Traxulev

White to almost white crystalline powder.
Each vial contains: Sterile Ceftriaxone Sodium Equivalent to Ceftriaxone 1 g; Sterile Sulbactam Sodium Equivalent to Sulbactam 500 mg.

Pharmacology: Pharmacodynamics: The bactericidal activity of Ceftriaxone and Sulbactam is due to the Ceftriaxone component and the ability of Ceftriaxone to interfere with the biosynthesis of the peptidoglycan component of the bacterial cell wall by binding to and inactivating penicillin-binding proteins (PBPs).
Ceftriaxone induces filamentation in Escherichia coli and Pseudomonas aeruginosa, it binds primarily to PBP 3 which is responsible for formation of cross-wall or septum of dividing bacilli.
Ceftriaxone has a high degree of stability against the beta-lactamases, both penicillinases and cephalosporinases produced by both gram -ve and gram +ve bacteria but not against chromosomally and plasmid mediated ESBL's produced by some strains of Klebsiella, Escherichia coli, Enterobacter spp and Serratia spp.
Sulbactam irreversibly blocks the destruction of beta-lactam ring of Ceftriaxone by these wide variety of ESBLs and chromosomally mediated beta-lactamases by attaching to these enzymes and acting as a suicide substrate that forms a stable intermediate, rendering the enzyme inactive.
Sulbactam is a broader-spectrum beta-lactamase inhibitor than clavulanic acid. Sulbactam does not induce chromosomal beta-lactamases like clavulanic acid, nor does it select for derepressed beta-lactamase-producing bacteria. Thus the full potential of Ceftriaxone against Klebsiella, Pseudomonas, Escherichia coli is restored by addition of Sulbactam.
Antimicrobial spectrum of Ceftriaxone-Sulbactam: The combination of Ceftriaxone sodium and Sulbactam sodium is active against all the organisms sensitive to Ceftriaxone. In addition, it demonstrates synergistic activity (reduction in minimum inhibitory concentrations, for the combination versus those of each component) in a variety of organisms.
Pharmacokinetics: Ceftriaxone and Sulbactam can be administered IM or IV.
Following intramuscular administration, peak serum concentrations of Ceftriaxone and Sulbactam are seen between 15 minutes to 2 hrs. The maximum plasma concentration of Ceftriaxone after a single IM dose of 1.0 g is about 81 mg/L and is reached 2-3 hrs after the dose while that of Sulbactam sodium is 6-24 mg/L and is reached approximately 1 hr after the dose. Hence effective amount of beta-lactamases are destroyed by the time peak concentration of Ceftriaxone is reached allowing full potential of action of Ceftriaxone against ESBL producing Klebsiella, E. coli. Serum concentrations have been shown to be proportional to the amount of dose administered. The area under curve (AUC) after IM administration is equivalent to that after IV administration of an equivalent dose, indicating 100% bioavailability of intramuscularly administered Ceftriaxone sodium. On intravenous administration Ceftriaxone sodium diffuses into the tissue fluid where if given in the recommended doses bactericidal concentrations are maintained for up to 24 hrs. Ceftriaxone is highly bound to human serum protein by about 83-90%.
Distribution: The volume of distribution of Ceftriaxone sodium is 7-12 L and that of Sulbactam is 18-27.6 L. Ceftriaxone sodium penetrates well into the extravascular spaces, tissue fluid and the synovial fluid of inflamed joints. The concentrations in most extracellular foci reach or exceed several times the MIC of most pathogens for at least 24 hours after a single administration.
Ceftriaxone sodium reaches therapeutically effective concentrations in patients with bacterial meningitis which are at least ten-fold the MICs of common pathogens such as, Enterobacteriaceae, H. influenzae, Meningococci, Pneumococci, and group B Streptococci.
Ceftriaxone crosses placenta and is distributed in the amniotic fluid. It is also distributed in the milk.
Metabolism and excretion: Ceftriaxone is not metabolised in the body and is eliminated unchanged via two pathways, urine and bile. 40-50% of parenterally administered dose is excreted into the urine within 48 hours as active drug. Thus, high concentrations are attained in urine, whatever is not excreted via kidney is excreted through bile.
Metabolism of sulbactam is less than 25%. 70-80% of Sulbactam is excreted by the kidney biliary excretion is minimal and renal excretion is blocked by probenecid. Sulbactam and Ceftriaxone can be removed by hemodialysis.
Impaired renal function and Hepatic insufficiency: Ceftriaxone is excreted via both renal and biliary pathways therefore patients with renal failure normally require no adjustments of dose however concentration of the drug should be monitored in such patients and if there is evidence of drug accumulation then dosage adjustments should be made accordingly. Dosage adjustments are not necessary in patients with hepatic dysfunction, however, in patients with both hepatic dysfunction and significant renal failure, dosage should not exceed more than 2 gm daily with close monitoring of serum concentrations.

