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CLINICAL PHARMACOLOGY High plasma levels of cefotetan are attained after intravenous and intramuscular administration of single doses to normal volunteers . PLASMA CONCENTRATIONS AFTER 1 GRAM INTRAVENOUS a OR INTRAMUSCULAR DOSE Mean Plasma Concentration (mcg/mL) Time After Injection Route 15 min 30 min 1 h 2 h 4 h 8 h 12 h IV 92 158 103 72 42 18 9 IM 34 56 71 68 47 20 9 a 30-minute infusion PLASMA CONCENTRATIONS AFTER 2 GRAM INTRAVENOUSa OR INTRAMUSCULAR DOSE Mean Plasma Concentration (mcg/mL) Time After Injection Route 5 min 10 min 1 h 3 h 5 h 9 h 12 h IV 237 223 13 74 48 22 12b IM — 20 75 91 69 33 19 a Injected over 3 minutes b Concentrations estimated from regression line Repeated administration of CEFOTAN™ does not result in accumulation of the drug in normal subjects. Distribution Cefotetan is 88% plasma protein bound. Therapeutic concentrations of cefotetan are achieved in many body tissues and fluids including: skin ureter muscle bladder fat maxillary sinus mucosa myo metrium tonsil endo metrium bile cervix peritoneal fluid ovary umbilical cord serum kidney amniotic fluid Metabolism And Excretion The plasma eliminatio n half-life of cefotetan is 3 to 4.6 hours after either intravenous or intramuscular administration. No active metabolites of cefotetan have been detected; however, small amounts (less than 7%) of cefotetan in plasma and urine may be converted to its tautomer, which has antimicrobial activity similar to the parent drug. In normal patients, from 51% to 81% of an administered dose of CEFOTAN™ is excreted unchanged by the kidneys over a 24-hour period, which results in high and prolonged urinary concentrations. Following intravenous doses of 1 gram and 2 grams, urinary concentrations are highest during the first hour and reach concentrations of approximately 1700 and 3500 mcg/mL, respectively. Specific Populations Patients With Renal impairment In volunteers with reduced renal function, the plasma half-life of cefotetan is prolonged. The mean terminal half-life incre ases with declining renal function, from appro ximate ly 4 hours in volunteers with normal renal function to about 10 hours in those with moderate renal impairment. There is a linear correlation between the systemic clearance of cefotetan and creatinine clearance. When renal function is impaired, a reduced dosing schedule based on creatinine clearance must be used (see DOSAGE AND ADMINISTRATION). Geriatric Patients In pharmacokinetic studies of eight elderly patients (greater than 65 years) with normal renal function and six healthy volunteers (aged 25 to 28 years), mean±SD) Total Body Clearance (1.8±0.1 vs. 1.8±0.3 L/h) and mean±SD Vo lume of Distribution (10.4±1.2 vs. 10.3±1.6 L) were similar fo llo wing administration of a one gram intravenous bolus dose. Microbiology Mechanism Of Action Cefotetan is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefotetan has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Resistance Resistance to cefotetan is primarily through hydrolysis by some beta-lactamases, alteration of penicillin –binding proteins (PBPs) and decreased permeability. Antimicrobial Activity Cefotetan has been shown to be active against most isolates of the following micro organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE). Gram-Negative -Bacteria Escherichia coli Haemophilus influenzae Klebsiella species (including K. pneumoniae) Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Providencia rettgeri Serratia marcescens Gram-Positive Bacteria Staphylococcus aureus (methicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin-susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Streptococcus species Anaerobes Prevotella bivia Prevotella disiens Bacteroides fragilis Prevotella melaninogenica Bacteroides vulgatus Fusobacterium species Clostridium species Peptococcus niger Peptostreptococcus species The following in vitro data are available but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefotetan against isolates of similar genus or organism group. However, the efficacy of cefotetan in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-Negative Bacteria Citrobacter species (including C. koseri and C. freundii) Moraxella catarrhalis Salmonella species Serratia species Shigella species Yersinia enterocolitica Anaerobes Porphyromonas asaccharolytica Prevotella oralis Bacteroides splanchnicus Propionibacterium species Veillonella species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in the selection of an appropriate antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antibacterial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure (broth or agar)1,4. The MIC values should be interpreted according to criteria provided in Table 1. Diffusion Techniques Quantitative methods that require me asurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,4. This procedure uses paper disks impregnated with 30 mcg cefotetan to test the susceptibility of micro organisms to cefotetan. The disc diffusion interpretive criteria are provided in Table 1. Anaerobic Techniques For anaerobic bacteria, the susceptibility to cefotetan as MICs can be determine d by standardized test methods 3,4. The MIC values obtained should be interpreted according to the following criteria: Table 1: Susceptibility Test Interpretive Criteria for Cefotetan Microorganisms1 Minimum Inhibitory Concentration (mcg/mL) S I R Anaerobes ≤4 8 ≥16 Enterobacteriaceae ≤4 8 ≥16 Haemophilus influenzae ≤4 8 ≥16 Neisseria gonorrhoeae ≤4 8 ≥16 1 Susceptibility interpretive criteria for microorganisms are based on a dosing regimen of 2 g every 12 hours 2 For Staphylococcus spp., susceptibility to cefotetan may be deduced from testing penicillin and either oxacillin or cefoxitin . Staphylococci susceptible oxacillin or cefoxitin can be considered susceptible to cefotetan. 3 For non-meningitis Streptococcus pneumoniae isolates, susceptibility to penicillin (MIC less than 0.06 mcg/mL or oxacillin zone diameter greater than 20 mm ) can predict susceptibility to cefotetan 4For beta-hemolytic streptococci (including S. pyogenes and S. agalactiae) isolates susceptible to penicillin (MIC less than 0.12 mcg/mL) can be considered susceptible to cefotetan A report of Susceptible indicates that antibacterial is likely to inhibit growth of the pathogen if the antibacterial drug reaches the concentrations usually achievable at the site of infection. A report of Intermediate indicates that the result should be co nsidered equivocal, and if the micro o rg anism is not fully susceptible to alternative, c linically feasible drugs, the test should be repeated. This category implie s possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major disc re panc ies in interpretation. A report of Resistant indicates that the antibacterial drug is not likely to inhibit growth of the pathogen if the antibacterial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard cefotetan powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg disk the criteria in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Cefotetan QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) Escherichia coli ATCC 25922 0.06 – 0.25 28 – 34 Neisseria gonorrhoeae ATCC 49226 - 30 – 36 0.5 – 2 Staphylococcus aureus ATCC 25923 - 17 – 23 - Staphylococcus aureus ATCC 29213 4 - 16 - - Bacterioides fragilis ATCC 25285 1 – 8 - 4 – 16 Bacterioides thetaiotaomicron ATCC 29741 16 – 128 - 32 – 128 Eggerthella lenta ATCC 43055 16 – 64 - 32 – 128 REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests -Fifth Edition. Approved Standard NCCLS Do cument M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993 Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement, CLSI document M100-S27 [2017], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

Find Lowest Prices on CEFOTAN™ (cefotetan disodium) For Injection, USP DESCRIPTION CEFOTAN™ (cefotetan for Injection, USP), as cefotetan diso dium, is a sterile, se misynthetic , broad-spectrum, beta-lac tamase resistant, cephalosporin (cephamyc in) antibacterial for parenteral administration. It is the disodium salt of [6 R-(6α,7α)]-7-[[[4 -(2-amino -1-car boxy-2-oxo ethylide ne )-1,3-dithietan-2yl]c arbo nyl]amino ]-7-me tho xy-3-[[(1-me thyl-1H-te trazo l-5-yl)thio]me thyl]-8-oxo5-thia-1-azabicyclo [4 .2.0 ]o ct-2-ene-2-carbo xylic acid. Structural fo rmula: CEFOTAN™ (cefotetan for Injection, USP) is supplied in vials containing 80 mg (3.5 mEq) of sodium per gram of cefotetan activity. It is a white to pale yellow powder which is very soluble in water. Reconstituted solutions of CEFOTAN™ (cefotetan for Injection, USP) are intended for intravenous and intramusc ular administration. The solution varies from colorless to yellow depending on the concentration. The pH of freshly reconstituted solutions is usually between 4.5 to 6.5. CEFOTAN™ (cefotetan for Injection, USP) is available in two vial strengths. Each 1 gram vial contains cefotetan disodium equivalent to 1 gram cefotetan activity. Each 2 gram vial contains cefotetan disodium equivalent to 2 g rams cefotetan activity.

