1. Name Of The Medicinal Product
Ceftriaxone 1g Powder for solution for injection
2. Qualitative And Quantitative Composition
Each vial contains ceftriaxone sodium equivalent to 1g of ceftriaxone.
Each gram of ceftriaxone contains approximately82 mg (3.6mmol) of sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for injection (Powder for injection).
White to pale yellow crystalline powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Ceftriaxone sodium is a broad-spectrum bactericidal cephalosporin antibiotic. Ceftriaxone is active in vitro against a wide range of Gram-positive and Gram-negative organisms, which include β-lactamase producing strains.
Ceftriaxone is indicated in the treatment of the following infections either before the infecting organism has been identified or when known to be caused by bacteria of established
Skin and soft tissue infections
Infections in neutropenic patients
Gonorrhoea
Peri-operative prophylaxis of infections associated with surgery
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.
4.2 Posology And Method Of Administration
Ceftriaxone may be administered by deep intramuscular injection, or as a slow intravenous injection, after reconstitution of the solution according to the directions given below. The 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, one dose will give satisfactory therapeutic results.
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 (see sections 4.3, 4.4 and 6.2).
Intramuscular injection: 1g ceftriaxone should be dissolved in 3.5ml of 1% Lidocaine Injection BP. The solution should be administered by deep intramuscular injection. Doses greater than 1g should be divided and injected at more than one site.
Intravenous injection: 1g ceftriaxone should be dissolved in 10ml of Water for Injections PhEur. The injection should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.
Adults and children 12 years and over:
Standard therapeutic dosage: 1g once daily.
Severe infections: 2-4 g daily, normally as a once daily dose.
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: One dose of 250mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.
Peri-operative prophylaxis: Usually one dose of 1g given by intramuscular or slow intravenous injection. In colorectal surgery, 2g should be given intramuscularly (in divided doses at different injection sites), by slow intravenous injection or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.
Elderly: These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory (see below).
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 (see Special warning and precautions for use).
Children under 12 years
Standard therapeutic dosage: 20-50mg/kg body-weight once daily.
Up to 80mg/kg body-weight daily may be given in severe infections, except in premature neonates where a daily dosage of 50mg/kg should not be exceeded. For children with body weights of 50kg or more, the usual 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 dosage is required following the dialysis. Plasma concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.
4.3 Contraindications
Known or suspected allergy to cephalosporins.
Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta
Ceftriaxone constituted with Lidocaine Injection BP must never be used:
- by the intravenous route
- in infants under 30 months
- in subjects with a previous history of hypersensitivity to Lidocaine Injection BP
- in patients who have an unpaced heart block
- in patients with severe heart failure.
Ceftriaxone should not be given to:
• premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life); or
• full-term newborns (up to 28 days of age)
o with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired
o if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).
4.4 Special Warnings And Precautions For Use
The stated dosage should not be exceeded.
Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, cephalosporins, penicillins, or other beta
In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under Posology and method of administration.
In vivo and in vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Clinical data obtained in neonates have confirmed this finding. Ceftriaxone should therefore not be used in jaundiced newborns or in babies who are hypoalbuminaemic, acidotic or born prematurely, in whom bilirubin binding is likely to be impaired.
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. (see sections 4.3, 4.8, 5.2 and 6.2).
Ceftriaxone may precipitate in the gall bladder and then be detectable as shadows on ultrasound (see section 4.8). 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 normally not indicated.
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.
Regular blood counts (haemoglobin, erythrocyte, leucocyte and platelet counts and screening for prolongation of prothrombin time) should be carried out during treatment.
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.
Superinfections with yeasts, fungi or other resistant organisms may occur. A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone. Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.
Each gram of ceftriaxone sodium contains approximately 3.6mmol sodium.
This should be taken into account for patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Aminoglycoside antibiotics and diuretics: No impairment of renal function has been observed in man after simultaneous administration of ceftriaxone with diuretics. No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with ceftriaxone.
