CEFTRIAXONE- ceftriaxone_injection, powder, for solution

CLINICAL PHARMACOLOGY
Average plasma concentrations of ceftriaxone following a single 30-minute intravenous (IV) infusion of a 0. 5, 1 or 2 g dose and intramuscular (IM) administration of a single 0. 5 (250 mg/mL or 350 mg/mL concentrations) or 1 g 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 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 16 hr 24 hr 0. 5 g IV IV doses were infused at a constant rate over 30 minutes. 82 59 48 37 29 23 15 10 5 0. 5 g IM 250 mg/mL 22 33 38 35 30 26 16 ND 5 0. 5 g IM 350 mg/mL 20 32 38 34 31 24 16 ND 5 1 g IV 151 111 88 67 53 43 28 18 9 1 g IM 40 68 76 68 56 44 29 ND ND 2 g IV 257 192 154 117 89 74 46 31 15 ND = Not determined. Ceftriaxone was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV or IM doses ranging from 0. 5 to 2 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 to 2 hr 2 to 4 hr 4 to 8 hr 8 to 12 hr 12 to 24 hr 24 to 48 hr 0. 5 g IV 526 366 142 87 70 15 0. 5 g IM 115 425 308 127 96 28 1 g IV 995 855 293 147 132 32 1 g IM 504 628 418 237 ND ND 2 g IV 2692 1976 757 274 198 40 ND = Not determined. Thirty-three percent to 67% of a 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 a 1 g IV dose, average concentrations of ceftriaxone, determined from 1 to 3 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. 15 to 3 g dose range in healthy adult subjects, the values of elimination half-life ranged from 5. 7 hours; apparent volume of distribution from 5. 5 L; plasma clearance from 0. 45 L/hour; and renal clearance from 0. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of < 25 mcg/mL to a 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 a 50 mg/kg IV dose and after a 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 a 50 mg/kg IV dose and after a 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. 3 Plasma Clearance (mL/hr/kg) 49 60 Volume of Distribution (mL/kg) 338 373 CSF Concentrationem dashinflamed meninges (mcg/mL) 5. 4 Range (mcg/mL) 1. 3 to 44 Time after dose (hr) 3. 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 2 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. 5 Elderly Subjects (mean age, 70. 7 Patients With Renal Impairment Hemodialysis Patients (0 to 5 mL/min) Creatinine clearance. 7 Severe (5 to 15 mL/min) 15. 5 Moderate (16 to 30 mL/min) 11. 8 Mild (31 to 60 mL/min) 12. 3 Patients With Liver Disease 8. 6 The elimination of ceftriaxone is not altered when ceftriaxone is co-administered with probenecid. 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 1 to 50 hours after a single intramuscular injection of 50 mg/kg of ceftriaxone. Mean (+/- SD) ceftriaxone levels in the middle ear reached a 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, a 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. Two in vitro in vivo Mechanism of Action Ceftriaxone is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria. Mechanism of Resistance Resistance to ceftriaxone is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability. Interaction with Other Antimicrobials In an in vitro Antibacterial Activity Ceftriaxone has been shown to be active against most isolates of the following bacteria, both in vitro INDICATIONS AND USAGE Gram-negative bacteria Acinetobacter calcoaceticus Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Neisseria meningitidis Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens Gram-positive bacteria Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Viridans group streptococci Anaerobic bacteria Bacteroides fragilis Clostridium species Peptostreptococcus species The following in vitro but their clinical significance is unknown in vitro has not been Gram-negative bacteria Citrobacter diversus Citrobacter freundii Providencia Providencia rettgeri Salmonella Salmonella typhi Shigella Gram-positive bacteria Streptococcus agalactiae Anaerobic bacteria Porphyromonas (Bacteroides) melaninogenicus Prevotella (Bacteroides) bivius Susceptibility Testing 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.
ANIMAL PHARMACOLOGY
Concretions consisting of the precipitated calcium salt of ceftriaxone have been found in the gallbladder bile of dogs and baboons treated with ceftriaxone. These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since ceftriaxone has a greater plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.

