ADVERSE REACTIONS SECTION.
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 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 West-Ward Pharmaceuticals Corp. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.
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 effects on the testes of prepubertal rats. Subcutaneous administration of 500 mg/kg/day (approximately to 16 times the usual adult human dose) on days 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 to times the usual human dose) only 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 1,000 mg/kg/day SC for weeks, or in infant dogs (3 weeks old) that received up to 300 mg/kg/day IV for weeks. The relevance of these findings to humans is unknown.
CLINICAL PHARMACOLOGY SECTION.
CLINICAL PHARMACOLOGY. High plasma levels of cefotetan are attained after intravenous and intramuscular administration of single doses to normal volunteers. PLASMA CONCENTRATIONS AFTER GRAM IVa OR IM DOSEMean Plasma Concentration (mcg/mL) Time after Injection Route 15 min30 min1 h2 h4 h8 12 hIV921581037242189IM3456716847209a 30-minute infusionPLASMA CONCENTRATIONS AFTER GRAM IVa OR IM DOSEMean Plasma Concentration (mcg/mL) Time after Injection Route5 min10 min1 h3 h5 h9 h12 IV23722313574482212bIM--207591693319a Injected over minutesb Concentrations estimated from regression lineThe plasma elimination half-life of cefotetan is to 4.6 hours after either intravenous or intramuscular 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 24 hour period, which results in high and prolonged urinary concentrations. Following intravenous doses of gram and grams, urinary concentrations are highest during the first hour and reach concentrations of approximately 1,700 and 3,500 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 hours in volunteers with normal renal function to about 10 hours in those with moderate renal impairment. There is linear correlation between the systemic clearance of cefotetan and creatinine clearance. When renal function is impaired, 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 (+- 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) vs. 10.3 (1.6) L) were similar following administration of one gram intravenous bolus dose.Therapeutic levels of cefotetan are achieved in many body tissues and fluids including: skinureter musclebladderfatmaxillary sinus mucosamyometriumtonsilendometriumbilecervixperitoneal fluidovaryumbilical cord serumkidneyamniotic fluid. Microbiology. The bactericidal action of cefotetan results from inhibition of cell wall synthesis. Cefotetan has in vitro activity against wide range of aerobic and anaerobic gram-positive and gram-negative organisms. The methoxy group in the 7-alpha position provides cefotetan with 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 AerobesEscherichia coliHaemophilus influenzae (including ampicillin-resistant strains)Klebsiella species(including K. pneumoniae)Morganella morganiiNeisseria gonorrhoeae (nonpenicillinase-producing strains)Proteus mirabilisProteus vulgarisProvidencia rettgeriSerratia marcescensNOTE: 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 AerobesStaphylococcus aureus (including penicillinase- and nonpenicillinase-producing strains) Staphylococcus epidermidisStreptococcus agalactiae (group beta-hemolytic streptococcus) Streptococcus pneumoniaeStreptococcus pyogenesNOTE: 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. AnaerobesPrevotella bivia (formerly Bacteroides bivius)Prevotella disiens (formerly Bacteroides disiens)Bacteroides fragilisPrevotella melaninogenica (formerly Bacteroides melaninogenicus)Bacteroides vulgatusFusobacterium speciesGram-positive bacilli (including Clostridium species; see WARNINGS)NOTE: Most strains of C. difficile are resistant (see WARNINGS). Peptococcus nigerPeptostreptococcus speciesNOTE: 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 AerobesCitrobacter species (including C. diversus and C. freundii)Klebsiella oxytocaMoraxella (Branhamella) catarrhalis Neisseria gonorrhoeae (penicillinase-producing strains) Salmonella species Serratia species Shigella species Yersinia enterocolitica AnaerobesPorphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus)Prevotella oralis (formerly Bacteroides oralis) Bacteroides splanchnicusClostridium difficile (see WARNINGS) Propionibacterium species Veillonella species. Susceptibility Tests. For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
CONTRAINDICATIONS. Cefotetan is contraindicated in patients with known allergy to the cephalosporin group of antibiotics and in those individuals who have experienced cephalosporin associated hemolytic anemia.
DESCRIPTION. Cefotetan for Injection, USP, as cefotetan disodium, is sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibiotic for parenteral administration. It is the disodium salt of [6R-(6,7)]-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, USP is supplied in vials containing 80 mg (3.5 mEq) of sodium per gram of cefotetan activity. It is white to pale yellow powder which is very soluble in water. Reconstituted solutions of 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. Cefotetan for Injection, USP is available in two vial strengths. Each gram vial contains cefotetan disodium equivalent to gram cefotetan activity. Each gram vial contains cefotetan disodium equivalent to grams cefotetan activity.. STRUCTURE.
DOSAGE & ADMINISTRATION SECTION.
