Label: CEFOTAN - cefotetan disodium injection, powder, for solution
CEFOTAN - cefotetan disodium injection, powder, for solution

  • NDC Code(s): 52565-052-10, 52565-053-10
  • Packager: Teligent Pharma, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated March 9, 2017

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  • SPL UNCLASSIFIED SECTION

    Rx only

    For Intravenous or Intramuscular Use

    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 bacteria.

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  • DESCRIPTION

    CEFOTAN® (cefotetan for Injection, USP), as cefotetan disodium, is a sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibacterial for parenteral administration.  It is the disodium salt of  [6R-(6α,7α)]-7-[[[4-(2-amino-1-carboxy-2-oxoethylidene)-1,3-dithietan-2-yl]carbonyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.  Structural formula:

    cefotetan-structure

    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 intramuscular 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 grams cefotetan activity.

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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 INTRAVENOUSa 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

    135

    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

    myometrium

    tonsil

    endometrium

    bile

    cervix

    peritoneal fluid

    ovary

    umbilical cord serum

    kidney

    amniotic fluid

    Metabolism and Excretion

    The plasma elimination 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 increases with declining renal function, from approximately 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 Volume of Distribution (10.4±1.2 vs. 10.3±1.6 L) were similar following 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 microorganisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).

    Gram-Negative Bacteria

    Escherichia coli

    Haemophilus influenza

    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 measurement 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 method2,4. This procedure uses paper disks impregnated with 30 mcg cefotetan to test the susceptibility of microorganisms 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 determined by standardized test methods3,4.  The MIC values obtained should be interpreted according to the following criteria:

    Table 1: Susceptibility Test Interpretive Criteria for Cefotetan
    1Susceptibility interpretive criteria for microorganisms are based on a dosing regimen of 2 g every 12 hours
    2For 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.
    3For 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
    Microorganisms 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

    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 considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated.  This category implies 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 discrepancies 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.,,, 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
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  • INDICATIONS AND USAGE

    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 organisms:

    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 (methicillin-susceptible), 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 organisms and to determine their susceptibilities to cefotetan.  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 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, it is possible to use CEFOTAN® concomitantly with an aminoglycoside. Cefotetan combinations with aminoglycosides have been shown to be synergistic in vitro against many Enterobacteriaceae and also some other gram- negative bacteria.  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.

    NOTE: Increases in serum creatinine have occurred when CEFOTAN® was given alone.  If CEFOTAN® and an aminoglycoside are used concomitantly, renal function should be carefully monitored, 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.

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  • 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.

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  • 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 CROSS-HYPERSENSITIVITY 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 development 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 confirmed, 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 exogenous vitamin K administered as indicated.

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  • 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 development 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.

    Information for Patients

    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 effectiveness of the immediate treatment and (2) increase the likelihood 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 some other cephalosporins, 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®.

    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 monitored, 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 cephalosporins, 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.

    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 administration 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 seminiferous tubule degeneration in 10 of 10 animals.  Affected cells included spermatogonia and spermatocytes; Sertoli and Leydig cells were unaffected.  Incidence and severity of lesions 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 degeneration was mild.

    Similar lesions have been observed in experiments of comparable design with other methylthiotetrazole-containing antibiotics and impaired fertility has been reported, particularly at high dose levels.  No testicular effects were observed in 7-week-old rats treated with up to 1000 mg/kg/day SC for 5 weeks, or in infant dogs (3 weeks old) that received up to 300 mg/kg/day IV 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 of up to 2000 and 600 mg/kg/day, or 3 and 2 times the maximum recommended human dose on a body surface area basis. 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 some 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 more 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).

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  • ADVERSE REACTIONS

    In clinical studies, the following adverse effects were considered related to CEFOTAN therapy.  Those appearing in italics have been reported during postmarketing experience.

    Gastrointestinal: symptoms occurred in 1.5% of patients, the most 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 following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: pruritus, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, vomiting, abdominal pain, colitis, superinfection, vaginitis including vaginal candidiasis, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, elevated bilirubin, pancytopenia, and neutropenia.

    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 Teligent Pharma, Inc. at 1-856-697-1441, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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  • OVERDOSAGE

    Information on overdosage with CEFOTAN® in humans is not available.  If overdosage should occur, it should be treated symptomatically and hemodialysis considered, particularly if renal function is compromised.

