Document: spc-doc_PL 25174-0010 change

• spc-doc_PL 04515-0398
• spc-doc_PL 04569-1600
• spc-doc_PL 21844-0012
• spc-doc_PL 24598-0007
• spc-doc_PL 25174-0010

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ceftriaxone 1 g Powder for Solution for Injection or Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 g vial contains 1 g ceftriaxone (as hydrated disodium ceftriaxone).

Also contains 3.6 mmol sodium (see section 4.4).

3    PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

Almost white to yellowish crystalline powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ceftriaxone is indicated for the treatment of the following infections when known or likely to be due to one or more micro-organisms that are susceptible to ceftriaxone and if parenteral treatment is necessary (see section 5.1):

•    Bacterial meningitis

•    Septicaemia

•    Infections of bones or joints

•    Infections of skin or soft tissues

•    Pneumonia

•    Infections in neutropenic patients

•    Gonorrhoea

Ceftriaxone is indicated for perioperative prophylaxis in patients with a certain risk of severe postoperative infections (see section 4.4). Depending on the mode of surgery and the expected spectrum of pathogens ceftriaxone should be combined with an appropriate antimicrobial agent with additional anaerobic coverage.

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

Route and method of administration

Ceftriaxone may be administered by slow intravenous injection, by slow intravenous infusion or by deep intramuscular injection after reconstitution of the solution according to the directions given below (see section 6.6).

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 intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

Dosage and mode of administration should be determined by the severity and site of infection, susceptibility of the causative micro-organism and the patient's age and condition. Under most circumstances a once-daily dose - or, in the specified indications, a single dose - will give satisfactory therapeutic results.

An intravenous injection should be administered over at least 2-4 minutes directly into the vein or via the tubing of an intravenous infusion.

The intramuscular method of administration should only be used in exceptional clinical situations (see section 4.3) and should undergo a risk-benefit assessment.

For intramuscular injection the special advice below and also in section 6.6 must be followed.

For intramuscular administration ceftriaxone should be dissolved in lidocaine hydrochloride injection and given by deep intramuscular injection. Doses greater than 1 g should be divided and injected at more than one site. Not more than 1 g ceftriaxone should be injected on either side of the body. The maximum daily dose by intramuscular administration should not exceed 2 g. The summary of product characteristics of the lidocaine hydrochloride injection 1% has to be taken into account.

Adults and children 12 years and over with a body weight > 50 kg Standard therapeutic dosage: 1 g once daily.

Severe infections: 2 - 4 g 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 250 mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.

Peri-operative prophylaxis: Usually 1 g as a single intramuscular or slow intravenous dose. In colorectal surgery, 2 g should be given intramuscularly (dosages greater than 1 g should be divided and injected at more than one site), 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).

Neonates, infants and children up to 12 years

The following dosage schedules are recommended for once daily administration: Neonates

A daily dose of 20-50 mg/kg bodyweight intravenously, not to exceed 50 mg/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 (see section 4.4).

Infants and children of up to 12 years with a body weight < 50 kg

Standard therapeutic dosage: 20-50 mg/kg bodyweight once daily.

In severe infections up to 80 mg/kg bodyweight daily may be given.

For children with body weights of 50 kg or more, the usual adult dosage should be used. Doses of 50 mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80 mg/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 for the dosage to be reduced provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10 ml/min) should the daily dose of ceftriaxone be limited to 2 g 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 the dosage adjusted appropriately.

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.

4.3 Contraindications

Ceftriaxone is contraindicated in patients with known hypersensitivity to beta-lactam 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

Ceftriaxone is contraindicated in:

• premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life),

• 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) intravenous calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).

Contraindications of lidocaine must be excluded before intramuscular injection of

ceftriaxone when lidocaine is used as a solvent.

Intramuscular injection of the medicinal product is contraindicated:

•    in infants < 2 years of age

•    during pregnancy and lactation

4.4 Special warnings and precautions for use

As with other cephalosporins, anaphylactic reactions with fatal outcome have been 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 (see Section 4.3). Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to penicillin or any other beta-lactam drug.

