PRODUCT DETAILS
Ceftriaxone USP

The bactericidal activity of ceftriaxone results from inhibition of bacterial cell wall synthesis. Ceftriaxone exerts in-vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ceftriaxone is highly stable to most b-lactamases, both penicillinases and cephalosporinases, of gram-positive and gram-negative bacteria. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see Indications and usage.):
Gram-positive aerobes :
- Staphylococcus aureus (methicillin - sensitive)
- Staphylococci coagulase-negative
- Streptococcus pneumoniae
- Streptococcus group A (Str. pyogenes)
- Streptococcus group B (Str. agalactiae)
- Streptococcus viridans
- Streptococcus bovis

Note: Methicillin-resistant Staphylococcus spp. is resistant to cephalosporins, including ceftriaxone. Most strains of Enterococci (e.g. Enterococcus faecalis) are resistant.

Gram-negative aerobes : 
- Acinetobacter spp.
- Aeromonas spp.
- Alcaligenes spp.
- Branhamella catarrhalis (b-lactamase negative and positive)
- Citrobacter spp.
- Enterobacter spp. (some strains are resistant)
- Escherichia coli
- Haemophilus ducreyi
- Haemophilus influenzae (including penicillinase-producing strains)
- Haemophilus parainfluenzae
- Klebsiella spp. (including Kl. pneumoniae)
- Moraxella spp.
- Morganella morganii
- Neisseria gonorrhoeae (including penicillinase-producing strains)
- Neisseria meningitidis
- Plesiomonas shigelloides
- Proteus mirabilis
- Proteus vulgaris
- Providentia spp.
- Pseudomonas aeruginosa (some strains are resistant)
- Salmonella spp. (including S. typhi)
- Serratia spp. (including S. marcescens)
- Shigella spp.
- Vibrio spp. (including V. cholerae)
- Yersinia spp. (including Y. enterocolitica)

* Some isolates of some species are resistant to ceftriaxone, mainly due to the production of the chromosomally encoded b-lactamase.
** Some isolates of some species are resistant due to production of extended spectrum, plasmid-mediated b-lactamase.
Note: Many strains of the above microorganisms that are multiple resistant to other antibiotics, e.g. amino-penicillins and ureido-penicillins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone.

Treponema pallidum is sensitive in vitro and in animal experiments. Clinical investigations indicate that primary and secondary syphilis respond well to ceftriaxone therapy. With a few exceptions clinical P. aeruginosa isolates are resistant to ceftriaxone.

Anaerobic organisms
Bacteroides spp. (including some strains of B. fragilis)
Clostridium spp. (except Cl. difficile)
Fusobacterium spp. (except F. mortiferum and F. varium)
Peptococcus spp.
Peptostreptococcus spp.

* Some isolates of some species are resistant to ceftriaxone, due to b-lactamase-production.
Note: Many strains of b-lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant.

Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardized techniques for susceptibility testing such as those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The NCCLS issued the following interpretative breakpoints for ceftriaxone:

SusceptibleModerately susceptibleResistan
Dilution test inhibitory concentrations in mg/l= 816-32= 64;
Diffusion test (disk with 30 mg ceftriaxone),inhibition zone diameter in mm= 2120-14= 13

Microorganisms should be tested with the ceftriaxone disk since it has been shown by in-vitro tests to be active against certain strains resistant to cephalosporin class disks.
Where NCCLS recommendations are not in daily use, alternative, well standardized susceptibility-interpretative guidelines such as those issued by DIN, ICS and others may be substituted.

Pharmacokinetics : The pharmacokinetics of ceftriaxone are nonlinear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations.

Absorption : The maximum plasma concentration after a single i.m. dose of 1g is about 81 mg/l and is reached in 2-3 hours after administration. The area under the plasma concentration-time curve after i.m. administration is equivalent to that after i.v. administration of an equivalent dose, indicating 100% bioavailability of intramuscularly administered ceftriaxone.

