PEDIATRIC USE SECTION.

Pediatric Use: Safety and effectiveness of Ceftriaxone for Injection in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone for Injection should not be administered to hyperbilirubinemic neonates, especially prematures (see CONTRAINDICATIONS).

PRECAUTIONS SECTION.

PRECAUTIONS. General. Prescribing Ceftriaxone for Injection 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.Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages, the nephrotoxic potential of Ceftriaxone for Injection is similar to that of other cephalosporins.Ceftriaxone is excreted via both biliary and renal excretion (see CLINICAL PHARMACOLOGY). Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone for Injection are administered.Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the Ceftriaxone for Injection dosage should not exceed g daily.Alterations in prothrombin times have occurred rarely in patients treated with Ceftriaxone for Injection. Patients with impaired vitamin synthesis or low vitamin stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone for Injection treatment. Vitamin administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.Prolonged use of Ceftriaxone for Injection may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.Ceftriaxone for Injection should be prescribed with caution in individuals with history of gastrointestinal disease, especially colitis.There have been reports of sonographic abnormalities in the gallbladder of patients treated with Ceftriaxone for Injection; some of these patients also had symptoms of gallbladder disease. These abnormalities appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The chemical nature of the sonographically detected material has been determined to be predominantly ceftriaxone-calcium salt. The condition appears to be transient and reversible upon discontinuation of Ceftriaxone for Injection and institution of conservative management. Therefore, Ceftriaxone for Injection should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported rarely in patients treated with Ceftriaxone for Injection. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, total parenteral nutrition). cofactor role of Ceftriaxone for Injection-related biliary precipitation cannot be ruled out.As with other cephalosporins, anaphylactic shock cannot be ruled out even if thorough patient history is taken.. Information for Patients: Patients should be counseled that antibacterial drugs including Ceftriaxone for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., common cold). When Ceftriaxone for Injection 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 Ceftriaxone for Injection or other antibacterial drugs in the future.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.. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed. The maximum duration of animal toxicity studies was months.. Mutagenesis: Genetic toxicology tests included the Ames test, micronucleus test and test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.. Impairment of Fertility: Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of g/day.. Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at dose approximately times the human dose.There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.. Nonteratogenic Effects: In rats, in the Segment (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.. Nursing Mothers: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone for Injection is administered to nursing woman.. Pediatric Use: Safety and effectiveness of Ceftriaxone for Injection in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone for Injection should not be administered to hyperbilirubinemic neonates, especially prematures (see CONTRAINDICATIONS).. Geriatric Use: Of the total number of subjects in clinical studies of Ceftriaxone for Injection, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.The pharmacokinetics of ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to grams per day (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Ceftriaxone for Injection is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to Ceftriaxone for Injection therapy or of uncertain etiology, were observed:LOCAL REACTIONS -- pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration. The incidence of warmth, tightness or induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL.HYPERSENSITIVITY -- rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.HEMATOLOGIC -- eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.GASTROINTESTINAL -- diarrhea (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).HEPATIC -- elevations of SGOT (3.1%) or SGPT (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.RENAL -- elevations of the BUN (1.2%). Less frequently reported (< 1%) were elevations of creatinine and the presence of casts in the urine. CENTRAL NERVOUS SYSTEM -- headache or dizziness were reported occasionally (<1 %). GENITOURINARY -- moniliasis or vaginitis were reported occasionally (<1%).MISCELLANEOUS -- diaphoresis and flushing were reported occasionally (<1%).Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.. Postmarketing Experience: In addition to the adverse reactions reported during clinical trials, the following adverse experiences have been reported during clinical practice in patients treated with Ceftriaxone for Injection. Data are generally insufficient to allow an estimate of incidence or to establish causation. small number of cases of fatal outcomes in which crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Ceftriaxone for Injection and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Ceftriaxone for Injection and calcium-containing fluids and in some precipitate was observed in the intravenous infusion line. At least one fatality has been reported in neonate in whom Ceftriaxone for Injection and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.GASTROINTESTINAL -- stomatitis and glossitis. GENITOURINARY -- oliguria. DERMATOLOGIC -- exanthema, allergic dermatitis, urticaria, edema. As with many medications, isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyells syndrome/toxic epidermal necrolysis) have been reported. Cephalosporin Class Adverse Reactions In addition to the adverse reactions listed above which have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics: Adverse Reactions: Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection. Altered Laboratory Tests: Positive direct Coombs test, false-positive test for urinary glucose, and elevated LDH. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in animals have not been performed. The maximum duration of animal toxicity studies was months.. Mutagenesis: Genetic toxicology tests included the Ames test, micronucleus test and test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.. Impairment of Fertility: Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of g/day.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Average plasma concentrations of ceftriaxone following single 30-minute intravenous (IV) infusion of 0.5, or g dose and intramuscular (IM) administration of single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1g dose in healthy subjects are presented in Table 1.TABLE 1. Ceftriaxone Plasma Concentrations After Single Dose Administration Dose/Route Average Plasma Concentrations (mcg/mL) 0.5 hr hr hr hr hr hr 12 hr 16 hr 24 hr 0.5 IV 82 59 48 37 29 23 15 10 0.5 IM 250 mg/mL 22 33 38 35 30 26 16 ND 0.5 IM 350 mg/mL 20 32 38 34 31 24 16 ND 1 IV 151 111 88 67 53 43 28 18 1 IM 40 68 76 68 56 44 29 ND ND g IV 257 192 154 117 89 74 46 31 15 IV doses were infused at constant rate over 30 minutes.ND Not determined. Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between and hours post-dose. Multiple IV or IM doses ranging from 0.5 to g at 12- to 24-hour intervals resulted in 15% to 36% accumulation of ceftriaxone above single dose values.Ceftriaxone concentrations in urine are shown in Table 2.TABLE 2. Urinary Concentrations of Ceftriaxone After Single Dose Administration Dose/Route Average Urinary Concentrations (mcg/mL) 0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 hr 0.5 IV 526 366 142 87 70 15 0.5 IM 115 425 308 127 96 28 g IV 995 855 293 147 132 32 g IM 504 628 418 237 ND ND g IV 2692 1976 757 274 198 40 ND Not determined.Thirty-three percent to 67% of ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After 1 IV dose, average concentrations of ceftriaxone, determined from to hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma.Over 0.15 to g dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from value of 95% bound at plasma concentrations of 25 mcg/mL to value of 85% bound at 300 mcg/mL. Ceftriaxone crosses the blood placenta barrier.The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after 50 mg/kg IV dose and after 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Ceftriaxone penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after 50 mg/kg IV dose and after 75 mg/kg IV dose are also shown in Table 3.TABLE 3. Average Pharmacokinetic Parameters of Ceftriaxone in Pediatric Patients With Meningitis 50 mg/kg IV 75 mg/kg IV Maximum Plasma Concentrations (mcg/mL) 216 275 Elimination Half-life (hr) 4.6 4.3 Plasma Clearance (mL/hr/kg) 49 60 Volume of Distribution (mL/kg) 338 373 CSF Concentration inflamed meninges (mcg/mL) 5.6 6.4 Range (mcg/mL) 1.3-18.5 1.3-44 Time after dose (hr) 3.7 (+- 1.6) 3.3 (+- 1.4)Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone dosages up to g per day. Ceftriaxone was not removed to any significant extent from the plasma by hemodialysis; in six of 26 dialysis patients, the elimination rate of ceftriaxone was markedly reduced.TABLE 4. Average Pharmacokinetic Parameters of Ceftriaxone in Humans Subject Group Elimination Half-Life(hr) Plasma Clearance(L/hr) Volume of Distribution(L) Healthy Subjects 5.8-8.7 0.58-1.45 5.8-13.5 Elderly Subjects (mean age, 70.5 yr) 8.9 0.83 10.7 Patients With Renal Impairment Hemodialysis Patients(0-5 mL/min) 14.7 0.65 13.7 Severe(5-15 mL/min) 15.7 0.56 12.5 Moderate(16-30 mL/min) 11.4 0.72 11.8 Mild(31-60 mL/min) 