CETRIAXONE HUP

Ceftriaxone is a broad-spectrum third-generation cephalosporin antibiotic.

It has a very long half-life compared to other cephalosporins and is high penetrable into the meninges 1, eyes 9, and inner ear 6.

Ceftriaxone has broader and stronger gram-negative coverage then first or second-generation cephalosporins, but worse activity against methicillin-susceptible S.aureus.

Ceftriaxone is a commonly used antimicrobial due to its good activity against multi-drug resistant Enterobacteriaceae, its relatively safe adverse effect profile, and its long half-life which allows for the convenience of daily or twice-daily dosing.

Ceftriaxone is used for the treatment of the infections (respiratory, skin, soft tissue, UTI, ENT) caused by susceptible organisms.

Organisms that are generally susceptible to ceftriaxone include S. pneumoniae, S. pyogenes (group A beta-hemolytic streptococci), coagulase-negative staphylococci, Some Enterobacter spp, H. influenzae, N. gonorrhoeae, P. mirabilis, E. coli, Klebsiella spp, M. catarrhalis, B. burgdorferi, and some oral anaerobes.

Ceftriaxone is a cephalosporin/cephamycin beta-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually gram-positive, organisms.

Ceftriaxone has in vitro activity against gram-positive aerobic, gram-negative aerobic, and anaerobic bacteria.

The bactericidal activity of ceftriaxone results from the inhibition of cell wall synthesis and is mediated through ceftriaxone binding to penicillin-binding proteins (PBPs).

Ceftriaxone is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended-spectrum beta-lactamases.

However, resistance to ceftriaxone usually occurs through beta-lactamase hydrolysis, altered PBPs, or reduced bacterial cell permeability.

Ceftriaxone should not be mixed with or giving in the same Intravenous line as diluents/products containing calcium as they may cause ceftriaxone to precipitate.

Ceftriaxone use may also cause biliary sludge or gallbladder pseudolithiasis. 11, 2.

Penicillin-binding protein 2B (Streptococcus pneumoniae (strain ATCC BAA-255 / R6)) Inhibitor.

Ceftriaxone is only given as an injection, either Intramuscular or Intravenous.

Ceftriaxone is less than 1% bioavailable if given Oral.

The apparent volume of distribution of an intravenous or intramuscular dose in healthy patients is 5.78-13.5 L.

The volume of distribution of an intravenous or intramuscular dose in septic patients is 6.48-35.2 L.

Ceftriaxone has good enough

CSF penetration to be used as an effective treatment of bacterial meningitis.

of ceftriaxone is negligible.

Ceftriaxone is primarily eliminated in the urine (33-67%).

The remainder is eliminated through secretion in the bile and removed from the body via the feces.

The elimination half-life of ceftriaxone is 5.8-8.7 hours.

The half-life of ceftriaxone in the middle ear fluid has been estimated to be 25 hours. 11, 6.

The plasma clearance of ceftriaxone in healthy adults receiving a 0.15-3 g dose is 0.58-1.45 L/hour.

The renal clearance of ceftriaxone is 0.32-0.73 L/hour.

In intensive care unit patients, ceftriaxone's total drug clearance was 0.96 L/h (0.55-1.28 L/h), and unbound drug clearance was 1.91 L/h (1.46-6.20 L/h).

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Ceftriaxone overdose may increase the risk of urolithiasis and subsequent post-renal acute renal failure (PARF).

Other symptoms of overdose unavailable in the literature.

However, they are likely similar to the adverse effects of the medication.

If overdose of ceftriaxone occurs, treat with symptomatic and supportive treatment, as ceftriaxone levels will not be reduced by dialysis.

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 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.e., 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 studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium.

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.

Some cases occurred in patients with severe renal impairment who did not receive appropriate dosage adjustment.

However, in other cases, neurological adverse reactions occurred in patients receiving an appropriate dosage adjustment.

The neurological adverse reactions were reversible and resolved after discontinuation.

If neurological adverse reactions associated with ceftriaxone for injection therapy occur, discontinue ceftriaxone for injection and institute appropriate supportive measures.

Make appropriate dosage adjustments in patients with severe renal impairment See DOSAGE AND ADMINISTRATION.

Clostridium difficile -Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of

C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since

CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Ceftriaxone for injection 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 – Hypersensitivity Reactions.

Neonates Premature neonates

Ceftriaxone for injection is contraindicated in premature neonates up to a post-menstrual age of 41 weeks (gestational age + chronological age).

Hyperbilirubinemic neonates

Hyperbilirubinemic neonates should not be treated with ceftriaxone for injection.

Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.

Neonates Requiring Calcium Containing IV Solutions

Ceftriaxone for injection 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.

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 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 a precipitate was observed in the intravenous infusion line.

There have been no similar reports in patients other than neonates.

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.

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 for injection.

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 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.

For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 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 to 14 days.

The usual adult daily dose is 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 is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

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 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.

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.

Directions for Use Intramuscular Administration

Reconstitute ceftriaxone sodium powder with the appropriate diluent See DOSAGE AND ADMINISTRATION: 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.

A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

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 250 mg 0.9 mL – 500 mg 1.8 mL 1 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 DOSAGE AND ADMINISTRATION: Compatibility and Stability.

Vial Dosage Size Amount of Diluent to be Added 250 mg 2.4 mL 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.

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection vials or to further dilute a reconstituted vial for IV administration.

Particulate formation can result.

Ceftriaxone has been shown to be compatible with Flagyl® 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 compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents.

Metronidazole at concentrations greater than 8 mg/mL will precipitate.

Do not refrigerate the admixture as precipitation will occur.

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 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 sodium sterile powder should be stored at 20° to 25°C (68° to 77°F) 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 intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods: Diluent Concentration Storage mg/mL Room Temperature (25°C) Refrigerated (4°C) Sterile Water for Injection 100 250, 350 2 days 24 hours 10 days 3 days 0.9% Sodium Chloride Solution 100 250, 350 2 days 24 hours 10 days 3 days 5% Dextrose Solution 100 250, 350 2 days 24 hours 10 days 3 days Bacteriostatic Water + 0.9% Benzyl Alcohol 100 250, 350 24 hours 24 hours 10 days 3 days 1% Lidocaine Solution (without epinephrine) 100 250, 350 24 hours 24 hours 10 days 3 days Ceftriaxone intravenous solutions, at concentrations of and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers: Diluent Storage Room Temperature (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 2 days Incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible * Data available for to 40 mg/mL concentrations in this diluent in PVC containers only.

The following intravenous ceftriaxone 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.

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 for injection should be thawed at room temperature before use.

After thawing, unused portions should be discarded.

Ceftriaxone for injection, USP is supplied as a sterile crystalline powder in glass vials as follows: NDC Vials containing 250 mg equivalent to ceftriaxone.

Package of 10 0409-7337-01 Vials containing 500 mg equivalent to ceftriaxone.

Package of 10 0409-7338-01 Vials containing 1 g equivalent to ceftriaxone.

Package of 10 0409-7332-01 Vials containing 2 g equivalent to ceftriaxone.

Package of 10 0409-7335-03 Storage Prior to Reconstitution Store at 20° to 25°C (68° to 77°F) .

Protect from light.

Store at 20° to 25°C (68° to 77°F) .

Protect from light.

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 a dose approximately 3 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.

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.

Low concentrations of ceftriaxone are excreted in human milk.

Caution should be exercised when ceftriaxone is administered to a nursing woman.

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 studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Ceftriaxone should not be administered to hyperbilirubinemic neonates, especially prematures See CONTRAINDICATIONS.

Of the total number of subjects in clinical studies of ceftriaxone, 32% were 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.