CEFOTETAN - cefotetan disodium injection, powder, for solution 
APP Pharmaceuticals, LLC

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Cefotetan for Injection

Rx only

For Intravenous Use Only

PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefotetan and other antibacterial drugs, cefotetan should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Cefotetan for Injection, as cefotetan disodium, is a sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibiotic 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 for injection is supplied in a Pharmacy Bulk Package 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 cefotetan for injection are intended for intravenous 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.

Each Pharmacy Bulk Package is supplied as a dry powder containing sterile cefotetan disodium equivalent to 10 grams cefotetan and is intended for intravenous use only.  Cefotetan for injection contains 80 mg (3.5 mEq) of sodium per gram of cefotetan activity.

USP water test pending.

A Pharmacy Bulk Package is a container of sterile preparation for parenteral use that contains many single doses.  The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion.  FURTHER DILUTION IS REQUIRED BEFORE USE (see DOSAGE AND ADMINISTRATION, and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

CLINICAL PHARMACOLOGY

High plasma levels of cefotetan are attained after intravenous administration of single doses to normal volunteers.

PLASMA CONCENTRATIONS AFTER 1 GRAM IVa OR IM DOSE Mean Plasma Concentration (mcg/mL)
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 IVa OR IM DOSE Mean Plasma Concentration (mcg/mL)
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

The plasma elimination half-life of cefotetan is 3 to 4.6 hours after intravenous administration.

Repeated administration of cefotetan does not result in accumulation of the drug in normal subjects.

Cefotetan is 88% plasma protein bound.

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 cefotetan 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.

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).

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 (± 1 sd) Total Body Clearance (1.8 (0.1) L/h vs. 1.8 (0.3) L/h) and mean Volume of Distribution (10.4 (1.2) L vs. 10.3 (1.6) L) were similar following administration of a one gram intravenous bolus dose.

Therapeutic levels 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

Microbiology

The bactericidal action of cefotetan results from inhibition of cell wall synthesis.  Cefotetan has in vitro activity against a wide range of aerobic and anaerobic gram-positive and gram-negative organisms.  The methoxy group in the 7-alpha position provides cefotetan with a high degree of stability in the presence of beta-lactamases including both penicillinases and cephalosporinase of gram-negative bacteria. 

Cefotetan has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).

Gram-Negative Aerobes

Escherichia coli

Haemophilus influenzae (including ampicillin-resistant strains)

Klebsiella species (including K. pneumoniae)

Morganella morganii

Neisseria gonorrhoeae (nonpenicillinase-producing strains)

Proteus mirabilis

Proteus vulgaris

Providencia rettgeri

Serratia marcescens

NOTE : Approximately one-half of the usually clinically significant strains of Enterobacter species (e.g., E. aerogenes and E. cloacae) are resistant to cefotetan.  Most strains of Pseudomonas aeruginosa and Acinetobacter species are resistant to cefotetan.

Gram-Positive Aerobes

Staphylococcus aureus (including penicillinase- and nonpenicillinase-producing strains)

Staphylococcus epidermidis

Streptococcus agalactiae (group B beta-hemolytic streptococcus)

Streptococcus pneumoniae

Streptococcus pyogenes

NOTE : Methicillin-resistant staphylococci are resistant to cephalosporins.  Some strains of Staphylococcus epidermidis and most strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis) are resistant to cefotetan. 

Anaerobes

Prevotella bivia (formerly Bacteroides bivius)

Prevotella disiens (formerly Bacteroides disiens)

Bacteroides fragilis

Prevotella melaninogenica (formerly Bacteroides melaninogenicus)

Bacteroides vulgatus

Fusobacterium species

Gram-positive bacilli (including Clostridium species; see WARNINGS)

NOTE: Most strains of C. difficile are resistant (see WARNINGS).

Peptococcus niger

Peptostreptococcus species

NOTE : Many strains of B. distasonis, B. ovatus and B. thetaiotaomicron are resistant to cefotetan in vitro.  However, the therapeutic utility of cefotetan against these organisms cannot be accurately predicted on the basis of in vitro susceptibility tests alone.