12.4 0.70 13.3 Patients With Liver Disease 8.8 1.1 13.6Creatinine clearance.The elimination of ceftriaxone is not altered when Ceftriaxone for Injection is co-administered with probenecid.Pharmacokinetics in the Middle Ear Fluid: In one study, total ceftriaxone concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from to 50 hours after single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (+- SD) ceftriaxone levels in the middle ear reached peak of 35 (+- 12) mcg/mL at 24 hours, and remained at 19 (+- 7) mcg/mL at 48 hours. Based on middle ear fluid ceftriaxone concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, half-life of 25 hours was calculated. Ceftriaxone is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown.Interaction with Calcium: Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to mM (in excess of concentrations achieved in vivo following administration of grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of mM (24 mg/dL) or higher in adult plasma or mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation.Microbiology: The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone has high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. Ceftriaxone has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections described in the INDICATIONS AND USAGE section. Aerobic gram-negative microorganisms: Acinetobacter calcoaceticus Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae (including ampicillin-resistant and beta-lactamase producing strains) Haemophilus parainfluenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis (including beta-lactamase producing strains) Morganella morganii Neisseria gonorrhoeae (including penicillinase- and nonpenicillinase-producing strains) Neisseria meningitidis Proteus mirabilis Proteus vulgaris Serratia marcescens Ceftriaxone is also active against many strains of Pseudomonas aeruginosa.NOTE: Many strains of the above organisms that are resistant to multiple antibiotics, e.g., penicillins, cephalosporins, and aminoglycosides, are susceptible to ceftriaxone.Aerobic gram-positive microorganisms: Staphylococcus aureus (including penicillinase-producing strains) Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Viridans group streptococci NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins, including ceftriaxone. Most strains of Group streptococci and enterococci, e.g., Enterococcus (Streptococcus) faecalis, are resistant. Anaerobic microorganisms: Bacteroides fragilis Clostridium species Peptostreptococcus species NOTE: Most strains of Clostridium difficile are resistant. The following in vitro data are available, but their clinical significance is unknown. Ceftriaxone exhibits in vitro minimal inhibitory concentrations (MICs) of <= mcg/mL or less against most strains of the following microorganisms, however, the safety and effectiveness of ceftriaxone in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Aerobic gram-negative microorganisms: Citrobacter diversus Citrobacter freundii Providencia species (including Providencia rettgeri) Salmonella species (including Salmonella typhi) Shigella species Aerobic gram-positive microorganisms: Streptococcus agalactiae Anaerobic microorganisms: Prevotella (Bacteroides) bivius Porphyromonas (Bacteroides) melaninogenicus 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 standardized procedure.1 Standardized procedures are based on dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftriaxone powder. The MIC values should be interpreted according to the following criteria2 for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp, including Streptococcus pneumoniae: MIC (mcg/mL) Interpretation <= (S) Susceptible 16-32 (I) Intermediate >= 64 (R) ResistantThe following interpretive criteria2 should be used when testing Haemophilus species using Haemophilus Test Media (HTM). MIC (mcg/mL) Interpretation <= (S) SusceptibleThe absence of resistant strains precludes defining any categories other than Susceptible. Strains yielding results suggestive of Nonsusceptible category should be submitted to reference laboratory for further testing. The following interpretive criteria2 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement. MIC (mcg/mL) Interpretation <= 0.25 (S) SusceptibleThe absence of resistant strains precludes defining any categories other than Susceptible. Strains yielding results suggestive of Nonsusceptible category should be submitted to reference laboratory for further testing. The following interpretive criteria2 should be used when testing Streptococcus spp including Streptococcus pneumoniae using cation-adjusted Mueller-Hinton broth with to 5% lysed horse blood. MIC (mcg/mL) Interpretation <= 0.5 (S) Susceptible (I) Intermediate >= (R) ResistantA report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. report of Intermediate indicates that the results 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 the drug can be used. This category also provides buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. 