Before instituting treatment with Ceftriaxone for Injection, USP, 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, USP and other antibacterial drugs, Ceftriaxone for Injection, USP 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, USP is indicated for the treatment of the following infections when caused by susceptible organisms: LOWER RESPIRATORY TRACT INFECTIONS Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis Serratia marcescens. ACUTE BACTERIAL OTITIS MEDIA Streptococcus pneumoniae, Haemophilus influenzae Moraxella catarrhalis NOTE: In one study lower clinical cure rates were observed with a single dose of Ceftriaxone for Injection, USP compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose Ceftriaxone for Injection, USP and the comparator. The potentially lower clinical cure rate of Ceftriaxone for Injection, USP should be balanced against the potential advantages of parenteral therapy (see CLINICAL STUDIES). SKIN AND SKIN STRUCTURE INFECTIONS Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis Peptostreptococcus URINARY TRACT INFECTIONS (complicated and uncomplicated) Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii Klebsiella pneumoniae. UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) Neisseria gonorrhoeae, Neisseria gonorrhoeae. PELVIC INFLAMMATORY DISEASE Neisseria gonorrhoeae. Chlamydia trachomatis Chlamydia trachomatis BACTERIAL SEPTICEMIA Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae Klebsiella pneumoniae. BONE AND JOINT INFECTIONS Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae Enterobacter INTRA-ABDOMINAL INFECTIONS Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium Clostridium difficile Peptostreptococcus MENINGITIS Haemophilus influenzae, Neisseria meningitidis Streptococcus pneumoniae. Staphylococcus epidermidis Escherichia coli. *Efficacy for this organism in this organ system was studied in fewer than ten infections. SURGICAL PROPHYLAXIS: , , When administered prior to surgical procedures for which it is indicated, a single 1 g dose of Ceftriaxone for Injection, USP provides protection from most infections due to susceptible organisms throughout the course of the procedure.

DOSAGE AND ADMINISTRATION
Ceftriaxone may be administered intravenously or intramuscularly. Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a 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). Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone. Ceftriaxone is contraindicated in premature neonates (see CONTRAINDICATIONS). Ceftriaxone is contraindicated in neonates (<= 28 days) 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). Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy. For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams. For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 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. In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days. The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams. If Chlamydia trachomatis For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended. For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended. Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. When treating infections caused by Streptococcus pyogenes No dosage adjustment is necessary for patients with impairment of renal or hepatic function (see PRECAUTIONS). The dosages recommended for adults require no modification in elderly patients, up to 2 g per day, provided there is no severe renal and hepatic impairment (see PRECAUTIONS Intramuscular Administration Reconstitute ceftriaxone powder with the appropriate diluent (see COMPATIBILITY AND STABILITY). Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose. After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below. If required, more dilute solutions could be utilized. As with all intramuscular preparations, ceftriaxone should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel. Vial Dosage Size Amount of Diluent to be Added 250 mg/mL 350 mg/mL 500 mg 1. 2 mL Intravenous Administration Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY). Vial Dosage Size Amount of Diluent to be Added 500 mg 4. 6 mL 2 g 19. 2 mL After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent. Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result. Ceftriaxone has been shown to be compatible with Flagyl registered registered registered Vancomycin, amsacrine, aminoglycosides, and fluconazole are 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. Ceftriaxone solutions should not Ceftriaxone for Injection sterile powder should be stored at 20° to 25°C (68° to 77°F) [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 intramuscular Storage Diluent Concentration mg/mL Room Temp. (25°C) Refrigerated (4°C) Sterile Water for Injection 100 2 days 10 days 250, 350 24 hours 3 days 0. 9% Sodium Chloride 100 2 days 10 days Solution 250, 350 24 hours 3 days 5% Dextrose Solution 100 2 days 10 days 250, 350 24 hours 3 days Bacteriostatic Water + 0. 9% 100 24 hours 10 days Benzyl Alcohol 250, 350 24 hours 3 days 1% Lidocaine Solution 100 24 hours 10 days (without epinephrine) 250, 350 24 hours 3 days Ceftriaxone for injection intravenous Storage Diluent Room Temp. (25°C) Refrigerated (4°C) Sterile Water 2 days 10 days 0. 9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0. 9% Sodium Chloride Solution Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only. 2 days Incompatible 5% Dextrose + 0. 45% Sodium Chloride Solution 2 days Incompatible The following intravenous 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 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 (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks. Frozen solutions of ceftriaxone should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.
Adults
The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams. If Chlamydia trachomatis For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended. For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended. Generally, ceftriaxone therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. When treating infections caused by Streptococcus pyogenes No dosage adjustment is necessary for patients with impairment of renal or hepatic function (see PRECAUTIONS). The dosages recommended for adults require no modification in elderly patients, up to 2 g per day, provided there is no severe renal and hepatic impairment (see PRECAUTIONS
Directions for Use
Intramuscular Administration Reconstitute ceftriaxone powder with the appropriate diluent (see COMPATIBILITY AND STABILITY). Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose. After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below. If required, more dilute solutions could be utilized. As with all intramuscular preparations, ceftriaxone should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel. Vial Dosage Size Amount of Diluent to be Added 250 mg/mL 350 mg/mL 500 mg 1.8 mL 1.0 mL 1 g 3.6 mL 2.1 mL 2 g 7.2 mL 4.2 mL Intravenous Administration Ceftriaxone should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY). Vial Dosage Size Amount of Diluent to be Added 500 mg 4.8 mL 1 g 9.6 mL 2 g 19.2 mL After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.