INDICATIONS To reduce the development of drug -resistant bacteria and maintain the effectiveness of CEFOTAN™ and other antibacterial drugs, CEFOTAN™ 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. Treatment CEFOTAN™ (cefotetan for Injection, USP) is indicated for the therapeutic treatment of the following infections when caused by susceptible strains of the designated o rg anisms: Urinary Tract Infections caused by E. coli, Klebsiella spp (including K. pneumoniae), Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, and Morganella morganii. Lower Respiratory Tract Infections caused by Streptococcus pneumoniae, Staphylococcus aureus (methicillin susceptible), Haemophilus influenzae, Klebsiella species (including K. pneumoniae), E. coli, Proteus mirabilis, and Serratia marcescens.* Skin and Skin Structure Infections due to Staphylococcus aureus (methicillinsusceptible), Staphylococcus epidermidis (methicillin susceptible), Streptococcus pyogenes, Streptococcus species, Escherichia coli, Klebsiella pneumoniae, Peptococcus niger*, Peptostreptococcus species. Gynecologic Infections caused by Staphylococcus aureus (methicillin susceptible), Staphylococcus epidermidis (methicillin susceptible, Streptococcus species, Streptococcus agalactiae, E. coli, Proteus mirabilis, Neisseria gonorrhoeae, Bacteroides fragilis, Prevotella melaninogenica Bacteroides vulgatus, Fusobacterium species*, and gram-positive anaerobic cocci (including Peptococcus niger and Peptostreptococcus species). Cefotetan, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of pelvic inflammatory disease, and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added. Intra-abdominal lnfections caused by E. coli, Klebsiella species (including K. pneumoniae), Streptococcus species, Bacteroides fragilis, Prevotella melaninogenica, Bacteroides vulgatus and Clostridium species (other than Clostridium difficile (see WARNINGS)*. Bone and Joint Infections caused by Staphylococcus aureus (methicillin susceptible)*. * Efficacy for this organism in this organ system was studied in fewer than ten infections in clinical studies Specimens for bacteriological examination should be obtained in order to isolate and identify causative o rg anisms and to determine their susceptibilities to cefotetan. Therapy may be instituted before results of susceptibility studies are known; however, once these results beco me available, the antibiotic treatment should be adjusted accordingly. In cases of confirmed or suspected g ram-positive or gram-negative sepsis or in patients with other serious infections in which the causative o rg anism has not been identified, it is possible to use CEFOTAN™ co nco mitantly with an amino glycoside. Cefotetan combinatio ns with aminoglycosides have been shown to be syne rg istic in vitro against many Enterobacteriaceae and also so me other gram-negative bacteria. The dosage reco mmended in the labeling of both antibiotics may be given and depends on the severity of the infe c tio n and the patient's condition. NOTE: Increases in serum creatinine have occurred when CEFOTAN™ was given alone. If CEFOTAN™ and an aminoglycoside are used co ncomitantly, renal function should be carefully mo nito red, because nephrotoxicity may be potentiated. Prophylaxis The preoperative administration of CEFOTAN™ may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures that are classified as clean contaminated or potentially contaminated (e.g., cesarean section, abdominal or vaginal hysterectomy, transurethral surgery, biliary tract surgery, and gastrointestinal surgery). If there are signs and symptoms of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapeutic measures may be initiated. DOSAGE AND ADMINISTRATION Treatment The usual adult dosage is 1 gram (g) or 2 g rams of CEFOTAN™ (cefotetan for Injection, USP) administered intravenously or intramusc ularly. Proper dosage and route of administratio n should be de te rmine d by the condition of the patient, severity of the infection, and susceptibility of the causative o rg anism. General Guidelines for Dosage of CEFOTAN™ (cefotetan for Injection, USP) Type of Infection Daily Dose Frequency and Route Urinary Tract 1 g to 4 g 500 mg every 12 hours intravenous or intramuscular 1 or 2 g every 24 hours intravenous or intramuscular 1 or 2 g every 12 hours intravenous or intramuscular Skin & Skin Structure Mild - Moderatea 2 g 2 g every 24 hours intravenous 1 g every 12 hours intravenous or intramuscular Severe 4 g 2 g every 12 hours intravenous Other Sites 2 g to 4 g 1 g or 2 g every 12 hours intravenous or intramuscular Severe 4 g 2 g every 12 hours intravenous Life-Threatening 6 gb 3 g every 12 hours intravenous a Klebsiella pneumoniae skin and skin structure infections should be treated with 1 or 2 grams every 12 hours Intravenous or Intramuscular. b Maximum daily dosage should not exceed 6 grams. If Chlamydia trachomatis is a suspected pathogen in gynecologic infections, appropriate antichlamydial coverage should be added, since cefotetan has no activity against