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. Standardized ceftriaxone powder should provide the following MIC values:2 Microorganism ATCC (R) MIC mcg /mL) Escherichia coli 25922 0.03-0.12 Staphylococcus aureus 29213 1-8 Pseudomonas aeruginosa 27853 8-32 Haemophilus influenzae 49247 0.06-0.25 Neisseria gonorrhoeae 49226 0.004-0.015 Streptococcus pneumoniae 49619 0.03-0.12 bimodal distribution of MICs results at the extremes of the acceptable range should be suspect and control validity should be verified with data from other control strains. ATCC(R) is registered trademark of the American Type Culture Collection.. 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 procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 30 mcg of ceftriaxone to test the susceptibility of microorganisms to ceftriaxone.Reports from the laboratory providing results of the standard single-disc susceptibility test with 30 mcg ceftriaxone disc should be interpreted according to the following criteria for aerobic organisms other than Haemophilus spp, Neisseria gonorrhoeae, and Streptococcus spp: Zone Diameter (mm) Interpretation >= 21 (S) Susceptible 14-20 (I) Intermediate <= 13 (R) ResistantThe following interpretive criteria3 should be used when testing Haemophilus species when using Haemophilus Test Media (HTM). Zone Diameter (mm) Interpretation >= 26 (S) SusceptibleThe absence of resistant strains precludes defining any categories other than Susceptible. Strains yielding results suggestive of Nonsusceptible category should be submitted to reference laboratory for further testing.The following interpretive criteria3 should be used when testing Neisseria gonorrhoeae when using GC agar base and 1% defined growth supplement. Zone Diameter (mm) Interpretation >= 35 (S) SusceptibleThe absence of resistant strains precludes defining any categories other than Susceptible. Strains yielding results suggestive of Nonsusceptible category should be submitted to reference laboratory for further testing.The following interpretive criteria3 should be used when testing Streptococcus spp other than Streptococcus pneumoniae when using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2. Zone Diameter (mm) Interpretation >= 27 (S) Susceptible 25-26 (I) Intermediate <= 24 (R) ResistantInterpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disc test with the MIC for ceftriaxone.Disc diffusion interpretive criteria for ceftriaxone discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of 20mm are susceptible (MIC <= 0.06 mcg/mL) to penicillin and can be considered susceptible to ceftriaxone. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of <= 19mm. The ceftriaxone MIC should be determined for those isolates with oxacillin zone diameters <= 19mm.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 ceftriaxone disc should provide the following zone diameters in these laboratory test quality control strains:3 Microorganism ATCC (R) Zone Diameter Ranges (mm) Escherichia coli 25922 29-35 Staphylococcus aureus 25923 22-28 Pseudomonas aeruginosa 27853 17-23 Haemophilus influenzae 49247 31-39 Neisseria gonorrhoeae 49226 39-51 Streptococcus pneumoniae 49619 30-35. Anaerobic Techniques: For anaerobic bacteria, the susceptibility to ceftriaxone as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria: MIC (mcg/mL) Interpretation <= 16 (S) Susceptible 32 (I) Intermediate >= 64 (R) ResistantAs with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftriaxone powder should provide the following MIC values for the indicated standardized anaerobic dilution4 testing method: Method Microorganism ATCC (R) MIC mcg /mL) Agar Bacteroides fragilis 25285 32 128 Bacteroides thetaiotaomicron 29741 64 256 Broth Bacteroides thetaiotaomicron 29741 32 128.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Clinical Trials in Pediatric Patients With Acute Bacterial Otitis MediaIn two adequate and well-controlled U.S. clinical trials single IM dose of ceftriaxone was compared with 10 day course of oral antibiotic in pediatric patients between the ages of months and years. The clinical cure rates and statistical outcome appear in the table below: Clinical Efficacy in Evaluable Population Study Day Ceftriaxone Single Dose Comparator -10 Days of Oral Therapy 95% Confidence Interval Statistical Outcome Study - U.S. amoxicillin/clavulanate Ceftriaxone is lower than control at study day 14 and 28. 14 74% (220/296) 82% (247/302) (-14.4%, -0.5%) 28 58% (167/288) 67% (200/297) (-17.5%, -1.2%) Study - U.S.5 TMP-SMZ Ceftriaxone is equivalent to control at study day 14 and 28. 14 54% (113/210) 60% (124/206) (-16.4%, 3.6%) 28 35% (73/206) 45% (93/205) (-19.9%, 0.0%) An open-label bacteriologic study of ceftriaxone without comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:Week and Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen: Study Day 13-15 Study Day 30+2 Organism No. Analyzed No. Erad. (%) No. Analyzed No. Erad. (%) Streptococcus pneumoniae 38 32 (84) 35 25 (71) Haemophilus influenzae 33 28 (85) 31 22 (71) Moraxella catarrhalis 15 12 (80) 15 (60).