Hemolytic Anemia
An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.
ADVERSE REACTIONS
Ceftriaxone is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone therapy or of uncertain etiology, were observed: LOCAL REACTIONS GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS HYPERSENSITIVITY - INFECTIONS AND INFESTATIONS HEMATOLOGIC BLOOD AND LYMPHATIC DISORDERS GASTROINTESTINAL HEPATIC RENAL CENTRAL NERVOUS SYSTEM GENITOURINARY MISCELLANEOUS INVESTIGATIONS 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, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness. 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. Data are generally insufficient to allow an estimate of incidence or to establish causation. A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone 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 GENITOURINARY DERMATOLOGIC en dash HEMATOLOGICAL CHANGES: Isolated cases of agranulocytosis (< 500/mm 3 NEUROLOGIC: Encephalopathy, seizures, myoclonus, and non-convulsive status epilepticus (see WARNINGS AND PRECAUTIONS OTHER, Adverse Reactions: symptomatic precipitation of ceftriaxone calcium salt in the gallbladder, kernicterus, oliguria, and anaphylactic or anaphylactoid 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: Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection. Positive direct Coombs’ test, false-positive test for urinary glucose, and elevated LDH (see PRECAUTIONS). 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. To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www. gov/medwatch.
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. Data are generally insufficient to allow an estimate of incidence or to establish causation. A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone 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 GENITOURINARY DERMATOLOGIC en dash HEMATOLOGICAL CHANGES: Isolated cases of agranulocytosis (< 500/mm 3 NEUROLOGIC: Encephalopathy, seizures, myoclonus, and non-convulsive status epilepticus (see WARNINGS AND PRECAUTIONS OTHER, Adverse Reactions: symptomatic precipitation of ceftriaxone calcium salt in the gallbladder, kernicterus, oliguria, and anaphylactic or anaphylactoid reactions.
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: Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection. Positive direct Coombs’ test, false-positive test for urinary glucose, and elevated LDH (see PRECAUTIONS). 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. To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

Hypersensitivity Ceftriaxone is contraindicated in patients with known hypersensitivity to ceftriaxone, any of its excipients or to any other cephalosporin. Patients with previous hypersensitivity reactions to penicillin and other beta lactam antibacterial agents may be at greater risk of hypersensitivity to ceftriaxone (see WARNINGS en dash Hypersensitivity). Neonates Premature neonates Hyperbilirubinemic neonates Neonates Requiring Calcium Containing IV Solutions Ceftriaxone is contraindicated in neonates (<= 28 days) 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 Cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. There have been no similar reports in patients other than neonates. Lidocaine Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated. When lidocaine solution is used as a solvent with ceftriaxone for intramuscular injection, exclude all contraindications to lidocaine. Refer to the prescribing information of lidocaine.