Distribution : The volume of distribution of ceftriaxone is 7-12 l. Ceftriaxone has shown excellent tissue and body fluid penetration after a dose of 1-2 g; concentrations well above the minimal inhibitory concentrations of most pathogens responsible for infection are detectable for more than 24 hours in over 60 tissues or body fluids including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone as well as cerebrospinal, pleural, prostatic and synovial fluids.
On intravenous administration, ceftriaxone diffuses rapidly into the interstitial fluid, where bactericidal concentrations against susceptible organisms are maintained for 24 hours (see figure).

Protein binding :  Ceftriaxone is reversibly bound to albumin, and the binding decreases with the increase in concentration, e.g. from 95% binding at plasma concentrations of <100 mg/1 to 85% binding at 300 mg/1. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Penetration into particular tissues: Ceftriaxone penetrates the inflamed meninges of neonates, infants and children: Ceftriaxone concentrations exceed 1.4 mg/l in the Cerebrospinal Fluid (CSF) 24 hours after i.v. injection of Rofecin® in doses of 50-100 mg/kg (neonates and infants respectively). Peak concentration in CSF is reached about 4 hours after i.v. injection and gives an average value of 18 mg/l. Mean CSF levels are 17% of plasma concentrations in patients with bacterial meningitis and 4% in patients with aseptic meningitis.
In adult meningitis patients, administration of 50 mg/kg leads within 2-24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations required for the most common meningitis pathogens. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations.

Metabolism: Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora.

Elimination: Total plasma clearance is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged in the urine, while 40-50% is excreted unchanged in the bile. The elimination half-life in adults is about 8 hours.

Pharmacokinetics in special clinical situations : In neonates, urinary recovery accounts for about 70% of the dose. In infants aged less than 8 days and in elderly persons aged over 75 years the average elimination half-life is usually two to three times that in young adults.
In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

Presentation:

Active ingredient:  Ceftriaxone in the form of the disodium salt. Vials containing dry substance equivalent to 0.25 g, 0.5 g, 1 g and 2 g ceftriaxone.

Solvent for parenteral use:  The solvent ampoule for i.m. injection contains 1% lidocaine hydrochloride solution, and for i.v. injection sterile water for injections.

1 ml solvent for i.m. injection contains 10.66 mg lidocaine hydrochloride monohydrate equivalent to 10 mg anhydrous lidocaine hydrochloride.

Rofecin® contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone.

  Dosage and Administration

Standard dosage Adults and children over 12 years: The usual dosage is 1-2 g of Rofecin® once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, once daily. Neonates, infants and children up to 12 years: The following dosage schedules are recommended for once daily administration: Neonates (up to 14 days): A daily dose of 20-50 mg/kg bodyweight, not to exceed 50 mg/kg, on account of the immaturity of the infant’s enzyme systems. It is not necessary to differentiate between premature and term infants. Infants and children (15 days to 12 years): A daily dose of 20-80 mg/kg. For children with bodyweights of 50 kg or more, the usual adult dosage should be used. Intravenous doses of ≥50 mg/kg body weight should be given by infusion over at least 30 minutes. Elderly patients: The dosages recommended for adults require no modification in the case of geriatric patients. Duration of therapy : The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Rofecin® should be continued for a minimum of 48-72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained. Combination therapy : Synergy between Rofecin® and aminoglycosides has been demonstrated with many gram-negative bacteria under experimental conditions. Although enhanced activity of such combinations is not always predictable, it should be considered in severe, life threatening infections due to microorganisms such as Pseudomonas aeruginosa. Because of physical incompatibility the two drugs must be administered separately at the recommended dosages. Special dosage instructions Meningitis: In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly. The best results have been found with the following duration of therapy:

Neisseria meningitidis 4 days
Haemophilus influenzae 6 days
Streptococcus pneumoniae 7 days
Lyme borreliosis: 50 mg/kg up to a maximum of 2 g in children and adults, once daily for 14 days. Gonorrhoea(penicillinase-producing and nonpenicillinase-producing strains): For the treatment, a single i.m. dose of 250 mg Rofecin® is recommended. Perioperative prophylaxis: A single dose of 1-2 g depending on the risk of infection of 30-90 minutes prior to surgery. In colorectal surgery, administration of Rofecin® with or without a 5-nitroimidazole, e.g. ornidazole (separate administration, see Method of administration) has been proven effective. Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage of Rofecin® provided hepatic function is intact. Only in cases of preterminal renal failure (creatinine clearance <10 ml/min) should the Rofecin® dosage not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact. In patients with both severe renal and hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals and if necessary the dose should be adjusted. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Plasma concentrations should , however, be monitored, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be altered. Method of administration : As a general rule the solutions should be used immediately after preparation. Reconstituted solutions retain their physical and chemical stability for six hours at room temperature (or 24 hours at 2°-8°C). The solutions range in colour from pale yellow to amber, depending on the concentration and the length of storage. The colouration of the solutions is of no significance for the efficacy or tolerance of the drug. Intramuscular injection: For i.m. injection, Rofecin® 0.25 g or 0.5 g is dissolved in 2 ml, and Rofecin® 1 g in 3.5 ml, of 1% lidocaine hydrochloride solution and administered by deep intragluteal injection. It is recommended that not more than 1 g be injected at one site. The lidocaine solution must never be administered intravenously. Intravenous injection: For i.v. injection, Rofecin® 0.25 g or 0.5 g is dissolved in 5 ml, and Rofecin® 1 g in 10 ml sterile water for injections, and then administered by i.v. injection lasting two to four minutes. Intravenous infusion: The infusion should last at least 30 minutes. For i.v. infusion, 2 g Rofecin® is dissolved in 40 ml of one of the following calcium-free infusion solutions: sodium chloride 0.9%, sodium chloride 0.45% + dextrose 2.5%, dextrose 5%, dextrose 10%, hydroxy ethyl starch 6-10%, levulose 5%, dextran 6% in dextrose 5%, sterile water for injections. Rofecin® solutions should not be mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, owing to possible incompatibility.

  Side Effects

Gastrointestinal complaints (about 2% of cases) :  loose stools or diarrhea, nausea, vomiting, stomatitis and glossitis.
Hematological changes (about 2%):  eosinophilia, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia.
Skin reactions (about 1%):  exanthema, allergic dermatitis, pruritus, urticaria, edema, erythema multiforme.
Other, rare side effects:  headache and dizziness, increase in liver enzymes, gallbladder sludge, oliguria, increase in serum creatinine, mycosis of the genital tract, shivering and anaphylactic or anaphylactoid reactions.
Pseudomembranous enterocolitis and coagulation disorders have been reported as very rare side effects.
Local side effects In rare cases, phlebitic reactions occurred after i.v. administration. These may be minimized by slow (two to four minutes) injection.
Intramuscular injection without lidocaine solution is painful.
ceftriaxone is generally well tolerated. During the use of Rofecin®, the following side effects, which were reversible either spontaneously or after withdrawal of the drug, have been observed:

  Contraindications

Ceftriaxone is contraindicated in patients with known hypersensitivity to the cephalosporin class of antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind.

Hyperbilirubinaemic newborns and preterm newborns should not be treated with ceftriaxone. 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.

Rofecin® should not be administered concurrently with calcium treatment in newborns because of the risk of precipitation of ceftriaxone-calcium salt (see

  Drug Interaction

No impairment of renal function has so far been observed after concurrent administration of large doses of Rofecin® and potent diuretics (e.g. furosemide). There is no evidence that Rofecin® increases renal toxicity of aminoglycosides. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Rofecin® . Ceftriaxone dose not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Rofecin® is not altered by probenecid.

  Storage

Store below 30° C. Keep out of reach of children

  Commercial Pack

For i.m injection 
250mg with 1 ampoule containing 2ml of 1% Lidocaine solution in Blister Pack
500mg with 1 ampoule containing 2ml of 1% Lidocaine solution in Blister Pack
1g with 1 ampoule containing 3.5ml of 1% Lidocaine solution in Blister Pack
For i.v injection 
250mg with 1 ampoule containing 5ml of water for injection in Blister Pack
500mg with 1 ampoule containing 5ml of water for injection in Blister Pack
1g with 1 ampoule containing 10ml of water for injection in Blister Pack
2g for infusion with 2 ampoules containing 10ml of water for injection in a tray

  Others

Stability : This medicine should not be used after the expiry date (Exp.) shown on the pack.

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