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Ceftriaxone for Injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.. Neonates (<= 28 days). Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone for Injection. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.Ceftriaxone for Injection is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CLINICAL PHARMACOLOGY, WARNINGS and DOSAGE AND ADMINISTRATION).A small number of cases of fatal outcomes in which crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Ceftriaxone for Injection and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Ceftriaxone for Injection and calcium-containing fluids and in some precipitate was observed in the intravenous infusion line. At least one fatality has been reported in neonate in whom Ceftriaxone for Injection and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.

DESCRIPTION SECTION.

DESCRIPTION. Ceftriaxone for injection, USP is sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.The chemical formula of ceftriaxone sodium is C1 8H1 6N8Na2O7S3o3.5H2O. It has calculated molecular weight of 661.60 and the following structural formula:Ceftriaxone for Injection, USP is white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of 1% aqueous solution is approximately 6.7. The color of ceftriaxone for injection, USP solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.Each Pharmacy Bulk Package is supplied as dry powder in vials containing sterile ceftriaxone sodium, USP equivalent to 10 grams of ceftriaxone and is intended for intravenous infusion only. Ceftriaxone sodium contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.A Pharmacy Bulk Package is container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. (s ee DOSAGE AND ADMINISTRATION and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE). ceftriaxone sodium structural formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Ceftriaxone for Injection may be administered intravenously or intramuscularly. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. Ceftriaxone should be administered intravenously by infusion over period of 30 minutes.Do not use diluents containing calcium, such as Ringers solution or Hartmanns solution, to reconstitute Ceftriaxone for Injection vials or to further dilute reconstituted vial for IV administration because precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Ceftriaxone for Injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for Injection must not be administered simultaneously with calcium-containing IV solution, including continuous calcium-containing infusions such as parenteral nutrition via Y-site. However, in patients in other than neonates, Ceftriaxone for Injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with compatible fluid (see WARNINGS).There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).NEONATES: Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone for Injection (see CONTRAINDICATIONS).Ceftriaxone is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).PEDIATRIC PATIENTS: For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once day (or in equally divided doses twice day). The total daily dose should not exceed grams.For the treatment of acute bacterial otitis media, single intramuscular dose of 50 mg/kg (not to exceed gram) is recommended (see INDICATIONS AND USAGE).For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed grams.In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed grams). Thereafter, total daily dose of 100 mg/kg/day (not to exceed grams daily) is recommended. The daily dose may be administered once day (or in equally divided doses every 12 hours). The usual duration of therapy is to 14 days.ADULTS: The usual adult daily dose is to grams given once day (or in equally divided doses twice day) depending on the type and severity of infection. The total daily dose should not exceed grams.If Chlamydia trachomatis is suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.For the treatment of uncomplicated gonococcal infections, single intramuscular dose of 250 mg is recommended.For preoperative use (surgical prophylaxis), single dose of gram administered intravenously 1/2 to hours before surgery is recommended.Generally, Ceftriaxone for Injection therapy should be continued for at least days after the signs and symptoms of infection have disappeared. The usual duration of therapy is to 14 days; in complicated infections, longer therapy may be required.When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.No dosage adjustment is necessary for patients with impairment of renal or hepatic function. DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE: The 10 gram vial should be reconstituted with 95 mL of an appropriate IV diluent in suitable work area such as laminar flow hood. The resulting solution will contain approximately 100 mg/mL of ceftriaxone. This closure may be penetrated only one time after reconstitution, using suitable sterile transfer device or dispensing set which allows measured dispensing of the contents.The withdrawal of container contents should be accomplished without delay. However, should this not be possible, maximum time of HOURS from initial closure entry is permitted to complete fluid transfer operations. Unused portions of solution held longer than the recommended time periods should be discarded. Reconstituted Bulk Solutions Should Not Be Used For Direct Infusion. Transfer individual dose to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package. The stability of the solution that has been transferred into container varies according to diluent, concentration and temperature (see COMPATIBILITY AND STABILITY ). Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired.COMPATABILITY AND STABILITY: Ceftriaxone has been shown to be compatible with Flagyl(R) IV (metronidazole hydrochloride). The concentration should not exceed to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatability studies have been conducted with the Flagyl(R) IV RTU(R) (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.Registered trademark of G.D. Searle Co.Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.Do not use diluents containing calcium, such as Ringers solution or Hartmanns solution, to reconstitute Ceftriaxone for Injection vials or to further dilute reconstituted vial for IV administration. Particulate formation can result.Ceftriaxone for Injection solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).Ceftriaxone for Injection sterile powder should be stored at 20 25C (68 77F) [See USP Controlled Room Temperature] and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.Ceftriaxone for Injection intravenous solutions, at concentrations of 10, 20, and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers: Storage Diluent Room Temp. (25C) Refrigerated (4C) Sterile Water days 10 days 0.9% Sodium Chloride Solution days 10 days 5% Dextrose Solution days 10 days 10% Dextrose Solution days 10 days 5% Dextrose 0.9% Sodium Chloride SolutionData available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only. days Incompatible 5% Dextrose 0.45% Sodium Chloride Solution days IncompatibleThe following intravenous Ceftriaxone for Injection solutions are stable at room temperature (25 C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).After the indicated stability time periods, unused portions of solutions should be discarded.NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.Ceftriaxone for Injection reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (- 20C) in PVC or polyolefin containers, remains stable for 26 weeks.Frozen solutions of Ceftriaxone for Injection should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

