Drug formPowder for preparing solution for injection and infusion
ATC subcategoryCephalosporins (for injection and infusion)
Each vial contains:
active ingredient: ceftriaxone (as sodium salt) – 500 mg.
Third-generation cephalosporin antibiotic; J01DA13.
CAS number: 104376-79-6.
Mode of action
Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of bacterial β-lactamases and is active against a broad spectrum of bacterial pathogens including both Gram-positive and Gram-negative species.
Mechanism of resistance
Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-lactamases, including those which are able to hydrolyse advanced generation penicillin derivatives and other cephalosporins. Resistance to ceftriaxone is encoded mainly by the production of some beta-lactam hydrolysing enzymes (including carbapenemases and some ESBLs) especially in Gram-negative organisms. For Gram-positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly encoded by cell wall target site alterations. Outside of the advanced generation parenteral cephalosporins, cross-resistance to other drug classes is generally not encountered.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Ceftriaxone susceptibility among Gram-positive and Gram-negative bacterial species in Europe from January 1999-December 2001:
Commonly susceptible species (i.e. resistance < 10% in all EU Member States)
Species for which acquired resistance may be a problem (i.e. resistance 10% in at least one EU Member State)
Inherently resistant organisms
a Methicillin-susceptible Coagulase-Negative Staphylococcus
b Methicillin-susceptible Staphylococcus aureus
c Non-susceptible range (no resistant breakpoints defined)
d Methicillin-resistant Coagulase-Negative Staphylococcus
e Methicillin-resistant Staphylococcus aureus
* Species for which the efficacy of ceftriaxone has been demonstrated both in vitro and in vivo
+ Species for which high rates of resistance have been observed in one or more regions within the EU approximate guidance on probabilities whether micro-organisms will be susceptible. The table above comprises current levels of susceptibility according to routinely produced susceptibility test results in France, Germany, Greece, Italy, the Netherlands, Spain, and the United Kingdom. All data is presented using contemporary NCCLS derived susceptibility breakpoints except France (CA-SFM). Data is derived from The Surveillance Network™ (TSN) Databases in each respective region. The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only approximate guidance on probabilities whether microorganisms will be susceptible to ceftriaxone or not.
The pharmacokinetics of Ceftriaxone are largely determined by its concentration-dependent binding to serum albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.
Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg Rocephin in 1.06% Lidocaine produces mean peak plasma concentrations of 40 – 70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.
Excretion: Ceftriaxone is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10 – 22ml/min. The renal clearance is 5 – 12ml/min. The elimination half-life in adults is about 8 hours. The half-life is not significantly affected by the dose, the route of administration or by repeated administration.
Pharmacokinetics in special clinical situations
In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adult. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.
In elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times longer than in the young adult group. As with all cephalosporins, a decrease in renal function in the elderly may lead to an increase in half-life. Evidence gathered to date with ceftriaxone however, suggests that no modification of the dosage regimen is needed.
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.
Cerebrospinal fluid: Ceftriaxone crosses non-inflamed and inflamed meninges, attaining concentrations 4 – 17% of the simultaneous plasma concentration.
Treatment may be started before the results of susceptibility tests are known.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Ceftriaxone may be administered by deep intramuscular injection, slow intravenous injection, or as a slow intravenous infusion, after reconstitution of the solution according to the directions given below. Diluents containing calcium, (e.g. Ringer’s solution or Hartmann’s solution), should not be used 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. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously .
Dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient’s condition. Under most circumstances a once-daily dose – or, in the specified indications, a single dose – will give satisfactory therapeutic results.
Adults and children 12 years and over
Standard therapeutic dosage: 1g once daily.
Severe infections: 2 – 4g daily, normally as a single dose every 24 hours.
The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of Ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.
Acute, uncomplicated gonorrhoea: A single dose of 250mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.
Peri-operative prophylaxis: Usually 1g as a single intramuscular or slow intravenous dose. In colorectal surgery, 2g should be given intramuscularly (dosages greater than 1g should be divided and injected at more than one site), or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.
These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory .
Neonates, infants and children up to 12 years
The following dosage schedules are recommended for once daily administration:
A daily dose of 20 – 50mg/kg body weight, not to exceed 50mg/kg. In the neonate, the intravenous dose should be given over 60 minutes to reduce the displacement of bilirubin from albumin, thereby reducing the potential risk of bilirubin encephalopathy .
Infants and children of up to 12 years
Standard therapeutic dosage: 20 – 50mg/kg body weight once daily.
In severe infections up to 80mg/kg body weight daily may be given. For children with body weights of 50kg or more, the usual adult dosage should be used. Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.
Renal and hepatic impairment
In patients with impaired renal function, there is no need to reduce the dosage of Ceftriaxone provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to 2g or less.
In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact.
In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of Ceftriaxone should be determined at regular intervals and dosage adjusted.
In patients undergoing dialysis, no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.
In the case of overdose nausea, vomiting, diarrhoea, can occur. Ceftriaxone concentration can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.
Full-term newborns (up to 28 days of age)
Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent.
Rarely, severe, and in some cases fatal, adverse reactions have been reported in preterm and full-term newborns aged.
Infections and infestations
Rare ( 0.01% – < 0.1%): Mycosis of the genital tract.
Superinfections of various sites with yeasts, fungi or other resistant organisms are possible.
