CEFOXITIN

Cefoxitin for Injection, USP is a semi-synthetic, broad-spectrum cepha antibiotic sealed under nitrogen for intravenous administration. It is derived from cephamycin C, which is produced by Streptomyces lactamdurans. Its chemical name is sodium (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate carbamate (ester). The molecular formula is C 16 H 16 N 3 N a O 7 S 2 , and the structural formula is: Cefoxitin for injection contains approximately 53.8 mg (2.3 milliequivalents) of sodium per gram of cefoxitin activity. Solutions of Cefoxitin for Injection, USP range from colorless to light amber in color. The pH of freshly constituted solutions usually ranges from 4.2 to 7.0. Each Pharmacy Bulk Package Bottle of Cefoxitin for Injection, USP contains sterile cefoxitin sodium, USP equivalent to 10 grams of cefoxitin. This Pharmacy Bulk Package Bottle is a container of sterile preparation for intravenous use that contains many single doses. The contents are intended for use in a pharmacy admixture service and are restricted to the preparation of admixtures for intravenous infusion. AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED BEFORE USE. NOT FOR DIRECT INFUSION. chemical structure

Treatment Cefoxitin for Injection, USP is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below. (1) Lower respiratory tract infections, including pneumonia and lung abscess, caused by Streptococcus pneumoniae, other streptococci (excluding enterococci, e.g., Enterococcus faecalis [formerly Streptococcus faecalis ]), Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, Haemophilus influenzae, and Bacteroides species. (2) Urinary tract infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Morganella morganii, Proteus vulgaris and Providencia species (including P. rettgeri ). (3) Intra-abdominal infections, including peritonitis and intra-abdominal abscess, caused by Escherichia coli, Klebsiella species, Bacteroides species including Bacteroides fragilis, and Clostridium species. (4) Gynecological infections, including endometritis, pelvic cellulitis, and pelvic inflammatory disease caused by Escherichia coli, Neisseria gonorrhoeae (including penicillinase-producing strains), Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, Peptostreptococcus species and Streptococcus agalactiae. Cefoxitin for Injection, USP, like cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when Cefoxitin for Injection, USP is 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. (5) Septicemia caused by Streptococcus pneumoniae, Staphylococcus aureus (including penicillinase­-producing strains), Escherichia coli, Klebsiella species, and Bacteroides species including B. fragilis. (6) Bone and joint infections caused by Staphylococcus aureus (including penicillinase-producing strains). (7) Skin and skin structure infections caused by Staphylococcus aureus (including penicillinase­-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes and other streptococci (excluding enterococci e.g., Enterococcus faecalis [formerly Streptococcus faecalis ]), Escherichia coli, Proteus mirabilis, Klebsiella species, Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, and Peptostreptococcus species. Appropriate culture and susceptibility studies should be performed to determine the susceptibility of the causative organisms to cefoxitin. Therapy may be started while awaiting the results of these studies. In randomized comparative studies, cefoxitin and cephalothin were comparably safe and effective in the management of infections caused by gram-positive cocci and gram-negative rods susceptible to the cephalosporins. Cefoxitin Injection, USP has a high degree of stability in the presence of bacterial beta-lactamases, both penicillinases and cephalosporinases. Many infections caused by aerobic and anaerobic gram-negative bacteria resistant to some cephalosporins respond to cefoxitin. Similarly, many infections caused by aerobic and anaerobic bacteria resistant to some penicillin antibiotics (ampicillin, carbenicillin, penicillin G) respond to treatment with Cefoxitin Injection, USP. Many infections caused by mixtures of susceptible aerobic and anaerobic bacteria respond to treatment with Cefoxitin Injection, USP. Prevention Cefoxitin for Injection is indicated for the prophylaxis of infection in patients undergoing uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, or cesarean section. If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate treatment may be instituted. To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefoxitin for injection and other antibacterial drugs, Cefoxitin 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.

The intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. TREATMENT Adults The usual adult dosage range is 1 gram to 2 grams every six to eight hours. Dosage should be determined by susceptibility of the causative organisms, severity of infection, and the condition of the patient (see Table 3 for dosage guidelines). If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefoxitin sodium has no activity against this organism. Cefoxitin for Injection may be used in patients with reduced renal function with the following dosage adjustments: In adults with renal insufficiency, an initial loading dose of 1 gram to 2 grams may be given. After a loading dose, the recommendations for maintenance dosage (Table 4) may be used as a guide. When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function. Males: Weight (kg) x (140 - age) 72 x serum creatinine (mg/100 mL) Females: 0.85 x above value In patients undergoing hemodialysis, the loading dose of 1 gram to 2 grams should be given after each hemodialysis, and the maintenance dose should be given as indicated in Table 4. Antibiotic therapy for group A beta-hemolytic streptococcal infections should be maintained for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated. Pediatric Patients The recommended dosage in pediatric patients three months of age and older is 80 to 160 mg/kg of body weight per day divided into four to six equal doses. The higher dosages should be used for more severe or serious infections. The total daily dosage should not exceed 12 grams. At this time no recommendation is made for pediatric patients from birth to three months of age (see PRECAUTIONS ). In pediatric patients with renal insufficiency, the dosage and frequency of dosage should be modified consistent with the recommendations for adults (see Table 4). PREVENTION Effective prophylactic use depends on the time of administration. Cefoxitin for Injection usually should be given one-half to one hour before the operation, which is sufficient time to achieve effective levels in the wound during the procedure. Prophylactic administration should usually be stopped within 24 hours since continuing administration of any antibiotic increases the possibility of adverse reactions but, in the majority of surgical procedures, does not reduce the incidence of subsequent infection. For prophylactic use in uncontaminated gastrointestinal surgery, vaginal hysterectomy, or abdominal hysterectomy, the following doses are recommended: Adults: 2 grams administered intravenously just prior to surgery (approximately one-half to one hour before the initial incision) followed by 2 grams every 6 hours after the first dose for no more than 24 hours. Pediatric Patients (3 months and older): 30 to 40 mg/kg doses may be given at the times designated above. Cesarean section patients: For patients undergoing cesarean section, either a single 2 gram dose administered intravenously as soon as the umbilical cord is clamped OR a 3-dose regimen consisting of 2 grams given intravenously as soon as the umbilical cord is clamped followed by 2 grams 4 and 8 hours after the initial dose is recommended. (See CLlNICAL STUDIES . ) Table 3 - Guidelines for Dosage of Cefoxitin for Injection Type of Infection Daily Dosage Frequency and Route Uncomplicated forms* of infections such as pneumonia, urinary tract infection, cutaneous infection 3-4 grams 1 gram every 6-8 hours IV Moderately severe or severe infections 6-8 grams 1 gram every 4 hours or 2 grams every 6-8 hours IV Infections commonly needing antibiotics in higher dosage (e.g., gas gangrene) 12 grams 2 grams every 4 hours or 3 grams every 6 hours IV *Including patients in whom bacteremia is absent or unlikely. Table 4 - Maintenance Dosage of Cefoxitin for Injection in Adults with Reduced Renal Function Renal Function Creatinine Clearance (mL/min) Dose (Grams) Frequency Mild impairment Moderate impairment Severe impairment Essentially no function 50 – 30 29 – 10 9 – 5 < 5 1 – 2 1 – 2 0.5 – 1 0.5 – 1 Every 8-12 hours Every 12-24 hours Every 12-24 hours Every 24-48 hours Table 5 - Preparation of Solution for Intravenous Administration Strength Amount of Diluent to be Added (mL)* Approximate Withdrawable Volume (mL) Approximate Average concentration (mg/mL) 10 grams Pharmacy Bulk Package 43 or 93 49 or 98.5 200 or 100 *Shake to dissolve and let stand until clear DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE BOTTLE - NOT FOR DIRECT INFUSION For Bulk Packages The Pharmacy Bulk Package bottle is for use in a pharmacy admixture service under a laminar flow hood. Penetration into the Pharmacy Bulk Package bottle should be made only one time after reconstitution with a sterile transfer set or other sterile dispensing device, which allows measured distribution of the contents. Dispense the contents in aliquots using aseptic technique. The use of a syringe with a needle is not recommended as it may cause leakage (see DOSAGE AND ADMINISTRATION ). AFTER INITIAL ENTRY USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY. A maximum time of 4 HOURS from initial entry is permitted to complete fluid transfer operations. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 4 HOURS. This time limit should begin with the introducing of solvent or diluent into the Pharmacy Bulk Package bottle. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. PREPARATION OF SOLUTION Table 5 is provided for convenience in constituting Cefoxitin for Injection Pharmacy Bulk Package. The 10 grams bulk packages should be constituted with 43 mL or 93 mL of Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION. These primary solutions may be further diluted in 50 to 1000 mL of the diluents listed under the COMPATIBILITY AND STABILITY section. Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, in whom use of Cefoxitin for Injection may be indicated, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluent containing benzyl alcohol should not be used when Cefoxitin for Injection is constituted for administration to pediatric patients in this age range. ADMINISTRATION Cefoxitin for Injection may be administered intravenously after constitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The intent of this pharmacy bulk package is for the preparation of solutions for intravenous infusion only. Intravenous Administration The intravenous route is preferable for patients with bacteremia, bacterial septicemia, 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 intravenous 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. Using 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 intravenous solutions. However, during infusion of the solution containing Cefoxitin for Injection, it is advisable to temporarily discontinue administration of any other solutions at the same site. For the administration of higher doses by continuous intravenous infusion, a solution of Cefoxitin for Injection may be added to an intravenous bottle containing 5 percent Dextrose Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose and 0.9 percent Sodium Chloride Injection. BUTTERFLY ® †† or scalp vein-type needles are preferred for this type of infusion. Solutions of Cefoxitin for Injection, like those of most beta-lactam antibiotics, should not be added to aminoglycoside solutions (e.g., gentamicin sulfate, tobramycin sulfate, amikacin sulfate) because of potential interaction. However, cefoxitin for injection and aminoglycosides may be administered separately to the same patient. COMPATIBILITY AND STABILITY Cefoxitin for Injection supplied in pharmacy bulk package bottles and constituted to 1 gram/10 mL with Sterile Water for Injection, Bacteriostatic Water for Injection, (see PREPARATION OF SOLUTION ), 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection, should be DISCARDED 4 HOURS AFTER INITIAL ENTRY. FURTHER DILUTION IS REQUIRED BEFORE USE. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. These primary solutions may be further diluted in 50 mL to 1000 mL of the following diluents and maintain potency for an additional 18 hours at room temperature or an additional 48 hours under refrigeration: 0.9 percent Sodium Chloride Injection 5 percent or 10 percent Dextrose Injection 5 percent Dextrose and 0.9 percent Sodium Chloride Injection 5 percent Dextrose Injection with 0.2 percent or 0.45 percent saline solution Lactated Ringer’s Injection 5 percent Dextrose in Lactated Ringer's Injection 5 percent Sodium Bicarbonate Injection M/6 sodium lactate solution Mannitol 5% and 10% After the periods mentioned above, any unused solutions should be discarded.

