Pharmacodynamics: Cefotaxime is a third-generation cephalosporin antibiotic. The active metabolite of cefotaxime, desacetyl-cefotaxime, has the additive or synergistic effect against the following species.
Pharmacokinetics: After a 1 g intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 mcg/mL. Doses of 500 mg and 2000 mg produce plasma concentrations of 38 and 200 mcg/mL, respectively. There is no accumulation following administration of 1000 mg intravenously or 500 mg intramuscularly for 10 or 14 days.
The apparent volume of distribution at steady-state of cefotaxime is 21.6 L/1.73 m² after 1 g intravenous 30 minutes infusion.
Concentrations of cefotaxime (usually determined by nonselective 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 mcg/mL in children with meningitis. Cefotaxime usually passes the blood-brain barrier at levels above the MIC of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 mcg/mL), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 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, 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 metabolized 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 390 mL/minute and renal clearance 145 to 217 mL/minute.
After intravenous administration of cefotaxime, 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.
Microbiology: Spectrum: As with other cephalosporin, in vitro studies have showed that cefotaxime is not active against staphylococcus compared to 1^st generation cephalosporins, but it has a broad spectrum of activity against Gram-negative bacteria compared to 1^st and 2^nd generation cephalosporins. In in vitro studies, cefotaxime is effective against infections caused by the following pathogens.
Gram-positive pathogens: Among Gram-positive bacteria cefotaxime is active against staphylococci and streptococci. Staphylococcus aureus, including penicillinase-producing strains but not methicillin resistant Staphylococcus aureus, is sensitive with an MIC₉₀ of about 2 to 4 mcg/mL, reduced in the presence of desacetyl-cefotaxime. Staphylococcus epidermidis is sensitive with an MIC₉₀ of about 8 mcg/mL, but penicillinase-producing strains are resistant. Streptococcus agalactiae (group B streptococci), Streptococcus pneumoniae, and Streptococcus pyogenes (group A streptococci) are all very sensitive (MIC₉₀ 0.1 mcg/mL) although truly penicillin resistant pneumococci are apparently not sensitive. Enterococci and Listeria monocytogenes are resistant. Cefotaxime also inhibits Streptococci viridans strains at concentrations 4 mcg/mL.
Gram-negative pathogens: Includes penicillin-resistant strains: Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, and Neisseria meningitis. Brucella melitensis is also reported to be sensitive. For many of these Gram-negative bacteria the MIC (minimum inhibitory concentrations) is under 1 mcg/mL and often much less. Some strains of Pseudomonas spp. are moderately susceptible to cefotaxime, but most are resistant.
Desacetyl-cefotaxime is active against many of these Gram-negative bacteria, but not against Pseudomonas spp.
Citrobacter freundi, C. diversus, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. rettgeri, P. vulgaris, Providencia, Salmonella, Serratia marcescens, Shigella spp., Yersinia enterocolitica, Pseudomonas aeruginosa, Ps. Maltophilia. Neisseria meningitis, Neisseria gonorrhoeae (including penicillinase-producing strains), and Acinetobacter.
Anaerobic pathogens: Bacteroides spp. (including B. fragilis strains); Clostridium (including C. perfrigens), Eubacterium, Fusobacterium, Peptococcus and Peptostreptococcus.
Resistance: Cefotaxime contains a-syn-methoximino chain which protects B-lactam ring from penicillinase and cephalosporin hydrolysis. Cefotaxime is more resistant to B-lactamase hydrolysis compared to the 1^st and 2^nd generation of cephalosporin. Cefotaxime, in general is resistant to B-lactamase of Richmond Sykes types I, II, III, IV, and V and some penicillinase produced by S. aureus hydrolysis. However, B-lactamase produced by B. fragilis and P. vulgaris can hydrolyze cefotaxime. Cephalosporinase Richmond Sykes type I produced by E. cloacae can slowly hydrolyzes cefotaxime.