Hypersensitivity reactions against ceftriaxone are more likely in patients with any other type of hypersensitivity reaction or asthma bronchiale.

Injections with ceftriaxone should be used with special caution in patients with allergic diathesis.

Hypersensitivity reactions may occur in all degrees of severity up to anaphylactic shock (see section 4.8).

Interaction with Calcium-Containing Products

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 intravenous 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).

As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.

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.

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.

In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations (see section 4.2).

In case of simultaneous impairment of renal and liver function, serum-level of ceftriaxone should be monitored in regular intervals.

Monitoring of renal and hepatic function and haematological parameters at regular intervals are indicated during long-term treatment (see section 4.8).

Ceftriaxone may precipitate in the gallbladder and kidneys 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 80 mg/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.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been 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 cannot be ruled-out.

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. In this respect, there may be some cross-reactivity with penicillins.

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 cephalosporin associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined.

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.

This medicinal product contains approximately 3.6 mmol (or 83 mg) sodium per gram, which should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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. Simultaneous use of ceftriaxone and bacteriostatic antibiotics is not recommended.

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.

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.

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 intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous 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.

Laboratory-diagnostic tests

The Coombs test may become false-positive in rare cases during treatment with ceftriaxone (see section 4.4).

Non-enzymatic methods for glucose determinations in urine may yield false-positive results. For this reason, urine glucose determination during therapy with ceftriaxone should be carried out enzymatically.

Ceftriaxone may result in false-positive results for galactosaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Lactation

Ceftriaxone is excreted in low concentrations in human milk. Caution should be exercised when ceftriaxone is administered to breast-feeding woman. Diarrhoea and fungal infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be borne in mind.

Powder for solution for injection- intramuscular administration:

The use of ceftriaxone and lidocaine is contraindicated during pregnancy and lactation (see section 4.3).

4.7 Effects on ability to drive and use machines

Since ceftriaxone sometimes induces dizziness the ability to drive and use machines can be impaired.

4.8 Undesirable effects

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).

In this section, undesirable effects are defined as follows:

Very common Common Uncommon Rare

Very rare, including isolated reports

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and Infestations Uncommon: Mycosis of the genital tract.

Superinfections of various sites with yeasts, fungi or other resistant organisms are possible.

Blood and lymphatic system disorders

Rare: Neutropenia, eosinophilia, leucopenia, thrombocytopenia, anaemia (including haemolytic anaemia), granulocytopenia, slight prolongation of prothrombin time.

Very rare including isolated reports: Positive Coombs’ test, coagulation disorders, agranulocytosis (<500/mm³) mostly after 10 days of treatment and following total doses of 20 g ceftriaxone and more.

Immune system disorders

Rare: Anaphylactic (e.g. bronchospasm) and anaphylactoid reactions (see section 4.4).

These reactions require immediate discontinuation of the administration of ceftriaxone and the initiation of appropriate emergency measures.

Nervous system disorders

Uncommon: Headache, dizziness, vertigo.

Gastrointestinal disorders

Common: Loose stools or diarrhoea, nausea, vomiting.

Uncommon: Stomatitis, glossitis, anorexia, abdominal pain. These undesirable effects are usually mild and commonly disappear during, treatment or after discontinuation of treatment.

Rare: Pancreatitis (possibly caused by obstruction of bile ducts).

Very rare: Pseudomembranous colitis (mostly caused by Clostridium difficile, see section 4.4).

If diarrhoea occurs during or after treatment, pseudomembranous colitis which is a serious, even life-threatening complication, should be considered.

Hepato-biliary disorders

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (see section 4.4), 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 some 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.

Very common: Symptomatic precipitation of ceftriaxone calcium salt in the gallbladder of children / reversible cholelithiasis. This disorder is rare in adults (see below).

Common: Increase in serum liver enzymes (AST, ALT, alkaline phosphatase).