GENERAL PRECAUTIONS SECTION.

General. Prescribing Ceftriaxone for Injection 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.Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages, the nephrotoxic potential of Ceftriaxone for Injection is similar to that of other cephalosporins.Ceftriaxone is excreted via both biliary and renal excretion (see CLINICAL PHARMACOLOGY). Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone for Injection are administered.Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the Ceftriaxone for Injection dosage should not exceed g daily.Alterations in prothrombin times have occurred rarely in patients treated with Ceftriaxone for Injection. Patients with impaired vitamin synthesis or low vitamin stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone for Injection treatment. Vitamin administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.Prolonged use of Ceftriaxone for Injection may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.Ceftriaxone for Injection should be prescribed with caution in individuals with history of gastrointestinal disease, especially colitis.There have been reports of sonographic abnormalities in the gallbladder of patients treated with Ceftriaxone for Injection; some of these patients also had symptoms of gallbladder disease. These abnormalities appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The chemical nature of the sonographically detected material has been determined to be predominantly ceftriaxone-calcium salt. The condition appears to be transient and reversible upon discontinuation of Ceftriaxone for Injection and institution of conservative management. Therefore, Ceftriaxone for Injection should be discontinued in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported rarely in patients treated with Ceftriaxone for Injection. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, total parenteral nutrition). cofactor role of Ceftriaxone for Injection-related biliary precipitation cannot be ruled out.As with other cephalosporins, anaphylactic shock cannot be ruled out even if thorough patient history is taken.

GERIATRIC USE SECTION.