The following in vitro data are available but their clinical significance is unknown.  Cefotetan has been shown to be active in vitro against most strains of the following organisms:

Gram-Negative Aerobes

Citrobacter species (including C. diversus and C. freundii)

Klebsiella oxytoca

Moraxella (Branhamella) catarrhalis

Neisseria gonorrhoeae (penicillinase-producing strains)

Salmonella species

Serratia species

Shigella species

Yersinia enterocolitica

Anaerobes

Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus)

Prevotella oralis (formerly Bacteroides oralis)

Bacteroides splanchnicus

Clostridium difficile (see WARNINGS)

Propionibacterium species

Veillonella species

Susceptibility Tests

Dilution Techniques 

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs).  These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MICs should be determined using a standardized procedure.  Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefotetan powder.  The MIC values should be interpreted according to the following criteria:

MIC (mcg/mL )	Interpretation
≤ 16	Susceptible (S)
32	Intermediate (I)
≥  64	Resistant (R)

A report of 'Susceptible' indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.  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 which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of 'Resistant' indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.  Standard cefotetan powder should provide the following MIC values:

Microorganism	MIC (mcg/mL)
E. coli ATCC 25922	0.06-0.25
S. aureus ATCC 29213	4-16

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  One such standardized procedure2 requires the use of the standardized inoculum concentrations.  This procedure uses paper disks impregnated with 30 mcg cefotetan to test the susceptibility of microorganisms to cefotetan.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cefotetan disk should be interpreted according to the following criteria:

Zone Diameter (mm )	Interpretation
≥ 16	Susceptible (S)
13-15	Intermediate (I)
≤ 12	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefotetan.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures.  For the diffusion technique, the 30 mcg cefotetan disk should provide the following zone diameters in these laboratory test quality control strains.

Microorganism	Zone Diameter (mm)
E. coli ATCC 25922	28-34
S. aureus ATCC 25923	17-23

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to cefotetan as MIC's can be determined by standardized test methods3.  The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤ 16	Susceptible (S)
32	Intermediate (I)
≥ 64	Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures.  Standardized cefotetan powder should provide the following MIC values:

Microorganism	MIC (mcg/mL)
Bacteroides fragilis ATCC 25285	4-16
Bacteroides thetaiotaomicron ATCC 29741	32-128
Eubacterium lentum ATCC 43055	32-128

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefotetan and other antibacterial drugs, cefotetan 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

Cefotetan for injection 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 and Proteus spp (which may include the organisms now called Proteus vulgaris, Providencia rettgeri, and Morganella morganii).

Lower Respiratory Tract Infections caused by Streptococcus pneumoniae, Staphylococcus aureus (penicillinase- and nonpenicillinase-producing strains), Haemophilus influenzae (including ampicillin-resistant strains), Klebsiella species (including K. pneumoniae), E. coli, Proteus mirabilis, and Serratia marcescens.*

Skin and Skin Structure Infections due to Staphylococcus aureus (penicillinase- and nonpenicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus species (excluding enterococci), Escherichia coli, Klebsiella pneumoniae, Peptococcus niger*, Peptostreptococcus species.

Gynecologic Infections caused by Staphylococcus aureus, (including penicillinase- and nonpenicillinase-producing strains), Staphylococcus epidermidis, Streptococcus species (excluding enterococci), Streptococcus agalactiae, E. coli, Proteus mirabilis, Neisseria gonorrhoeae, Bacteroides species (excluding B. distasonis, B. ovatus, B. thetaiotaomicron), 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 (excluding enterococci), Bacteroides species (excluding B. distasonis, B. ovatus, B. thetaiotaomicron) and Clostridium species*.

Bone and Joint Infections caused by Staphylococcus aureus*.

* Efficacy for this organism in this organ system was studied in fewer than ten infections.

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 cefotetan 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 cefotetan was given alone.  If cefotetan and an aminoglycoside are used concomitantly, renal function should be carefully monitored, because nephrotoxicity may be potentiated.

Prophylaxis

The preoperative administration of cefotetan may reduce the incidence of certain post- operative 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.

CONTRAINDICATIONS

Cefotetan 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.

WARNINGS

BEFORE THERAPY WITH CEFOTETAN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTETAN, 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 CEFOTETAN 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 2-3 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, cefotetan 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.

PRECAUTIONS

General

Prescribing cefotetan 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 cefotetan 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.

Cefotetan 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 cefotetan, should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When cefotetan 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 cefotetan 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 cefotetan administration.  Patients should be cautioned about the ingestion of alcoholic beverages following the administration of cefotetan.

Drug Interactions

Increases in serum creatinine have occurred when cefotetan was given alone.  If cefotetan and an aminoglycoside are used concomitantly, renal function should be carefully monitored, because nephrotoxicity may be potentiated.