Pregnancy
Pregnancy Category B: 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. In rats, in the Segment I (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 is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of ceftriaxone in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro
Geriatric Use
Of the total number of subjects in clinical studies of ceftriaxone, 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 2 grams per day provided there is no severe renal and hepatic impairment (see CLINICAL PHARMACOLOGY). Influence on Diagnostic Tests : Nonenzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically. The presence of ceftriaxone may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.
Neonates
Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone. Ceftriaxone is contraindicated in premature neonates (see CONTRAINDICATIONS). Ceftriaxone is contraindicated in neonates (<= 28 days) 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). Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy.
Pediatric Patients
For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams. For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 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 2 grams. In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

Interaction with Calcium-Containing Products
Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro
Compatibility and Stability
Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result. Ceftriaxone has been shown to be compatible with Flagyl registered registered registered Vancomycin, amsacrine, aminoglycosides, and fluconazole are 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. Ceftriaxone solutions should not Ceftriaxone for Injection sterile powder should be stored at 20° to 25°C (68° to 77°F) [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 intramuscular Storage Diluent Concentration mg/mL Room Temp. (25°C) Refrigerated (4°C) Sterile Water for Injection 100 2 days 10 days 250, 350 24 hours 3 days 0.9% Sodium Chloride 100 2 days 10 days Solution 250, 350 24 hours 3 days 5% Dextrose Solution 100 2 days 10 days 250, 350 24 hours 3 days Bacteriostatic Water + 0.9% 100 24 hours 10 days Benzyl Alcohol 250, 350 24 hours 3 days 1% Lidocaine Solution 100 24 hours 10 days (without epinephrine) 250, 350 24 hours 3 days Ceftriaxone for injection intravenous Storage Diluent Room Temp. (25°C) Refrigerated (4°C) Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only. 2 days Incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible The following intravenous 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 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 (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks. Frozen solutions of ceftriaxone should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

WARNINGS
Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients. Antibacterial drugs 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. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i. , anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro Serious neurological adverse reactions have been reported during postmarketing surveillance with ceftriaxone use. These reactions include encephalopathy (disturbance of consciousness including somnolence, lethargy, and confusion), seizures, myoclonus, and non-convulsive status epilepticus (see ADVERSE REACTIONS). DOSAGE AND ADMINISTRATION Clostridium difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.
Carcinogenesis,Mutagenesis, Impairment of Fertility
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 6 months. Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro 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 2 g/day.
OVERDOSAGE
Ceftriaxone overdosage has been reported in patients with severe renal impairment. Reactions have included neurological outcomes, including encephalopathy, seizures, myoclonus, and non-convulsive status epilepticus. In the event of overdosage, discontinue Ceftriaxone for Injection therapy and provide general supportive treatment (see DOSAGE AND ADMINISTRATION WARNINGS AND PRECAUTIONS 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.
CLINICAL STUDIES
In two adequate and well-controlled U.S. clinical trials a single IM dose of ceftriaxone was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below: Table 5 Clinical Efficacy in Pediatric Patients with Acute Bacterial Otitis Media Clinical Efficacy in Evaluable Population Study Day Ceftriaxone Single Dose Comparator en dash 10 Days of Oral Therapy 95% Confidence Interval Statistical Outcome Study 1 en dash U.S. amoxicillin/clavulanate 14 74% (220/296) 82% (247/302) (-14.4%, -0.5%) Ceftriaxone is lower than control at study day 14 and 28. 28 58% (167/288) 67% (200/297) (-17.5%, -1.2%) Study 2 en dash U.S. 1 TMP-SMZ 14 54% (113/210) 60% (124/206) (-16.4%, 3.6%) Ceftriaxone is equivalent to control at study day 14 and 28. 28 35% (73/206) 45% (93/205) (-19.9%, 0.0%) An open-label bacteriologic study of ceftriaxone without a 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 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen: Table 6 Bacteriologic Eradication Rates 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 9 (60)
REFERENCES
1. Barnett ED, Teele DW, Klein JO, et al. Comparison of Ceftriaxone and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Manufactured for: WG Critical Care, LLC Paramus, NJ 07652 Made in Italy Revised: November 2021

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