this organism. Prophylaxis To prevent postoperative infection in clean contaminated or potentially contaminated surgery in adults, the recommended dosage is 1 or 2 g of CEFOTAN™ (cefotetan for Injection, USP) administered once , intravenously, 30 to 60 minutes prior to surgery. In patients undergoing cesarean section, the dose should be administered as soon as the umbilical cord is clamped. Impaired Renal Function When renal function is impaired, a reduced dosage schedule must be employed. The fo llowing dosage guidelines may be used. DOSAGE GUIDELINES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION CreatinineClearance Dose Frequency Greater than 30 Usual Recommended Dosage* Every 12 hours 10 to 30 Usual Recommended Dosage* Every 24 hours Less than 10 Usual Recommended Dosage* Every 48 hours * Dose determined by the type and severity of infection, and susceptibility of the causative organism. Alternatively, the dosing interval may remain constant at 12 hour intervals, but the dose reduced to one-half the usual recommended dose for patients with a creatinine clearance of 10 to 30 mL/min, and one-quarter the usual recommended dose for patients with a creatinine clearance of less than 10 mL/min. When only serum creatinine levels are available, creatinine clearance may be calculated from the following formula. The serum creatinine level should represent a steady state of renal function. Males: (weight in kg) x (140 – age) (72) x serum creatinine (mg/100 mL) Females: (0.85) x (above value) Cefotetan is dialyzable and it is reco mmended that for patients undergoing intermittent hemo dialysis, one-quarter of the usual rec o mmended dose be given every 24 hours on days between dialysis and one-half the usual recommended dose on the day of dialysis. Preparation Of Solution For Intravenous Use Reconstitute with Sterile Water for Injection. Shake to dissolve and let stand until clear. Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg /mL) 1 gram 10 10.5 95 2 gram 10 to 20 11 to 21 182 to 95 For Intramuscular Use Reconstitute with Sterile Water for Injection; Bacteriostatic Water for Injection; Sodium Chloride Injection 0.9%, USP; 0.5% Lidocaine HCl; or 1% Lidocaine HCl. Shake to dissolve and let stand until clear. Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg /mL) 1 gram 2 2.5 400 2 gram 3 4 500 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 of CEFOTAN™ (cefotetan for Injection, USP) in Sterile Water for Injection can be injected over a period of three to five minutes. Using an infusion system, the solution may also be given over a longer period of time through the tubing system by which the patient may be receiving other intravenous solutions. Butterfly® or scalp vein-type needles are preferred for this type of infusion. However, during infusio n of the solution containing CEFOTAN™ (cefotetan for Injection, USP), it is advisable to discontinue tempo rarily the administration of other solutions at the same site. NOTE: Solutions of cefotetan must not be admixed with solutions containing amino glycosides. If CEFOTAN™ and amino glycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection. Intramuscular Administration As with all intramuscular preparations, CEFOTAN™ (cefotetan for Injection, USP) 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. Compatibility And Stability Frozen samples should be thawed at room temperature before use. After the periods mentioned below, any unused solutions or frozen material should be discarded. DO NOT REFREEZE. NOTE: Solutions of CEFOTAN™ (cefotetan for Injection, USP) must not be admixed with solutions containing aminoglycosides. If CEFOTAN™ (cefotetan for Injection, USP) and aminog lycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection. DO NOT ADD SUPPLEMENTARY MEDICATION. CEFOTAN™ (cefotetan for Injection, USP) reconstituted as described above (see DOSAGE AND ADMINISTRATION, Preparation Of Solution) maintains satisfactory potency for 24 hours at room temperature (25°C/77°F), for 96 hours under refrigeration (5°C/41°F), and for at least 1 week in the frozen state (-20°C/4°F). After reconstitution and subsequent storage in disposable glass or plastic syringes, CEFOTAN™ (cefotetan for Injection, USP) is stable for 24 hours at room temperature and 96 hours under refrigeration. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container pe rmit. HOW SUPPLIED CEFOTAN™ (cefotetan for Injection, USP) is a dry, white to pale yellow powder supplied in vials containing cefotetan disodium equivalent to 1 g and 2 g cefotetan activity for intravenous and intramuscular administration. The vials should be stored at 20°C to 25° C (68° to 77° F) [see USP Controlled Room Temperature] and should be protected from light. The following packages are available: NDC No. Strength 52565-052-10 1 gram 10 mL vial, packaged in a tray of 10. 52565-053-20 2 grams 20 mL vial, packaged in a tray of 10. Vial stoppers do not contain natural rubber latex. Manufactured for: Teligent Pharma, Inc. Buena, NJ 08310 Made in Italy. Revised: March 2017.