Rare: Symptomatic precipitation of ceftriaxone calcium salt in the gallbladder of adults, which disasppeared after cessation of therapy with ceftriaxone.

Skin and subcutaneous tissue disorders

Common: Allergic skin reactions such as maculopapular rash or exanthema, urticaria, dermatitis, pruritus, oedema.

Rare: Erythema multiforme, Stevens Johnson Syndrome, Lyell's Syndrome/toxic epidermal necrolysis.

Renal and urinary disorders

Uncommon: Oliguria, increase in serum creatinine.

Rare: 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 with total doses exceeding 10 g ceftriaxone and with other risk factors such as dehydration or immobilization. Renal precipitation is reversible upon discontinuation of ceftriaxone. Anuria and renal impairment have been reported in association. Glycosuria, haematuria.

General disorders and administration site conditions

Common: Phlebitis and injection site pain following intravenous administration. This can be minimised by slow injection over at least 2-4 minutes.

In rapid intravenous injection intolerability reactions in the form of sensation of heat or nausea may occur. This can be avoided by slow injection (2-4 minutes).

An intramuscular injection without lidocaine solution is painful.

Rare: Rigors, pyrexia.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In the case of overdose nausea, vomiting, diarrhoea, can occur.

Excessive serum concentration of ceftriaxone cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cephalosporins and related substances, ATC code: J01DD04

Mechanism of action

Ceftriaxone has bactericidal activity that results from the inhibition of bacterial cell wall synthesis ultimately leading to cell wall death. Ceftriaxone is stable to a broad range of bacterial P-lactamases and is active against a broad spectrum of bacterial pathogens including both Gram-negative and Gram-positive 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.

Breakpoints

Current MIC breakpoints used to interpret ceftriaxone susceptibility are shown below. The use of NCCLS breakpoints predominate and the breakpoints used in data presented in the table. Values quoted comprise mg/L (MIC testing) or mm (disk diffusion testing) using a 30 mg/L drug concentration.

National Committee for Clinical Laboratory Standards (NCCLS) (M100-S12) -2002

	Susceptible	Intermediate	Resistant
Enterobacteriaceae, P. aeruginosa and other non-Enterobacteriaceae, Staphylococcus spp.	< 8 Disk: < 13	16-32 Disk: 14-20	> 64 Disk: > 21
Haemophilus spp.	< 2 Disk: > 26
Neisseria spp.	< 0.25	-	-

* Recent 2002 S. pneumoniae breakpoints (NCCLS M100-S12) defined as

<    1 (Sensitive), 2 (Intermediate) and > 4 (Resistant) for non-meningitis specimens and

<    0.5 (Sensitive), 1 (Intermediate) and > 2 (Resistant) for meningitis specimens.

** Recent 2002 Streptococcus viridans group breakpoints (NCCLS M100-S12) defined < 1 (Sensitive), 2 (Intermediate) and > 4 (Resistant).

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:

^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.

The table above comprises current levels of susceptibility according to routinely produced susceptibility tests 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.

5.2 Pharmacokinetic properties

Ceftriaxone is a cephalosporin for parenteral administration. Ceftriaxone is not absorbed after oral application.

Distribution: Ceftriaxone distributes well in various compartments and also passes the placental barrier. The mean volume of distribution in healthy adults is 0.13 l/kg

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 300 mg/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 120 mg/L following a 500 mg dose and about 200 mg/L following a 1 g dose; mean levels of 250 mg/L are achieved after infusion of 2 g over 30 minutes. Intramuscular injection of 500 mg ceftriaxone in 1% lidocaine produces mean peak plasma concentrations of 40 - 70 mg/L within 1 hour. Bioavailability after intramuscular injection is 100%.

Ceftriaxone crosses the placenta and is excreted in human milk at low concentrations.

Biotransformation: Ceftriaxone does not undergo systemic metabolism but it is broken down in the small intestine by bacterial action.

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 - 22 ml/min. The renal clearance is 5 - 12 ml/min. The elimination half-life in adults is about 8 hours. The half-life in not significantly affected by the dose, the route of administration or by repeated administration.

