CEFOTAXIME

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

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 used successfully in treating patients with infections caused by susceptible organisms. Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and identify causative organisms and to determine their susceptibilities to cefotaxime. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly. In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, Cefotaxime for Injection, USP may be used concomitantly with an aminoglycoside. The dosage recommended in the labeling of both antibiotics may be given and depends on the severity of the infection and the patient's condition. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. It is possible that nephrotoxicity may be potentiated if Cefotaxime for Injection, USP is used concomitantly with an aminoglycoside. Prevention The administration of Cefotaxime for Injection, USP preoperatively reduces the incidence of certain infections in patients undergoing surgical procedures (e.g., abdominal or vaginal hysterectomy, gastrointestinal and genitourinary tract surgery) that may be classified as contaminated or potentially contaminated. In patients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative use of Cefotaxime for Injection, USP may also reduce the incidence of certain postoperative infections. See DOSAGE AND ADMINISTRATION section. Effective use for elective surgery depends on the time of administration. To achieve effective tissue levels, Cefotaxime for Injection, USP should be given 1/2 or 1 1/2 hours before surgery. See DOSAGE AND ADMINISTRATION section. For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical cleansing as well as with a non-absorbable antibiotic (e.g., neomycin) is recommended. If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapy may be instituted. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefotaxime for Injection, USP and other antibacterial drugs, Cefotaxime for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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 length and condition of storage. For intramuscular use: Reconstitute VIALS with Sterile Water for Injection or Bacteriostatic Water for Injection as described above. For intravenous use: Reconstitute VIALS with at least 10 mL of Sterile Water for Injection. Reconstitute INFUSION BOTTLES with 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. For other diluents, see COMPATIBILITY AND STABILITY section. NOTE: Solutions of cefotaxime must not be admixed with aminoglycoside solutions. If cefotaxime and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection. A SOLUTION OF 1 G CEFOTAXIME IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC. IM Administration: As with all IM preparations, cefotaxime should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel. Individual IM doses of 2 grams may be given if the dose is divided and is administered in different intramuscular sites. IV Administration: The IV route is preferable for patients with bacteremia, bacterial septicemia, peritonitis, meningitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending. For intermittent IV administration, a solution containing 1 gram or 2 grams in 10 mL of Sterile Water for Injection can be injected over a period of three to five minutes. Cefotaxime should not be administered over a period of less than three minutes. (See WARNINGS ). With an infusion system, it may also be given over a longer period of time through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing cefotaxime, it is advisable to discontinue temporarily the administration of other solutions at the same site. For the administration of higher doses by continuous IV infusion, a solution of cefotaxime may be added to IV bottles containing the solutions discussed below. Compatibility and Stability Solutions of cefotaxime reconstituted as described above ( Preparation of cefotaxime for injection sterile ) remain chemically stable (potency remains above 90%) as follows when stored in original containers and disposable plastic syringes: Strength Reconstituted Concentration mg/mL Stability at or below 22ºC Stability under Refrigeration (at or below 5ºC) Original Containers Plastic Syringes 500 mg vial IM 230 12 hours 7 days 5 days 1 g vial IM 300 12 hours 7 days 5 days 2 g vial IM 330 12 hours 7 days 5 days 500 mg vial IV 50 24 hours 7 days 5 days 1 g vial IV 95 24 hours 7 days 5 days 2 g vial IV 180 12 hours 7 days 5 days Reconstituted solutions stored in original containers and plastic syringes remain stable for 13 weeks frozen. Reconstituted solutions may be further diluted up to 1000 mL with the following solutions and maintain satisfactory potency for 24 hours at or below 22°C, and at least 5 days under refrigeration (at or below 5°C): 0.9% Sodium Chloride Injection; 5 or 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.2% Sodium Chloride Injection; Lactated Ringer's Solution; Sodium Lactate Injection (M/6); 10% Invert Sugar Injection, 8.5% TRAVASOL ® (Amino Acid) Injection without Electrolytes. NOTE: Cefotaxime solutions exhibit maximum stability in the pH 5-7 range. Solutions of cefotaxime should not be prepared with diluents having a pH above 7.5, such as Sodium Bicarbonate Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

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 .

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 ).