Ceftriaxone and Sulbactam is indicated for the treatment of following infection when caused by susceptible bacteria: meningitis, for the treatment of nosocomial infections, surgical prophylaxis, urinary tract infection (complicated by underlying urological abnormalities), skin and soft tissue infections like cellulitis, erysipelas, cholecystitis, osteomyelitis, sexually transmitted disease (gonorrhoea, chancroid, syphilis), chronic suppurative bacterial otitis media and infections in dialysis unit.

Adults: The usual adult daily dose (in terms of Ceftriaxone) is 1-2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of the infection. The total daily dose should not exceed 4 grams.
Dosage regimen for (Ceftriaxone-Sulbactam) should be adjusted in patients with marked decrease in renal function (creatinine clearance of <30 mL/min) and to compensate for reduced clearance less than 15 mL/min patient should receive a maximum of 500 mg of sulbactam every 12 hours (maximum dose 1 gram of sulbactam).
Pediatric patients: For treatment of skin and soft tissue infections, the recommended total daily dose (in terms of Ceftriaxone) is 50-75 mg/kg given once a day or (in equally divided doses twice a day). The total daily dose should not exceed 1 gram.
For the treatment of acute bacterial otitis media: A single intramuscular dose of 50 mg/kg (not to exceed 1 grams) is recommended.
In the treatment of Meningitis: The initial therapeutic dose in terms of Ceftriaxone should be 100 mg/kg (not to exceed 4 grams). Daily dose may be administered once a day or in equally divided dose 12 hourly. The usual duration of therapy is 7-14 days.
For the treatment of serious infections other than meningitis: recommended total daily dose in terms of Ceftriaxone is 50-75 mg/kg given in divided doses every 12 hours.
The total daily dose (in terms of Ceftriaxone) should not exceed more than 2 grams.
Or as prescribed by a physician.

In the case of overdose nausea, vomiting, diarrhea can occur. Ceftriaxone concentration cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

Ceftriaxone Injection is contraindicated in patients with known hypersensitivity to cephalosporin antibiotics. In patients hypersensitive to penicillin, consider possibility of allergic cross-reactions.
The use of Sulbactam is contraindicated in individuals with a history of hypersensitivity reactions to any of the penicillins.

Serious or occasionally fatal anaphylactic reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of hypersensitivity reactions to multiple allergens.
Pseudomembranous colitis has been reported with the use of cephalosporins (and other broad spectrum antibiotics), therefore it is important to consider its diagnosis in patients who develop diarrhea in association with antibiotic use.

Transient elevations of BUN and serum creatinine have been observed, at recommended doses, the nephrotoxic potential of Ceftriaxone is same as other cephalosporins. Since Ceftriaxone is excreted both via renal and bile patients with renal failure normally require no adjustment in dosage when usual doses of Ceftriaxone are administered.
Dosage adjustments are not necessary in patients with hepatic dysfunction; however in patients with both renal failure and hepatic dysfunction, dosage should not exceed more than 2 g daily with close monitoring of serum concentrations.

Pregnancy: Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed. Therefore, ceftriaxone should not be used in pregnancy unless absolutely indicated.
Lactation: Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman.

