Cefotaxime

INDICATIONS AND USAGE Treatment Cefotaxime for Injection, USP is indicated for the treatment of patients with serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below. (1) Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae ), Streptococcus pyogenes* (Group A streptococci) and other streptococci (excluding enterococci, e.g., Enterococcus faecalis ), Staphylococcus aureus (penicillinase and non-penicillinase producing), Escherichia coli , Klebsiella species, Haemophilus influenzae (including ampicillin resistant strains), Haemophilus parainfluenzae , Proteus mirabilis , Serratia marcescens* , Enterobacter species, indole positive Proteus and Pseudomonas species (including P. aeruginosa ). (2) Genitourinary infections . Urinary tract infections caused by Enterococcus species, Staphylococcus epidermidis , Staphylococcus aureus* , (penicillinase and non-penicillinase producing), Citrobacter species, Enterobacter species, Escherichia coli , Klebsiella species, Proteus mirabilis , Proteus vulgaris* , Providencia stuartii , Morganella morganii* , Providencia rettgeri* , Serratia marcescens and Pseudomonas species (including P. aeruginosa ). Also, uncomplicated gonorrhea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae , including penicillinase producing strains. (3) Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by Staphylococcus epidermidis , Streptococcus species, Enterococcus species, Enterobacter species*, Klebsiella species*, Escherichia coli , Proteus mirabilis , Bacteroides species (including Bacteroides fragilis* ), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. nucleatum* ). Cefotaxime for Injection, USP, like other cephalosporins, has no activity against Chlamydia trachomatis . Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added. (4) Bacteremia/Septicemia caused by Escherichia coli , Klebsiella species, and Serratia marcescens , Staphylococcus aureus and Streptococcus species (including S. pneumoniae ). (5) Skin and skin structure infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing), Staphylococcus epidermidis , Streptococcus pyogenes (Group A streptococci) and other streptococci, Enterococcus species, Acinetobacter species*, Escherichia coli , Citrobacter species (including C. freundii* ), Enterobacter species, Klebsiella species, Proteus mirabilis , Proteus vulgaris* , Morganella morganii , Providencia rettgeri* , Pseudomonas species, Serratia marcescens , Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus species). (6) Intra-abdominal infections including peritonitis caused by Streptococcus species*, Escherichia coli , Klebsiella species, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus* species) Proteus mirabilis* , and Clostridium species*. (7) Bone and/or joint infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Streptococcus species (including S. pyogenes* ), Pseudomonas species (including P. aeruginosa* ), and Proteus mirabilis* . (8) Central nervous system infections, e.g., meningitis and ventriculitis, caused by Neisseria meningitidis , Haemophilus influenzae , Streptococcus pneumoniae , Klebsiella pneumoniae* and Escherichia coli* . (*) Efficacy for this organism, in this organ system, has been studied in fewer than 10 infections. Although many strains of enterococci (e.g., S. faecalis ) and Pseudomonas species are resistant to cefotaxime sodium in vitro , Cefotaxime for Injection, USP has been …

DOSAGE AND ADMINISTRATION Adults Dosage and route of administration should be determined by susceptibility of the causative organisms, severity of the infection, and the condition of the patient (see table for dosage guideline). Cefotaxime may be administered IM or IV after reconstitution. The maximum daily dosage should not exceed 12 grams. GUIDELINES FOR DOSAGE OF CEFOTAXIME FOR INJECTION Type of Infection Daily Dose (grams) Frequency and Route Gonococcal urethritis/cervicitis in males and females 0.5 0.5 gram IM (single dose) Rectal gonorrhea in females 0.5 0.5 gram IM (single dose) Rectal gonorrhea in males 1 1 gram IM (single dose) Uncomplicated infections 2 1 gram every 12 hours IM or IV Moderate to severe infections 3-6 1-2 grams every 8 hours IM or IV Infections commonly needing antibiotics in higher dosage (e.g., septicemia) 6-8 2 grams every 6-8 hours IV Life-threatening infections up to 12 2 grams every 4 hours IV If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefotaxime sodium has no activity against this organism. To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended dose is a single 1 gram IM or IV administered 30 to 90 minutes prior to start of surgery. Cesarean Section Patients The first dose of 1 gram is administered intravenously as soon as the umbilical cord is clamped. The second and third doses should be given as 1 gram intravenously or intramuscularly at 6 and 12 hours after the first dose. Neonates, Infants, and Children The following dosage schedule is recommended: Neonates (birth to 1 month): 0-1 week of age 50 mg/kg per dose every 12 hours IV 1-4 weeks of age 50 mg/kg per dose every 8 hours IV It is not necessary to differentiate between premature and normal-gestational age infants. Infants and Children (1 month to 12 years): For body weights less than 50 kg, the recommended daily dose is 50 to 180 mg/kg IM or IV body weight divided into four to six equal doses. The higher dosages should be used for more severe or serious infections, including meningitis. For body weights 50 kg or more, the usual adult dosage should be used; the maximum daily dosage should not exceed 12 grams. Geriatric Use This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, General and PRECAUTIONS, Geriatric Use .) Impaired Renal Function See PRECAUTIONS, General . NOTE: As with antibiotic therapy in general, administration of cefotaxime should be continued for a minimum of 48 to 72 hours after the patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended for infections caused by Group A beta-hemolytic streptococci in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment of several weeks and doses smaller than those indicated above should not be used. Preparation of cefotaxime for injection sterile Cefotaxime for IM or IV administration should be reconstituted as follows: Strength Diluent (mL) Withdrawable Volume (mL) Approximate Concentration (mg/mL) 500 mg vial* (IM) 2 2.2 230 1 g vial* (IM) 3 3.4 300 2 g vial* (IM) 5 6.0 330 500 mg vial* (IV) 10 10.2 50 1 g vial* (IV) 10 10.4 95 2 g vial* (IV) 10 11.0 180 (*) in conventional vials Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of cefotaxime range from very pale yellow to light amber, depending on concentration, diluent used, and …