DOSAGE AND ADMINISTRATION. Treatment. The usual adult dosage is or grams of Cefotetan for Injection 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 Cefotetan for InjectionType of Infection Daily Dose Frequency and Route Urinary Tract1 to grams500 mg every 12 hours IV or IM1 or g every 24 hours IV or IM or g every 12 hours IV or IMSkin Skin Structure Mild Moderatea Severe2 grams4 grams2 every 24 hours IV1 every 12 hours IV or IM2 every 12 hours IVOther Sites2 to grams1 or g every 12 hours IV or IMSevere4 grams2 every 12 hours IVLife-Threatening6 gramsb g every 12 hours IVaKlebsiella pneumoniae skin and skin structure infections should be treated with or2 grams every 12 hours IV or IM. Maximum daily dosage should not exceed grams.If Chlamydia trachomatis is 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 or 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, reduced dosage schedule must be employed. The following dosage guidelines may be used.DOSAGE GUIDELINES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION Creatinine ClearancemL/min Dose Frequency 30Usual Recommended DosageEvery 12 hours10 to 30Usual Recommended DosageEvery 24 hours< 10Usual Recommended DosageEvery 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 creatinine clearance of 10 to 30 mL/min, and one-quarter the usual recommended dose for patients with 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 steady state of renal function. Males: Weight (kg) (140 age) 72 serum creatinine (mg/100 mL)Females: 0.85 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 UseReconstitute with Sterile Water for Injection. Shake to dissolve and let stand until clear. Vial SizeAmount of Diluent Added (mL)Approximate Withdrawable Vol (mL)Approximate Average Concentration (mg/mL)1 gram1010.5952 grams10 to 2011 to 21182 to 95For Intramuscular UseReconstitute 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 SizeAmount of Diluent Added (mL)Approximate Withdrawable Vol (mL)Approximate Average Concentration(mg/mL)1 gram22.54002 grams34500Intravenous AdministrationThe 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, solution containing gram or grams of Cefotetan for Injection in Sterile Water for Injection can be injected over period of three to five minutes. Using an infusion system, the solution may also be given over longer period of time through the tubing system by which the patient may be receiving other intravenous solutions. Butterfly(R) or scalp vein-type needles are preferred for this type of infusion. However, during infusion of the solution containing Cefotetan for Injection 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 cefotetan and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection.Intramuscular AdministrationAs with all intramuscular preparations, Cefotetan for Injection should be injected well within the body of relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into 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 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 mixed injection. DO NOT ADD SUPPLEMENTARY MEDICATION. Cefotetan for Injection reconstituted as described above (see DOSAGE AND ADMINISTRATION, Preparation of Solution) maintains satisfactory potency for 24 hours at room temperature (25C/77F), for 96 hours under refrigeration (5C/41F), and for at least week in the frozen state (-20C/-4F). After reconstitution and subsequent storage in disposable glass or plastic syringes, Cefotetan for Injection 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.
DRUG INTERACTIONS SECTION.
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.
GENERAL PRECAUTIONS SECTION.
General. Prescribing cefotetan in the absence of proven or strongly suspected bacterial infection or 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 history of gastrointestinal disease, particularly colitis.
HOW SUPPLIED SECTION.
HOW SUPPLIED. Cefotetan for Injection, USP is dry, white to pale yellow powder supplied in vials containing cefotetan disodium equivalent to g and g cefotetan activity for intravenous and intramuscular administration. The following packages are available:NDC No. Strength 0143-9670-101 gram per vial10 mL vial, packaged in abox of 10.0143-9671-102 grams per vial20 mL vial, packaged in abox of 10.Do not exceed 22oC (72oF). PROTECT FROM LIGHT.Vials stoppers do not contain natural rubber latex.
INDICATIONS & USAGE SECTION.
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, 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 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 patients 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 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.
NURSING MOTHERS SECTION.
Nursing Mothers. Cefotetan is excreted in human milk in very low concentrations. Caution should be exercised when cefotetan is administered to nursing woman.
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.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
PRINCIPAL DISPLAY PANEL. NDC 0143-9670-01 CEFOTETAN FOR INJECTION, USP gram/vial FOR IV OR IM USE Rx ONLYNDC 0143-9670-10 Rx ONLYCEFOTETAN FOR INJECTION, USP gram/vial FOR IV OR IM USE 10 1 vials. PLB098-WES.2. PLB101-WES.2.
PEDIATRIC USE SECTION.
Pediatric Use. Safety and effectiveness in pediatric patients have not been established.
PRECAUTIONS. General. Prescribing cefotetan in the absence of proven or strongly suspected bacterial infection or 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 history of gastrointestinal disease, particularly colitis.. Information for Patients. Diarrhea is 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 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, 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 false positive reaction for glucose in the urine using Clinitest(R), Benedicts solution, or Fehlings 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 Jaffe 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 effects on the testes of prepubertal rats. Subcutaneous administration of 500 mg/kg/day (approximately to 16 times the usual adult human dose) on days 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 to times the usual human dose) only 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 1,000 mg/kg/day SC for weeks, or in infant dogs (3 weeks old) that received up to 300 mg/kg/day IV for weeks. The relevance of these findings to humans is unknown.. Pregnancy. Teratogenic Effects. Pregnancy Category BReproduction 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 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 ).
Pregnancy. Teratogenic Effects. Pregnancy Category BReproduction 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.
SPL UNCLASSIFIED SECTION.
For Intravenous or Intramuscular UseTo 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.
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 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 FOLD. IF PATIENT DEVELOPS ANEMIA ANYTIME WITHIN TO WEEKS SUBSEQUENT TO THE ADMINISTRATION OF CEFOTETAN, THE DIAGNOSIS OF 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 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 and 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 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 administered as indicated.