Document: spc-doc_PL 30306-0181 change

• spc-doc_PL 24780-0007
• spc-doc_PL 30306-0181

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ceftriaxone 2g Powder for Solution for Injection or Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains ceftriaxone sodium equivalent to 2 g ceftriaxone.

Excipient: Each vial contains 7.2 mmol (165.6 mg) sodium.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion.

Almost white or yellowish, slightly hygroscopic crystalline powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ceftriaxone is indicated for the treatment of the following infections when caused by micro-organisms that are susceptible to ceftriaxone and if parenteral treatment is necessary (see section 5.1):

-    bacterial meningitis

-    pneumonia

Consideration should be given to official local guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Route and method of administration

Ceftriaxone 2g Powder for Solution for Injection or Infusion may be administered by intravenous bolus injection, by intramuscular injection, or infusion 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 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).

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.

An intravenous injection should be administered over at least 2 to 4 minutes directly into the vein. Doses >50 mg/kg should be administered by slow intravenous infusion over at least 30 minutes.

The intramuscular method of administration should only be used in exceptional clinical situations (see section 4.3) and should undergo a risk-benefit assessment. Intramuscular administration is not usually recommended for children.

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

For intramuscular administration Ceftriaxone 2g Powder for Solution for Injection or Infusion dissolved in lidocaine hydrochloride solution is injected deep into the gluteus maximus muscle. Not more than 1 g of 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 lidocaine hydrochloride solution 1% has to be taken into account.

Normal dosage

Adults and adolescents aged over 12 years with a body weight >50 kg:

The usual dose is 1 to 2 g of ceftriaxone, administered once a day (every 24 hours). In cases of serious infections or infections caused by moderately sensitive microorganisms the dose can be raised up to 4 g, administered once a day intravenously.

Newborn infants (age 0 to 14 days):

20 to 50 mg per kg bodyweight intravenously once daily (24-hour intervals).

In severe infections the daily dose of 50 mg per kg bodyweight must not be exceeded.

For administration to newborn infants, see section 4.4.

Children 15 days to 12 years of age with a body weight of <50 kg:

20 to 80 mg per kg bodyweight intravenously once daily (24-hour intervals).

In severe infections the daily dose of 80 mg per kg bodyweight must not be exceeded, except in meningitis (see section 4.2: Special dosage recommendations).

Children with a bodyweight of 50 kg or more receive the usual adult dosage once daily (see above).

Elderly:

For elderly patients the dosage recommendations are the same as for adults - without modification.

Special dosage recommendations

Meningitis

Treatment is initiated with 100 mg per kg bodyweight once daily - not exceeding 4 g daily. After determining the sensitivity of the pathogen the dose may be reduced accordingly.

In newborns 0 to 14 days of age the dose should not exceed 50 mg/kg/24 h.

Renal insufficiency

In patients with impaired renal function, adjustment of the ceftriaxone dose is not necessary if the hepatic function is normal. In renal insufficiency with a reduced creatinine clearance of <10 ml/min the daily dose of ceftriaxone should not exceed 2 g in adult patients.

Hepatic insufficiency

The dose does not need to be altered in patients with a liver disease provided that the renal function is normal (see section 4.8).

In simultaneous severe renal and hepatic insufficiency the serum ceftriaxone concentrations should be monitored regularly and the dosage adjusted appropriately for children and adults (see sections 4.4 and 5.2).

Haemodialysis or peritoneal dialysis

As ceftriaxone is dialysable only to a very minor extent there is no need for an additional dose of ceftriaxone after 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 patients on continuous ambulatory peritoneal dialysis (CAPD), ceftriaxone may be administered either intravenously or in case of CAPD associated infections may be added directly to the dialysis solution (e.g. 1 to 2 g ceftriaxone in the first dialysis fluid of the respective day of treatment) (see section 6.6).

Duration of therapy

The normal duration of therapy depends on the characteristics of the infection. Generally the administration of ceftriaxone should be continued for at least 48 to 72 hours beyond the normalisation of body temperature and evidence of bacterial eradication has been obtained. Dosage recommendations for special indications should be taken into account.

4.3 Contra-indications

Hypersensitivity to the active substance, other cephalosporins. or to any of the excipients.

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)

-    with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired

-    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).

Intramuscular injection of the medicinal product is contraindicated:

-    in infants <2 years of age

-    during pregnancy and lactation.

Contraindications of lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine is used as a solvent.

4.4 Special warnings and precautions for use

As with other cephalosporins, anaphylactic shock cannot be ruled out even if a thorough patient history is taken.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea 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 diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.²

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 suspected or proven infections with Pseudomonas aeruginosa, high resistance rates (>60%) for ceftriaxone in at least some European countries should be taken into consideration (see section 5.1).

In infections caused by Pseudomonas aeruginosa with proven sensitivity to ceftriaxone a combination with amino-glycosides is warranted to avoid secondary resistance.

In infections caused by other bacteria in patients with neutropenic fever interventional treatment with ceftriaxone should be combined with an aminoglycoside.

Special caution is required to determine any other type of previous hypersensitivity reactions to penicillin or to other beta-lactam-medicinal products because patients hypersensitive to these medicines may be hypersensitive to ceftriaxone as well (crossallergy).

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, because hypersensitivity reactions emerge faster and proceed more severely after intravenous injection (see section 4.8).

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

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined in 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 is indicated during long-term treatment (see section 4.8).

Each administration of antibiotics can lead to multiplication of pathogens resistant to the active substance used. Signs of consecutive secondary infections with such pathogens (including candida and fungi) are to be heeded. Secondary infections are to be treated accordingly (see section 5.1).