Used in the treatment of infections due to susceptible organisms, especially serious and life-threatening infections. They include brain abscess, serious bone and joint infections, serious intra-abdominal and gynecologic infections (including peritonitis, endometritis, pelvic inflammatory disease, pelvic cellulitis),gonorrhea, endocarditis, intensive care (selective parenteral and enteral antisepsis regimens),typhoid fever, Lime disease, meningitis and other central nervous system (CNS) infections, serious lower respiratory tract infections (including pneumoniae) bacterial septicemia, surgical infections (prophylaxis), serious skin and skin structure infections and serious urinary tract infections and caused by susceptible bacteria.

Unless otherwise stated, dosage for adults and children >12 years is 1 g every 12 hours. Moderate to severe infections:1-2 g intravenous (IV) every 6-8 hours.
Severe and life-threatening infections: 2 g IV every 4 hours. Maximum daily dose is 12 g.
Prevention of postoperative infection:1 g by IM or IV 30-90 minutes before surgery.
Caesarean surgery:1 g IV immediately after the umbilical cord is clamped, and then followed by 1 g IM or IV 6-12 hours after the first dose.
Gonorrhea: 1 g IM as a single dose.
Uncomplicated infections: 2 g (1 g every 12 hours, IM or IV) or 1 g CEFOTAXIME (CLADEX) as single dose given IM.
Moderate to severe infections: 3-6 g (1-2 g every 8 hours IM or IV).
Infections requiring higher dose of antibiotic: 6-8 g (2 g every 6-8 hours, IV).
Life-threatening infection: up to 12 g (2 g every 4 hours IV).
Children: Children may be given 100 to 150 mg of CEFOTAXIME (CLADEX) per kg bodyweight (50 mg/kg for neonates) daily in divided doses at 6 to 12 hours intervals.
In life-threatening conditions, this can be increased to 200 mg/kg (150 to 200 mg/kg for neonates).
Daily dose in premature infants should not be more than 50 mg/kg body weight as the renal clearance in premature infants has not fully developed yet.
If larger doses are required, use 2 g of dry powder for injection whereas for babies, premature infants and children, use 0.5 g of preparation.
Patients with renal impairment: Patients with creatinine clearance >20 mL/minute/1.73m² dosage modification is not required. Patients with creatinine clearance <20 mL/minute/1.73m² dosage modification is required and the frequency of administration depending on the severity of the failure. It is recommended to reduce the dose to Vi of the normal dose. Patients undergoing hemodialysis: 0.5 to 2 g daily given as a single dose and additional dose given after each dialysis period.
Duration of treatment: The duration of treatment varies depending on the type of infections, but in general, treatment, should usually be continued for at least 48-72 hours after fever has subsided or infections have been cured. For infection due to group A β-hemolytic streptococci, treatment should be continued for at least 10 days to decrease the risks of rheumatic fever or glomerulonephritis.
Mode of Administrations: CEFOTAXIME (CLADEX) 1 g: For IM or IV, dissolves in 4 ml. of sterile water for injection. The pain of injection site following IM injection can be avoided by dissolving CEFOTAXIME (CLADEX) 1 g in 4 mL of lidocaine solution 1%. IV administration is recommended if the daily dose exceeds 2 g or if 1 g CEFOTAXIME (CLADEX) is injected more than twice daily.

Symptoms of overdose may largely correspond to the profile of side effects. With certain risk patterns and with the administration of very high doses, there is a risk of reversible encephalopathy, central nervous system excitation conditions, myoclonia and cramp, as have been described for other beta lactams. The risk of the appearance of these undesirable effects is increased in patients with severely restricted kidney function, epilepsy and meningitis.
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. Drug initiated cramps can be treated with diazepam or phenobarbital, but not with phenytoin. With anaphylactic reactions the usual emergency measures must be commenced, preferably with the first indications. No specific antidote exists. Plasma levels of cefotaxime can be reduced by hemodialysis or peritoneal dialysis.