PATIENT INFORMATION Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs, including CEFOTAN™ , should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CEFOTAN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effective ness of the immediate treatment and (2) increase the likeliho o d that bacteria will develop resistance and will not be treatable by CEFOTAN™ (cefotetan for Injection, USP) or other antibacterial drugs in the future. As with so me other cephalo spo rins, a disulfiram-like reaction characterized by flushing, sweating, headache, and tachycardia may occur when alcohol (beer, wine, etc.) is ingested within 72 hours after CEFOTAN™ (cefotetan for Injection, USP) administration. Patients should be cautioned about the ingestion of alcoholic beverages following the administration of CEFOTAN™ .

OVERDOSE Information on overdosage with CEFOTAN™ in humans is not available. If overdosage should occur, it should be treated sympto matically and he modialysis considered, particularly if renal function is compromised. CONTRAINDICATIONS CEFOTAN™ is contraindicated in patients with a known allergy to the cephalosporin group of antibiotics and in those individuals who have experienced a cephalosporin associated hemolytic anemia.

SIDE EFFECTS In clinical studies, the following adverse effects were co nsidered related to CEFOTAN therapy. Those appearing in italics have been reported during postmarketing experience. Gastrointestinal symptoms occurred in 1.5% of patients, the mo st frequent were diarrhea (1 in 80) and nausea (1 in 700); pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment or surgical prophylaxis (see WARNINGS). Hematologic laboratory abnormalities occurred in 1.4% of patients and included eosinophilia (1 in 200), positive direct Coombs test (1 in 250), and thrombocytosis (1 in 300); agranulocytosis, hemolytic anemia, leukopenia, thrombocytopenia, and prolonged prothrombin time with or without bleeding. Hepatic enzyme elevations occurred in 1.2% of patients and included a rise in ALT (SGPT) (1 in 150), AST (SGOT) (1 in 300), alkaline phosphatase (1 in 700), and LDH (1 in 700). Hypersensitivity reactions were reported in 1.2% of patients and included rash (1 in 150) and itching (1 in 700); anaphylactic reactions and urticaria. Local effects were reported in less than 1% of patients and included phlebitis at the site of injection (1 in 300), and discomfort (1 in 500). Renal Elevations in BUN and serum creatinine have been reported. Urogenital Nephrotoxicity has rarely been reported. Miscellaneous Fever In addition to the adverse reactions listed above which have been observed in patients treated with cefotetan, the fo llo wing adverse reactions and altered laboratory tests have been reported for cephalo spo rin-class antibiotics: pruritus, Stevens-Johnson syndrome, erythema multifo rme, toxic epidermal necrolysis, vomiting , abdominal pain, colitis, superinfection, vaginitis including vaginal candidiasis, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, he mo rrhage, elevated bilirubin, pancytopenia, and neutropenia. Several cephalosporins have been implicated in trigg ering seizures, particularly in patients with renal impairment, when the dosage was not reduced (see DOSAGE AND ADMINISTRATION and OVERDOSE). 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 Teligent Pharma, Inc. at 1-856-697-1441, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Increases in serum creatinine have occurred when CEFOTAN™ was given alone. If CEFOTAN™ and an aminoglycoside are used concomitantly, renal function should be carefully mo nitored, because nephrotoxicity may be potentiated. Drug/Laboratory Test Interactions The administration of CEFOTAN™ may result in a false positive reaction for glucose in the urine using Clinitest®‡, Benedict's solution, or Fehling's solution. It is recommended that glucose tests based on enzymatic glucose oxidase be used. As with other cephalo spo rins, high concentrations of cefotetan may interfere with measurement of serum and urine creatinine levels by Jaffé reaction and produce false increases in the levels of creatinine reported.