Ceftriaxone concentrates in the urine. The urine concentrations are 5-10 times higher than those found in the plasma. The pharmacokinetics of ceftriaxone are non-linear with respect to the dose. This non-linearity is explained by a concentration dependent decrease of binding to plasma proteins which leads to a respective increase in distribution and elimination.

With the exception of elimination half-life, all pharmacokinetic parameters are dose-dependent. Repeat dosing of 0.5 to 2 g results in 15% - 36 % accumulations above single dose values.

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 of ceftriaxone is usually about 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 newborn infants of 3 days of age, the half-life of ceftriaxone in the serum amounts to approximately 16 hours, and approximately 9 hours in newborn infants aged from 9 to 30 days.

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.

In case of terminal renal insufficiency, the half-life is distinctively higher and reaches approximately 14 hours.

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 data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

None.

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Solutions containing ceftriaxone should not be mixed with or added to solutions containing other agents. 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 intravenous 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 and labetalol.

Shelf life

Unopened:

Powder: 3 years.

Opened and after reconstitution:

For reconstituted solutions, chemical and physical in-use stability has been demonstrated for 6 hours at 25°C and for 24 hours at 2-8°C. Protect from light.

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 or 6 hours at 25°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 container in the outer carton in order to protect from light.

For storage details of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

10 ml Type II clear & colourless glass vial with a bromobutyl stopper and aluminium and polypropylene cap.

The vials are packed in boxes of 1 or 5 vials. Not all pack sizes may be marketed.

6.6 Special precautions for disposal Instructions for use and handling

Preparation of solutions for injection and infusion

The use of freshly prepared solutions is recommended. These maintain potency for at least 6 hours at or below 25°C or 24 hours at 2-8°C. Protect from light.

The reconstituted solution should be shaken up to 60 seconds to ensure complete dissolution of ceftriaxone.

Reconstituted solutions should be inspected visually. Only clear solutions free of visible particles should be used. The reconstituted product is for single use only and any unused solution must be discarded.

When reconstituted for intramuscular or intravenous injection, the white to yellowish crystalline powder gives a pale yellow to amber solution.

Ceftriaxone should not be mixed in the same syringe with any drug other than 1% w/v Lidocaine Injection BP (for intramuscular injection only).

Intramuscular injection

1 g ceftriaxone should be dissolved in 3.5 ml of 1% w/v Lidocaine Injection BP. The solution should be administered by deep intramuscular injection. Dosages greater than 1 g should be divided and injected at more than one site (see section 4.2).

Solutions in lidocaine should not be administered intravenously.

Intravenous injection

1    g ceftriaxone should be dissolved in 10 ml of Water for Injections BP. The injection should be administered over at least 2 - 4 minutes directly into the vein or via the tubing of an intravenous infusion (see section 4.2).

Intravenous infusion

2    g ceftriaxone should be dissolved in 40 ml of one of the following calcium-free solutions: Sodium Chloride Intravenous Infusion BP 0.9%, Sodium Chloride and Glucose Intravenous Infusion BP (sodium chloride 0.45% and glucose 2.5%),

Glucose Intravenous Infusion BP 5% or 10%, Dextran 6% in Glucose Intravenous Infusion BP 5%. See also the information included in section 6.2. The infusion should be administered over at least 30 minutes.

Displacement value

Vial size	Diluent	Volume of diluent added	Approximate resulting volume of ceftriaxone solution	Approximate displacement volume
1 g	1% lidocaine hydrochloride injection	3.5 ml	4.0 ml	0.5 ml
1 g	Water for Injections	10 ml	10.5 ml	0.5 ml
2 g	0.9% sodium chloride solution	40.0 ml	41.0 ml	1.0 ml

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Laboratorio Reig Jofre S.A.

C/Gran Capitan, 10

08970 Sant Joan Despi (Barcelona)

Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL 25174/0010

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/03/2009

DATE OF REVISION OF THE TEXT

16/02/2015