CONTRAINDICATIONS Cefotaxime is contraindicated in patients who have shown hypersensitivity to cefotaxime sodium, or the cephalosporin group of antibiotics.

ADVERSE REACTIONS Clinical Trials Experience Cefotaxime is generally well tolerated. The most common adverse reactions have been local reactions following IM or IV injection. Other adverse reactions have been encountered infrequently. The most frequent adverse reactions (greater than 1%) are: Local (4.3%) - Injection site inflammation with IV administration. Pain, induration, and tenderness after IM injection. Hypersensitivity (2.4%) - Rash, pruritus, fever, eosinophilia. Gastrointestinal (1.4%) - 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 (less than 1%) 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 AST, ALT, serum LDH, and serum alkaline phosphatase levels have been reported. Kidney - As with some other cephalosporins, transient elevations of BUN have been occasionally observed with cefotaxime. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of cefotaxime. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular System - Potentially life-threatening arrhythmias following rapid (less than 60 seconds) bolus administration via central venous catheter have been observed. 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 GT and bilirubin. Cephalosporin Class Labeling In addition to the adverse reactions listed above which have been observed in patients treated with cefotaxime sodium, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: allergic reactions, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and false-positive test for urinary glucose. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. See DOSAGE AND ADMINISTRATION and OVERDOSAGE . If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions A single intravenous dose and oral dose of probenecid (500 mg each) followed by two oral doses of probenecid 500 mg at approximately hourly intervals administered to three healthy male subjects receiving a continuous infusion of cefotaxime increased the steady-state plasma concentration of cefotaxime by approximately 80%. In another study, administration of oral probenecid 500 mg every 6 hours to six healthy male subjects with cefotaxime 1 gram infused over 5 minutes decreased the total clearance of cefotaxime by approximately 50%. Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered cefotaxime and ethanol.

Drug Interactions As with other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of nephrotoxic drugs such as aminoglycosides, NSAIDs and furosemide. Probenecid interferes with the renal tubular transfer of cefotaxime, decreasing the total clearance of cefotaxime by approximately 50% and increasing the plasma concentrations of cefotaxime. Administration of cefotaxime in excess of 6 grams/day should be avoided in patients receiving probenecid (see CLINICAL PHARMACOLOGY, Drug Interactions ).

DESCRIPTION Sterile cefotaxime sodium is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration. It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester). Cefotaxime for Injection, USP contains approximately 50.5 mg (2.2 mEq) of sodium per gram of cefotaxime activity. Solutions of Cefotaxime for Injection, USP range from very pale yellow to light amber depending on the concentration and the diluent used. The pH of the injectable solutions usually ranges from 5.0 to 7.5. The CAS Registry Number is 64485-93-4. C 16 H 16 N 5 NaO 7 S 2 MW 477.45 Cefotaxime for Injection, USP is supplied as a dry powder in vials. Each vial contains cefotaxime sodium, equivalent to 500 mg, 1 gram or 2 grams of cefotaxime. Structural Formula

OVERDOSAGE The acute toxicity of cefotaxime was evaluated in neonatal and adult mice and rats. Significant mortality was seen at parenteral doses in excess of 6000 mg/kg/day in all groups. Common toxic signs in animals that died were a decrease in spontaneous activity, tonic and clonic convulsions, dyspnea, hypothermia, and cyanosis. Cefotaxime sodium overdosage has occurred in patients. Most cases have shown no overt toxicity. The most frequent reactions were elevations of BUN and creatinine. There is a risk of reversible encephalopathy in cases of administration of high doses of beta-lactam antibiotics including cefotaxime. No specific antidote exists. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.

HOW SUPPLIED Sterile Cefotaxime for Injection, USP, is a dry off-white to pale yellow crystalline powder supplied in vials and bottles containing cefotaxime sodium as follows: 500 mg cefotaxime (free acid equivalent) vials in packages of 10 (NDC 0143-9930-10) 1 g cefotaxime (free acid equivalent) vials in packages of 25 (NDC 0143-9931-25) 2 g cefotaxime (free acid equivalent) vials in packages of 25 (NDC 0143-9933-25) NOTE: Cefotaxime for Injection, USP in the dry state should be stored at 20o to 25°C (68o to 77°F) [See USP Controlled Room Temperature]. The dry material as well as solutions tend to darken depending on storage conditions and should be protected from elevated temperatures and excessive light.