Geriatric Use: Of the total number of subjects in clinical studies of Ceftriaxone for Injection, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.The pharmacokinetics of ceftriaxone were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to grams per day (see CLINICAL PHARMACOLOGY).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Ceftriaxone for Injection, USP is available in Pharmacy Bulk Packages containing 10 equivalent of ceftriaxone. Box of (NDC 0143-9768-01).NOTE: Ceftriaxone for Injection sterile powder should be stored at 20 25C (68 77F) [See USP Controlled Room Temperature] and protected from light.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Before instituting treatment with Ceftriaxone for Injection, appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Therapy may be instituted prior to obtaining results of susceptibility testing.To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and other antibacterial drugs, Ceftriaxone for Injection 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.Ceftriaxone for Injection is indicated for the treatment of the following infections when caused by susceptible organisms:LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).NOTE: In one study lower clinical cure rates were observed with single dose of Ceftriaxone for Injection compared to 10 days of oral therapy. In second study comparable cure rates were observed between single dose Ceftriaxone for Injection and the comparator. The potentially lower clinical cure rate of Ceftriaxone for Injection should be balanced against the potential advantages of parenteral therapy (see CLINICAL STUDIES).SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis or Peptostreptococcus species. URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone for Injection, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Ceftriaxone for Injection has also been used successfully in limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis and Escherichia coli. Efficacy for this organism in this organ system was studied in fewer than ten infections.SURGICAL PROPHYLAXIS: The preoperative administration of single g dose of Ceftriaxone for Injection may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery). Although Ceftriaxone for Injection has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery.When administered prior to surgical procedures for which it is indicated, single g dose of Ceftriaxone for Injection provides protection from most infections due to susceptible organisms throughout the course of the procedure.

INFORMATION FOR PATIENTS SECTION.

Information for Patients: Patients should be counseled that antibacterial drugs including Ceftriaxone for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., common cold). When Ceftriaxone for Injection 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 Ceftriaxone for Injection or other antibacterial drugs in the future.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.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects: In rats, in the Segment (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.

NURSING MOTHERS SECTION.

Nursing Mothers: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone for Injection is administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE. In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL . PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL.

PREGNANCY SECTION.

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at dose approximately times the human dose.There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.. Nonteratogenic Effects: In rats, in the Segment (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.

REFERENCES SECTION.

REFERENCES. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Fifth Edition. NCCLS document M7-A5 (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.National Committee for Clinical Laboratory Standards, Supplemental Tables. NCCLS document M100-S10(M7) (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087 1898, 1997.Barnett ED, Teele DW, Klein JO, et al. Comparison of Ceftriaxone and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Pediatrics. Vol. 99, No.1, January 1997.Manufactured by: GlaxoSmithKline Manufacturing S.p.A. Verona ItalyDistributed by: West-Ward Injectables Eatontown New Jersey USAIssued May 2009. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Fifth Edition. NCCLS document M7-A5 (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.. National Committee for Clinical Laboratory Standards, Supplemental Tables. NCCLS document M100-S10(M7) (ISBN 1-56238-309-9). NCCLS, Wayne, PA 19087-1898, 2000.. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Seventh Edition. NCCLS document M2-A7 (ISBN 1-56238-393-0). NCCLS, Wayne, PA 19087-1898, 2000.. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Fourth Edition. NCCLS document M11-A4 (ISBN 1-56238-210-1). NCCLS, Wayne, PA 19087 1898, 1997.. Barnett ED, Teele DW, Klein JO, et al. Comparison of Ceftriaxone and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Pediatrics. Vol. 99, No.1, January 1997.

SPL UNCLASSIFIED SECTION.

CEFTRIAXONE FOR INJECTION, USPPHARMACY BULK PACKAGENOT FOR DIRECT INFUSIONRx onlyIssued May 2009To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and other antibacterial drugs, Ceftriaxone should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects: Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at dose approximately times the human dose.There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

WARNINGS SECTION.

WARNINGS. Hypersensitivity. BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES.. Interaction with Calcium-Containing Products. Do not use diluents containing calcium, such as Ringers solution or Hartmanns solution, to reconstitute Ceftriaxone for Injection vials or to further dilute reconstituted vial for IV administration because precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Ceftriaxone for Injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for Injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via Y-site. However, in patients other than neonates, Ceftriaxone for Injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infuions with compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).. Clostridium difficile. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Ceftriaxone for Injection, 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, antiobiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.