Blood and lymphatic system disorders
Rare ( 0.01% – < 0.1%): Neutropenia, leucopenia, eosinophilia, thrombocytopenia, anaemia (including haemolytic anaemia), slight prolongation of prothrombin time.
Very rare (< 0.01 %) including isolated reports: Positive Coombs’ test, coagulation disorders, agranulocytosis (< 500/m3), mostly after 10 days of treatment and following total doses of 20g ceftriaxone and more.
Immune system disorders
Rare (0.01% – < 0.1%): Anaphylactic (e.g. bronchospasm) and anaphylactoid reactions (see “Special warnings and precautions for use”)
Nervous system disorders
Rare (0.01% – < 0.1%): Headache, dizziness.
Common (1% – < 10%): Loose stools or diarrhoea, nausea, vomiting.
Rare (0.01% – < 0.1%): Stomatitis, glossitis. These side effects are usually mild and commonly disappear during treatment or after discontinuation of treatment.
Very rare (< 0.01%) including isolated reports: Pseudomembranous colitis (mostly caused by Clostridium difficile), pancreatitis (possibly caused by obstruction of bile ducts). Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use.
Rare (0.01% – < 0.1%): Increase in serum liver enzymes (AST, ALT, alkaline phosphatase).
Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (see “Special warnings and precautions for use”), mostly in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application, in some studies to above 30 %. The incidence seems to be lower with slow infusion (20-30 minutes). This effect is usually asymptomatic, but in rare cases, the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone.
Skin and subcutaneous tissue disorders
Uncommon ( 0.1% – < 1%): Allergic skin reactions such as maculopapular rash or exanthema, urticaria, dermatitis, pruritus, oedema.
Very rare (< 0.01%) including isolated reports: Erythema multiforme, Stevens Johnson Syndrome, Lyell’s Syndrome/toxic epidermal necrolysis.
Renal and urinary disorders
Rare (0.01% – < 0.1%): Increase in serum creatinine, oliguria, glycosuria, haematuria.
Very rare (< 0.01%) including isolated reports: Renal precipitation, mostly in children older than 3 years who have been treated with either high daily doses (80 mg/kg/day and more) or total doses exceeding 10g and with other risk factors such as dehydration or immobilisation. Renal precipitation is reversible upon discontinuation of ceftriaxone. Anuria and renal impairment have been reported in association.
General disorders and administration site conditions
Rare (0.01% – < 0.1%): Phlebitis and injection site pain following intravenous administration. This can be minimised by slow injection over at least 2-4 minutes. Rigors, pyrexia.
An intramuscular injection without lidocaine solution is painful.
No impairment of renal function has so far been observed after concurrent administration of large doses of Ceftriaxone and potent diuretics (e.g. furosemide).
No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with Ceftriaxone No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Ceftriaxone. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Ceftriaxone is not altered by probenecid.
In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown, but caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.
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.
Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.
In patients treated with Ceftriaxone, the Coombs’ test may rarely become false-positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Ceftriaxone should be done enzymatically.
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.
As with other cephalosporins, anaphylactic reactions with fatal outcome were also reported, even if a patient is not known to be allergic or previously exposed.
Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, any other cephalosporin, or to any penicillin or other beta-lactam drug. Ceftriaxone is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug . Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.
Ceftriaxone should be given with caution to patients who have other allergic diatheses.
Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.
In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used, or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions.
Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Ceftriaxone, and may range in severity from mild diarrhoea 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 diarrhoea 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.
Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.
An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Ceftriaxone. Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.
Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis have all been reported with the use of ceftriaxone. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Ceftriaxone should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted.
Ceftriaxone should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.
As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.
In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations .
Ceftriaxone may precipitate in the gallbladder and then be detectable as shadows on ultrasound. This can happen in patients of any age, but is more likely in infants and small children who are usually given a larger dose of Ceftriaxone on a body weight basis. In children, doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates. There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with Ceftriaxone As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are not normally indicated.
Shadows, which have been mistaken for gallstones are however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of Ceftriaxone therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended.
Discontinuation of Ceftriaxone treatment in symptomatic cases should be at the discretion of the physician.
Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug to produce a positive Coombs’ test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of Ceftriaxone -related biliary precipitation can not be ruled out.
Safety and effectiveness of Ceftriaxone in neonates, infants and children have been established for the dosages described under Dosage and administration. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.
During prolonged treatment a complete blood count should be performed at regular intervals.
In case lidocaine is used as a solvent Ceftriaxone solutions should only be used for intramuscular injection.
The stated dosage should not be exceeded.
Each gram of Ceftriaxone contains approximately 3.6mmol sodium. To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines
For ceftriaxone, limited clinical data on exposed pregnancies are available. Ceftriaxone crosses the placental barrier. Reproductive studies in animals have shown no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed. Since safety in human pregnancy is not established ceftriaxone should not be used unless absolutely indicated.
Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman.
White to yellowish-orange crystalline powder.
Vials containing 500 mg of Ceftriaxone.
10 vials in the cardboard box.
3 years. Do not use after the expiration date.
Store at a temperature below 25ºC, in a dry place, out of the reach of children. Protect from light.
After reconstitution, solution is storable for 6 hours in room temperature (25ºC) and 24 hours in refrigerator (4ºC).