The undesirable effects usually are mild and short-term.
Rarely, severe, and in some cases fatal, adverse reactions have been reported in preterm and full term newborns (aged <28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in newborns is due to their low blood volume and the longer half life of ceftriaxone compared with adults.
Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.
Gastrointestinal: Common (>1%-<10%): Loose stools or diarrhoea (diarrhoea may sometimes be a symptom of pseudomembranous colitis), nausea, vomiting, stomatitis, and glossitis.
Rare (>0.01%-<0.1%): Abdominal pain.
Infections: Superinfection caused by microorganisms non-susceptible to ceftriaxone such as yeasts, fungi (mycosis of the genital tract) or other resistant microorganisms may develop. Pseudomembranous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with ceftriaxone. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use.
Hypersensitivity: Uncommon (>0.1%-<1%): Maculopapular rash or exanthema, pruritus, urticaria, oedema, shivering and anaphylactic or anaphylactoid reactions (e.g. bronchospasm) and allergic dermatitis have occurred.
Rare (>0.01%-<0.1%): Drug fever, shivering. Anaphylactic-type reactions such as bronchospasm are rare.
Very rare (<0.01%): Isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome and Lyell's Syndrome/toxic epidermal necrolysis) have been reported.
Blood and lymphatic system disorders: Common (≥1%-≤10%): Haematological reactions have included anaemia (all grades), haemolytic anaemia, granulocytopenia, leucopenia, neutropenia, thrombocytopenia and eosinophilia. Coagulation disorders have been reported as very rare side effects.
Unknown frequency of agranulocytosis (<500/mm³) has been reported, mostly after 10 days of treatment and following total doses of 20 g or more.
There have been rare reports of fatal haemolysis in association with ceftriaxone. It has rarely been associated with prolongation of prothrombin time, however, bleeding and bruising due to hypoprothrombinaemia may be more prevalent in patients with renal or hepatic impairment, malnourished patients or those with low vitamin K levels and patients receiving prolonged ceftriaxone therapy.
Central Nervous System: Rare (≥0.01%-<0.1%): Headache, vertigo and dizziness.
Administration of high doses of cephalosporins, particularly in patients with renal insufficiency, may result in convulsions.
Renal and Urinary: Rare (≥0.01%-<0.1%): Glycosuria, oliguria, haematuria, increase in serum creatinine.
Very rare (<0.01%): Cases of renal precipitation have been reported, mostly in children older than 3 years and who have been treated with either high daily doses (e.g. ≥80 mg/kg/day) or total doses exceeding 10 grams and presenting other risk factors (e.g. fluid restrictions, confinement to bed, etc.) The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of ceftriaxone.
Acute renal tubular necrosis may occur rarely with ceftriaxone.
Hepatobiliary system: Rare (≥0.01%-<0.1%): Hepatitis and/or cholestatic jaundice, increase in liver enzymes. Transient elevations in liver function tests have been reported in a few cases.
Shadows which have been mistaken for gallstones, but which are precipitates of calcium ceftriaxone, have been detected by sonograms. These abnormalities are commonly observed after an adult daily dose of two grams per day or more, or its equivalent in children; these abnormalities were particularly observed in children with an incidence of above 30% in isolated reports. At doses of two grams a day or above these biliary precipitates may occasionally cause symptoms. Should patients develop symptoms, non-surgical management is recommended and discontinuation of ceftriaxone should be considered. The evidence suggests biliary precipitates usually disappear once ceftriaxone has been stopped. The risk of biliary precipitates may be increased by treatment duration greater than 14 days, renal failure, dehydration or total parenteral nutrition.
Pancreas: Very rare (<0.01%): There have been isolated reports of pancreatitis although a causal relationship to ceftriaxone has not been established.
Local effects: Rare (≥0.01%-<0.1%): Pain or discomfort may be experienced at the site of intramuscular injection immediately after administration but is usually well tolerated and transient. Intramuscular injection without lidocaine solution is painful. Local phlebitis has occurred rarely following intravenous administration but can be minimised by slow injection over at least 2-4 minutes.
Influence on diagnostic tests: In patients treated with ceftriaxone the Coombs' test rarely may become false-positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosemia.
Likewise, 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.

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.
The elimination of Ceftriaxone is not altered by probenecid.
Aminoglycoside antibiotics and diuretics: No impairment of renal function has so far been observed after concurrent administration of large doses of Ceftriaxone and potent diuretics (e.g. furosemide). There is no evidence that Ceftriaxone increases renal toxicity of aminoglycosides.
Alcohol: No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Ceftriaxone. It does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins.
Antibiotics: In an in-vitro study, antagonistic effects have been observed with the combination of chloramphenicol and Ceftriaxone.
Anticoagulants: As ceftriaxone has an N-methylthiotriazine side-chain, it might have the potential to cause hypoprothrombinaemia resulting in an increased risk of bleeding in patients treated with anticoagulants.
Oral Contraceptives: Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment. Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.
Interference with Laboratory Tests: In patients treated with ceftriaxone, the Coombs' test may in rare cases be false-positive.
Ceftriaxone, like other antibiotics may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods such as copper reduction methods (Benedict's, Fehling's or Clinitest) for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be carried out enzymatically.

Direction for Reconstitution: For I.M. use: Use 5 mL of Sterile Water For Injection.
For I.V. use: Use 10 mL of Sterile Water For Injection.
Use freshly prepared solution. Discard the unused solution.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DD63 - ceftriaxone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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