Alcohol: The ceftriaxone molecule does not contain the N-methylthio-tetrazole substituent, which has been associated with a disulfiram-like effect, when alcohol is taken during therapy with certain 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.Refer to section 4.8, Undesirable effects.
Interference with Laboratory Tests:
In patients treated with ceftriaxone, the Coombs' test may rarely become false-positive and can interfere with blood cross-matching.
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 done enzymatically.
4.6 Pregnancy And Lactation
Pregnancy: It is known that ceftriaxone crosses the placental barrier. Ceftriaxone has not been associated with adverse events on foetal development in laboratory animals but its safety in human pregnancy has not been established. Therefore it should not be used in pregnancy unless absolutely indicated.
Lactation: Ceftriaxone is excreted in the milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Only minimal amounts of ceftriaxone are excreted in breast milk. However, caution is advised in nursing mothers
4.7 Effects On Ability To Drive And Use Machines
Ceftriaxone has been associated with dizziness, which may affect the ability to drive or operate machinery.
4.8 Undesirable Effects
Ceftriaxone has been generally well tolerated. Adverse reactions are usually mild and transient.
Gastrointestinal
Common (
Rare (
Superinfections with yeasts or other resistant organisms may occur. A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone. Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.
Hypersensitivity
Uncommon (
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
Rare (
Central Nervous system
Rare (
Respiratory, renal and urinary
Rare (
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 (see sections 4.3, 4.4 and 5.2).
Very rare (< 0.01%): reversible symptomatic urinary precipitates of calcium ceftriaxone have occurred after ceftriaxone administration. Patients who are very young, immobilised or who are dehydrated are at increased risk. There have been a few reports of anuria and renal impairment following this reaction.
Genital
Rare (
Hepatobiliary system
Rare (
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 (
4.9 Overdose
In the case of overdosage, drug concentrations would not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
General Properties
ATC classification: JO1D A13
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.
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.
Breakpoints
Current MIC breakpoints used to interpret ceftriaxone susceptibility data are shown below. Values quoted comprise mg/L (MIC testing).
European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)
|
Susceptible/Resistant
|
Enterobacteriaceae2
|
1/2
|
Pseudomonas
|
--
|
Acinetobacter
|
--
|
Staphylococcus 3
|
Note3
|
Enterococcus
|
--
|
Streptococcus A, B, C, G
|
0.5/0.54
|
Streptococcus pneumoniae
|
0.5/24
|
Haemophilus influenzae
Moraxella Catarrhalis
|
0.12/0.124
|
Neisseria gonorrhoea
|
0.12/0.124
|
Neisseria Meningitidis
|
0.12/0.124
|
Gram-negative, anaerobes
|
--
|
Non-species related breakpoints1
S< />R
|
1/2
|
1. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).
2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.
3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).
4. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.
IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.
RD = rationale document listing data used by EUCAST for determining breakpoints.
Susceptibility
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)
|
Gram-Positive aerobes :
MSa coagulase negative Staphylococcus spp. (including S. epidermis )*
MSbStaphylococcus aureus*
Group B (Streptococcus agalactiae )
Streptococcus bovis
Streptococcus pneumoniae*
Group A Streptococcus (Streptococcus pyogenes)*
Streptococcus viridans*
Gram-Negative aerobes :
Citrobacter spp. (including C.freundii )
Escherichia coli*
Haemophilus influenzae (including beta-lactamase positive isolates)c*
Haemophilus para-influenzae*
Klebsiella spp. (including K. pneumoniae and K. oxytoca )*
Moraxella catarrhalis*
Morganella morganii*
Neisseria gonorrhoea (including penicillin-resistant isolates)*
Neisseria meningitidis*
Proteus spp. (including P. mirabilis and P. vulgaris )*
Salmonella spp. (including S. typhimurium )
Serratia spp. (including Serratia marsescens )*
Shigella spp.