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  • DOSAGE AND ADMINISTRATION

    Treatment

    The usual adult dosage is 1 gram (g) or 2 grams of CEFOTAN® (cefotetan for Injection, USP) administered intravenously or intramuscularly.  Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organism.

                     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




        Severe


    2 g
                                        
                                    
    2 g every 24 hours intravenous
    1 g every 12 hours intravenous or intramuscular
     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 grams

    2 g every 12 hours intravenous

    Life-Threatening

    6 gramsb

    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 following dosage guidelines may be used.

    DOSAGE GUIDELINES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION

    Creatinine Clearance

    mL/min

     

    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 (kg) x (140 - age)                

                          72 x serum creatinine (mg/100 mL)


    Females:   0.85 x value for males


    Cefotetan is dialyzable and it is recommended that for patients undergoing intermittent hemodialysis, one-quarter of the usual recommended 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 infusion of the solution containing CEFOTAN® (cefotetan for Injection, USP), it is advisable to discontinue temporarily the administration of other solutions at the same site.

    NOTE: Solutions of cefotetan must not be admixed with solutions containing aminoglycosides.  If CEFOTAN® and aminoglycosides 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 aminoglycosides 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 (25ºC/77ºF), for 96 hours under refrigeration (5ºC/41ºF), and for at least 1 week in the frozen state (-20ºC/-4ºF).  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 permit.

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  • 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 20⁰C to 25⁰ C (68⁰ to 77⁰ 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
    52565-053-10 2 grams 20 mL vial, packaged in a tray of 10

    Vial stoppers do not contain natural rubber latex.

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  • 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 AntimicrobialDisk Susceptibility Tests - Fifth Edition. Approved Standard NCCLS Document 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.

    Clinitest® is a registered trademark of Ames Division, Miles Laboratories, Inc.

    CEFOTAN® is a registered trademark of Teligent Pharma, Inc.

    Manufactured for:
    Teligent Pharma, Inc.
    Buena NJ 08310
    Made in Italy  

    Revised: March 2017

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  • PRINCIPAL DISPLAY PANEL


     

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  • PACKAGE LABEL. CARTON PRINCIPAL DISPLAY PANEL, 1 Gram Carton NDC 52565-052-10 Cefotan® (Cefotetan For Injection) Equivalent to 1 gram Cefotetan per vial 10 x 10mL Vials Protect from Light Must be reconstituted. For intravenous infusion or intramuscular injection.
  • PACKAGE LABEL. CARTON PRINCIPAL DISPLAY PANEL, 2 Gram Carton NDC 52565-053-10 Cefotan® (Cefotetan For Injection) Equivalent to 2 grams Cefotetan per vial 10 - 20 mL Vials Protect from Light KEEP TOP CLOSED Must be reconstituted. For intravenous infusion or intramuscular injection.
  • INGREDIENTS AND APPEARANCE
    CEFOTAN  
    cefotetan disodium injection, powder, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52565-052
    Route of Administration INTRAVENOUS, INTRAMUSCULAR
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Cefotetan Disodium (UNII: 0GXP746VXB) (Cefotetan - UNII:48SPP0PA9Q) Cefotetan 1 g  in 10 mL
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:52565-052-10 10 in 1 TRAY 10/01/2015
    1 10 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA050588 10/01/2015
    CEFOTAN  
    cefotetan disodium injection, powder, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52565-053
    Route of Administration INTRAVENOUS, INTRAMUSCULAR
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Cefotetan Disodium (UNII: 0GXP746VXB) (Cefotetan - UNII:48SPP0PA9Q) Cefotetan 2 g  in 20 mL
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:52565-053-10 10 in 1 TRAY 10/01/2015
    1 20 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA050588 10/01/2015
    Labeler - Teligent Pharma, Inc. (011036910)
    Registrant - Teligent Pharma, Inc. (011036910)
    Establishment
    Name Address ID/FEI Business Operations
    ACSDobfar S.p.A 542848580 api manufacture(52565-052, 52565-053)
    Establishment
    Name Address ID/FEI Business Operations
    Facta Farmaceutici 434623333 manufacture(52565-053, 52565-052)
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