Drug/Laboratory Test Interactions

The administration of cefotetan 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 8-16 times the usual adult human dose) 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 (approximately 2 to 4 times the usual human dose) 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.  The relevance of these findings to humans is unknown.

Pregnancy

Teratogenic Effects. Pregnancy Category B

Reproduction studies have been performed in rats and monkeys at doses up to 20 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefotetan.  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.

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).

ADVERSE REACTIONS

In clinical studies, the following adverse effects were considered related to cefotetan 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.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

Treatment

The usual adult dosage is 1 or 2 grams of Cefotetan for Injection administered intravenously.  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 Cefotetan for Injection
Type of Infection	Daily Dose	Frequency and Route
Urinary Tract	1 to 4 grams	500 mg every 12 hours IV 1 or 2 g every 24 hours IV 1 or 2 g every 12 hours IV
Skin & Skin Structure Mild -Moderatea Severe	2 grams 4 grams	2 g every 24 hours IV 1 g every 12 hours IV 2 g every 12 hours IV
Other Sites	2 to 4 grams	1 or 2 g every 12 hours IV
Severe	4 grams	2 g every 12 hours IV
Life-Threatening	6 gramsb	3 g every 12 hours IV

a Klebsiella pneumoniae skin and skin structure infections should be treated with 1 or 2 grams every 12 hours IV.

bMaximum 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 cefotetan for injection 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
> 30	Usual Recommended Dosage*	Every 12 hours
10 to 30	Usual Recommended Dosage*	Every 24 hours
< 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 Pharmacy Bulk Package for Intravenous Use

Reconstitute with Sterile Water for Injection; 5% Dextrose Injection; or 0.9% Sodium Chloride Injection.  Shake to dissolve and let stand until clear (see DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

Pharmacy Bulk Package	Amount of Diluent Added (mL)	Approximate Withdrawable Vol (mL)	Approximate Average Concentration(mg/mL)
10 gram Pharmacy Bulk	50	55	180
10 gram Pharmacy Bulk	100	105	95

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.

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 cefotetan for injection must not be admixed-with solutions containing aminoglycosides.  If cefotetan for injection 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.

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE

The closure may be penetrated only one time, using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents.  Use of this product is restricted to a suitable work area, such as a laminar flow hood.

The withdrawal of container contents should be accomplished without delay.  However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations.  This time limit should begin with the introduction of solvent or diluents into the Pharmacy Bulk Package.  Unused portions of solutions held longer than the recommended time periods should be discarded.

Transfer individual doses to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package.  The stability of the solution that has been transferred into a container of a suitable diluent varies according to the temperature. 

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED

Cefotetan for Injection, in the Pharmacy Bulk Package, is a dry, white to pale yellow powder supplied in a Pharmacy Bulk Package containing cefotetan disodium equivalent to 10 g cefotetan activity for intravenous administration as follows:

Product No.	NDC No.	Strength
309661	63323-386-61	10 grams	Supplied in individual cartons containing one Pharmacy Bulk Package vial.

Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].  PROTECT FROM LIGHT.

Vial stoppers do not contain natural rubber latex.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition.  Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993.
2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.
3. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December 1993.

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

 

451077E

Revised: January 2009

PACKAGE LABEL - PRINCIPAL DISPLAY - Cefotetan 10 grams* Vial Label

NDC 63323-396-61

309661

CEFOTETAN FOR INJECTION

PHARMACY BULK PACKAGE  

NOT FOR DIRECT INFUSION

10 grams*

For Intravenous Use

Caution - Not to be Dispensed as a Unit.

Rx only

 

PACKAGE LABEL - PRINCIPAL DISPLAY - Cefotetan 10 grams* Vial Carton Panel

NDC 63323-396-61

309661

CEFOTETAN FOR INJECTION

PHARMACY BULK PACKAGE  

NOT FOR DIRECT INFUSION

10 grams*

For Intravenous Use

Caution - Not to be Dispensed as a Unit.

Keep Top Closed

Rx only

One Pharmacy Bulk Package

 

CEFOTETAN  cefotetan disodium   injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63323-396 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CEFOTETAN DISODIUM (CEFOTETAN) CEFOTETAN DISODIUM 10 g

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63323-396-61 1 VIAL In 1 BOX contains a VIAL 1 1 VIAL In 1 VIAL This package is contained within the BOX (63323-396-61)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA065375	12/03/2009

Labeler - APP Pharmaceuticals, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
APP Pharmaceuticals, LLC (840771732)		840771732	MANUFACTURE

Revised: 12/2009APP Pharmaceuticals, LLC