Anaerobes:
Clostridium spp.*
|
Species for which acquired resistance may be a problem (i.e. resistance
|
Gram-Negative aerobes:
Pseudomonas aeruginosa +
Enterobacter spp. (including E. aerogenes and E. cloacae )*+
Acinetobacter spp. (including A. baumanii and A. calcoaceticus )*+
Anaerobes:
Bacteroides spp.*
Peptostreptococcus spp.*
|
Inherently resistant organisms
|
Gram-Positive aerobes:
MRd coagulase negative Staphylococcus spp. (including S. epidermidis )
MReStaphylococcus aureus
Enterococcus spp.
Gram-Negative aerobes:
Listeria monocytogenes
Mycoplasma spp.
Stenotrophomonas maltophilia
Ureaplasma urealyticum
Others:
Chlamydia spp.
|
aMethicillin-susceptible Coagulase-Negative Staphylococcus
bMethicillin-susceptible Staphylococcus aureus
cNon-susceptible range (no resistant breakpoints defined)
dMethicillin-resistant Coagulase-Negative Staphylococcus
eMethicillin-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
5.2 Pharmacokinetic Properties
The pharmacokinetics of ceftriaxone are largely determined by its concentration-dependent binding to plasma 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 ceftriaxone in 1% Lidocaine Injection BP produces mean peak plasma concentrations of 40-70 mg/l within one hour. Bioavailability after intramuscular injection is 100%.
Excretion: Ceftriaxone is eliminated mainly as unchanged drug, 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 10-22 ml/min. The renal clearance is 5-12 ml/min. A notable feature of ceftriaxone is its relatively long plasma elimination half-life of approximately eight hours which makes single or once daily dosage of the drug appropriate for most patients. 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 two to three times longer that 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.
5.3 Preclinical Safety Data
There are no preclinical safety data of relevance to the prescriber that are additional to those included in other sections.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None
6.2 Incompatibilities
Solutions containing ceftriaxone should not be mixed with or added to solutions containing other agents except 1% Lidocaine Injection BP (for intramuscular injection only). In particular, diluents containing calcium, (e.g. Ringer's solution, 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. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solutions (see section 4.2, 4.3, 4.4 and 4.8). Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole, aminoglycosides, pentamidine and labetalol.
6.3 Shelf Life
Unopened – Three years.
For reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 25oC and for four days at 2-8°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions
6.4 Special Precautions For Storage
Unopened: Do not store above 25°C. Keep the vials in the outer carton.
After reconstitution: Store at 2-8oC, see section 6.3 for complete storage instructions.
6.5 Nature And Contents Of Container
Ceftriaxone is supplied in Type III 10ml clear glass vials, closed with a Type I rubber stopper uncoated/coated in Omniflex and sealed with an aluminium cap.
The vials are packed in boxes of 1, 5, 10, 25 or 50 vials. Not all pack sizes are marketed.
6.6 Special Precautions For Disposal And Other Handling
Reconstitution table Water for Injection (Intravenous Injection):
Vial size
|
Volume of Diluent to be added
|
Approx available volume
|
Approx displacement volume
|
1g
|
10ml
|
10.5ml
|
0.5ml
|
Reconstitution table 1% Lidocaine Injection BP (Intramuscular Injection):
Vial size
|
Volume of Diluent to be added
|
Approx available volume
|
Approx displacement volume
|
1g
|
3.5ml
|
4.05ml
|
0.55ml
|
Ceftriaxone should not be mixed in the same syringe with any drug other than 1% Lidocaine Injection BP (for intramuscular injection only).
The reconstituted solution should be clear. Do not use if particles are present.
Ceftriaxone sodium when dissolved in Water for Injections Ph Eur forms a pale yellow to amber solution. Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety.
For single use only. Discard any unused contents.
7. Marketing Authorisation Holder
Wockhardt UK Ltd
Ash Road North
Wrexham
LL13 9UF
UK
8. Marketing Authorisation Number(S)
PL 29831/0034
PA 1339/4/1
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation:
|
16 October 2007 (UK)
19 December 2007 (Ireland)
|
10. Date Of Revision Of The Text
November 2009