Cefoxitin for Injection is contraindicated in patients who have shown hypersensitivity to cefoxitin and the cephalosporin group of antibiotics.

Cefoxitin for Injection is generally well tolerated. The most common adverse reactions have been local reactions following intravenous injection. Other adverse reactions have been encountered infrequently. Local Reactions Thrombophlebitis has occurred with intravenous administration. Allergic Reactions Rash (including exfoliative dermatitis and toxic epidermal necrolysis), urticaria, flushing, pruritus, eosinophilia, fever, dyspnea, and other allergic reactions including anaphylaxis, interstitial nephritis and angioedema have been noted. Cardiovascular Hypotension. Gastrointestinal Diarrhea, including documented pseudomembranous colitis which can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely. Neuromuscular Possible exacerbation of myasthenia gravis. Blood Eosinophilia, leukopenia including granulocytopenia, neutropenia, anemia, including hemolytic anemia, thrombocytopenia, and bone marrow depression. A positive direct Coombs test may develop in some individuals, especially those with azotemia. Liver Function Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase; and jaundice have been reported. Renal Function Elevations in serum creatinine and/or blood urea nitrogen levels have been observed. As with the cephalosporins, acute renal failure has been reported rarely. The role of cefoxitin in changes in renal function tests is difficult to assess, since factors predisposing to prerenal azotemia or to impaired renal function usually have been present. In addition to the adverse reactions listed above which have been observed in patients treated with cefoxitin, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: Urticaria, erythema multiforme, Stevens-Johnson syndrome, serum sickness-like reactions, abdominal pain, colitis, renal dysfunction, toxic nephropathy, false-positive test for urinary glucose, hepatic dysfunction including cholestasis, elevated bilirubin, aplastic anemia, hemorrhage, prolonged prothrombin time, pancytopenia, agranulocytosis, superinfection, vaginitis including vaginal candidiasis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. (See DOSAGE AND ADMINISTRATION . ) 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 the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics.

Special storage instructions Cefoxitin for Injection in the dry state should be stored between 2º to 25°C (36º to 77°F). Avoid exposure to temperatures above 50°C. The dry material as well as solutions tend to darken, depending on storage conditions; product potency, however, is not adversely affected.