Patients hypersensitive to cephalosporin antibiotics. Possibility of cross-sensitivity in patients who have shown allergy to penicillin.

As with other cephalosporin antibiotics, cefotaxime may cause allergic reactions. Prolonged treatment may cause overgrowth of nonsusceptible microorganisms, especially Candida and Pseudomonas. Vaginitis and monilliasis have been reported in <1% of patients taking cefotaxime. During treatment with cefotaxime resistant strains from some microorganisms may develop, particularly Enterobacter, Pseudomonas aeruginosa and Serratia. Close observation is recommended during cefotaxime treatment. If superinfection or suprainfection occurs, appropriate therapy must be implemented.
Cefotaxime may cause colitis if given to patients with history of gastrointestinal disorder. As with other cephalosporin antibiotic, cefotaxime may cause false-positive results in glucose urine determination using copper sulfate (Benedict's reagent, Clinitest) and may increase serum creatinine. May also cause positive antiglobulin test (Coombs'). Renal function test is recommended during combination therapy with aminoglycoside.

Pregnancy and Lactation: The safe use in pregnancy has not been established; use only when very necessary. Studies in animal reproduction showed no effect in fertility or fetal obstruction after administration of 30 times more than usual human dose. Caution must be exercised when prescribing cefotaxime to nursing mothers as cefotaxime is distributed in the mothers' milk.

The most frequent adverse reactions are: Local: injection site inflammation with intravenous administration. Pain, induration, and tenderness after intramuscular injection.
Hypersensitivity: rash, pruritus, fever, eosinophilia.
Gastrointestinal: colitis, diarrhea, nausea, and vomiting.
Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely.
Less frequent adverse reactions are: Hematologic system: neutropenia, leukopenia, have been reported. Some individuals have developed positive direct Coombs' tests during treatment with cefotaxime and other cephalosporin antibiotics.
Genitourinary system: moniliasis, vaginitis.
Central nervous system: headache. Liver: transient elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum lactate dehydrogenase (LDH), and serum alkaline phosphatase levels have been reported.
Renal: as with some other cephalosporins, transient elevations of blood urea nitrogen (BUN) have been occasionally observed with cefotaxime.
Postmarketing experiences: Central nervous system: administration of 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). Dizziness has also been reported.
Cutaneous: as with other cephalosporins, isolated cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported. Acute generalized exanthematous pustulosis (AGEP) has also been reported.
General disorders and administration site conditions: inflammatory reactions at the injection site, including phlebitis/ thrombophlebitis.
Hematologic system: hemolytic anemia, agranulocytosis, thrombocytopenia, pancytopenia, bone marrow failure.
Hypersensitivity: anaphylaxis (e.g. angioedema, bronchospasm, malaise possibly culminating in shock), urticaria.
Kidney: interstitial nephritis, transient elevations of creatinine, acute renal failure.
Liver: hepatitis, jaundice, cholestasis, elevations of gamma-glutamyltransferase and bilirubin.

Aminoglycosides: In vitro studies, the antibacterial activities of cefotaxime and aminoglycosides are additive and synergistic against several organisms including Pseudomonas aeruginosa and S. marcescens. However, synergistic effect is not predictable and antagonistic effect may occur when cefotaxime is combined with aminoglycosides. Concomitant administration with probenecid will increase cefotaxime concentration in the serum. Gives false-positive Coombs' test. Do not mix CEFOTAXIME (CLADEX) in 1 syringe with aminoglycosides.

Instruction and Special Precautions for Handling and Disposal: The reconstituted solution of cefotaxime will physically and chemically stable for 24 hours at room temperature (<30°C) or for 10 days at temperature 2-8°C in water for injection (4 mL) and lidocaine 10 mg/mL (4 mL).
The reconstituted solution should be clear, do not use the solution if particles are present.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DD01 - cefotaxime ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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