WARNINGS BEFORE THERAPY WITH CEFOTAN™ IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTETAN DISODIUM, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSSHYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFOTAN™ OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. AN IMMUNE MEDIATED HEMOLYTIC ANEMIA HAS BEEN OBSERVED IN PATIENTS RECEIVING CEPHALOSPORIN CLASS ANTIBIOTICS. SEVERE CASES OF HEMOLYTIC ANEMIA, INCLUDING FATALITIES, HAVE BEEN REPORTED IN ASSOCIATION WITH THE ADMINISTRATION OF CEFOTETAN. SUCH REPORTS ARE UNCOMMON. THERE APPEARS TO BE AN INCREASED RISK OF DEVELOPING HEMOLYTIC ANEMIA ON CEFOTETAN RELATIVE TO OTHER CEPHALOSPORINS OF AT LEAST 3 FOLD. IF A PATIENT DEVELOPS ANEMIA ANYTIME WITHIN 2 TO 3 WEEKS SUBSEQUENT TO THE ADMINISTRATION OF CEFOTETAN, THE DIAGNOSIS OF A CEPHALOSPORIN ASSOCIATED ANEMIA SHOULD BE CONSIDERED AND THE DRUG STOPPED UNTIL THE ETIOLOGY IS DETERMINED WITH CERTAINTY. BLOOD TRANSFUSIONS MAY BE CONSIDERED AS NEEDED (see CONTRAINDICATIONS). PATIENTS WHO RECEIVE COURSES OF CEFOTETAN FOR TREATMENT OR PROPHYLAXIS OF INFECTIONS SHOULD HAVE PERIODIC MONITORING FOR SIGNS AND SYMPTOMS OF HEMOLYTIC ANEMIA INCLUDING A MEASUREMENT OF HEMATOLOGICAL PARAMETERS WHERE APPROPRIATE. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefotetan, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the develo pment of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or co nfirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. In common with many other broad-spectrum antibiotics, CEFOTAN™ may be associated with a fall in prothrombin activity and, possibly, subsequent bleeding.Those at increased risk include patients with renal or hepatobiliary impairment or poor nutritional state, the elderly, and patients with cancer. Prothrombin time should be monitored and exo genous vitamin K administered as indicated. PRECAUTIONS General Prescribing CEFOTAN™ in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the develo pment of drug-resistant bacteria. As with other broad-spectrum antibiotics, prolonged use of CEFOTAN™ may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. CEFOTAN™ should be used with caution in individuals with a history of gastrointestinal disease, particularly colitis. Carcinogenesis, Mutagenesis, Impairment Of Fertility Although long-term studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic potential of cefotetan was found in standard laboratory tests. Cefotetan has adverse affects on the testes of prepubertal rats. Subcutaneous administratio n of 500 mg/kg/day (approximately 0.8 times the maximum adult human dose on a body surface area basis) on days 6 to 35 of life (thought to be developmentally analogous to late childhood and prepuberty in humans) resulted in reduced testicular weight and seminifero us tubule degeneration in 10 of 10 animals. Affected cells included spermatogonia and spermato cytes; Sertoli and Leydig cells were unaffected. Incidence and severity of lesio ns were dose-dependant; at 120 mg/kg/day (0.2 times the maximum human dose on a body surface area basis) only 1 of 10 treated animals was affected, and the degree of deg eneration was mild. Similar lesio ns have been observed in experiments of co mparable design with other methylthiotetrazo le-co ntaining antibiotics and impaired fertility has been reported, particularly at high dose levels. No testicular effects were observed in 7-week-o ld rats treated with up to 1000 mg/kg/day subcutaneous for 5 weeks, or in infant dogs (3 weeks old) that received up to 300 mg/kg/day intravenous for 5 weeks (both 1.6 times the maximum recommended human dose on a body surface area basis). The relevance of these findings to humans is unknown. Pregnancy Teratogenic Effects Pregnancy Category B There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats and monkeys at doses up to 2000 and 600 mg/kg/day (3 and 2 times the maximum recommended human dose on a body surface area basis, respectively), and have revealed no evidence of impaired fertility or harm to the fetus due to cefotetan. Nursing Mothers Cefotetan is excreted in human milk in very low concentrations. Caution should be exercised when cefotetan is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the 925 subjects who received cefotetan in clinical studies, 492 (53%) were 60 years and older, while 76 (8%) were 80 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of so me older individuals cannot be ruled out. 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 mo re likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION, Impaired Renal Function).