Pseudomembranous colitis has been reported with almost all antibiotics, including ceftriaxone. This diagnosis should be considered in patients who develop diarrhoea during or following treatment with ceftriaxone (see. section 4.8).

Ceftriaxone should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.

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 - except for meningitis - 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, and conservative management of ceftriaxone precipitate in the gallbladder 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 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.

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 new-borns or in those who are hypoalbuminaemic or acidotic, in whom bilirubin binding is likely to be impaired. Particular caution should be exercised in babies born prematurely.

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 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 saltsolution 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).

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the medicinal product to produce a positive Coombs’ test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

During prolonged treatment 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.

This medicinal product contains 7.2 mmol (or 165.6 mg) sodium sodium per 2 g dose. This should be taken into consideration for patients on controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Diuretics

No impairment of renal function has been observed in man after simultaneous administration of large doses of ceftriaxone and potent diuretics (e.g.furosemide). Aminoglycosides

In case of concomitant administration of cephalosporins and aminoglycosides there has not been reported an increased risk of oto- and nephrotoxicity. Furthermore, these medicinal products must be administered separately to avoid physicochemical incompatibility between ceftriaxone and the aminoglycoside.

Bacteriostatic antibiotics, such as chloramphenicol and tetracycline, may antagonise the activity of ceftriaxone, especially in acute infections accompanied by rapid proliferation of micro-organisms. In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

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

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-calicum.

Probenecid

Contrary to other cephalosporins, probenecid does not impede tubular secretion of ceftriaxone. The elimination of ceftriaxone is not altered by probenecid. Concomitant administration of probenecid (1-2 g/day) may inhibit the biliary secretion of ceftriaxone.

Oral contraceptives

Ceftriaxone may adversely affect the efficacy of hormonal contraceptives. Consequently, it is advisable to use supplementary non-hormonal contraceptive measures during treatment and in the month following treatment.

Other

Disulfiram-like effect

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.

Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

Laboratory-diagnostic tests

The Coombs test may be 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 lead to false-positive results of galactose determination in blood.

4.6 Fertility, pregnancy and lactation

Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.As a precautionary measure, ceftriaxone should only be used during pregnancy after benefit/risk assessment by the physician in charge, especially during the first trimester.

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman. Diarrhoea and fungal infection of the mucous membrane 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/infusion - 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

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.

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 lungs 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 section 4.3, 4.4and 5.2).

The following adverse reactions, that reverse spontaneously or after treatment discontinuation, have been observed in association with ceftriaxone use The undesirable effects usually are mild and short-term in.

Estimated frequency of events is as follows: Common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000).

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

Blood and lymphatic system disorders

Common:    Eosinophilia, leucopenia, granulocytopenia, haemolytic anemia,

thrombocytopenia.

Very rare:    Agranulocytosis (<500/mm³), mostly after 10-day treatment and a

total dose of 20 g ceftriaxone and more; coagulation disorders. Minor prolongation in the prothrombin time has been described.

Anaemia

Nervous system disorders

Uncommon:    Headache, dizziness, vertigo.

Gastrointestinal disorders

Common:    Stomatitis, glossitis, loose stools or diarrhea, nausea, vomiting.

Uncommon:    Anorexia, abdominal pain. These undesirable effects are mostly mild

and frequently subside during, otherwise after discontinuation of therapy.

Very rare:    Pseudomembranous enterocolitis (see section 4.4).

If severe, persistent diarrhoea occurs during or after treatment, pseudomembranous colitis which is a serious, even life-threatening complication mostly caused by clostridium difficile, should be considered. Discontinuation of therapy with ceftriaxone depending on the indication should be considered and appropriate treatment measures should be initiated: e.g. intake of specific antibiotics/chemotherapeutics with clinically proven efficacy. Antiperistaltics are contraindicated.

Renal and urinary disorders

Uncommon:    Oliguria, increase in serum creatinine.

Rare:    Precipitates of ceftriaxone in the kidneys in paediatric patients,

mostly in children older than 3 years treated either with high daily doses (e.g. 80 mg/kg BW per day and more) or with total doses above 10 g ceftriaxone and who presented several risk factors (e.g. restricted fluid supply, confinement to bed, etc). The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of ceftriaxone. Glucoseuria, hematuria,

Infections and infestations

Uncommon:    Mycosis of the genital tract.

Superinfections with non-susceptible micro-organisms (candida, fungi or other resistant microorganisms).

General disorders and administration site conditions Common:    Phlebitis following intravenous administration. This can be

minimised by slow injection (over 2 to 4 minutes).

Pain at the injection site.

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 to 4 minutes).

Pain and induration of tissue at the site of injection occur after intramuscular injection.

Intramuscular injection without lidocaine solution is painful.

Rare:    Pyrexia, chills.

Immune system disorders

Common:    Allergic skin reactions (e.g. dermatitis, urticaria, exanthema),

pruritus, oedema and oedematous swelling of skin and joints Rare:    Anaphylactoid reactions and severe acute hypersensitivity reactions

up to anaphylactic shock e.g. bronchospasms.

Lyell syndrome/toxic epidermal necrolysis, Stevens-Johnson syndrome or Erythema multiforme.

Severe acute hypersensitivity reactions and anaphylactic shock require immediate discontinuation of the administration of ceftriaxone and the initiation of appropriate emergency measures.

Hepatobilary disorders

Very common: Symptomatic precipitation of ceftriaxone calcium salt in the

gallbladder of children/reversible cholelithiasis in children. This disorder is rare in adults (see below).

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

Rare:    Pancreatitis (see section 4.4). Increase in liver enzymes.

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, 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.

Influence on diagnostic tests

In patients treated with ceftriaxone the Coombs’ test rarely may become falsepositive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosemia.

Likewise, nonenzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

4.9 Overdose

No case of overdose has been reported.

Symptoms of intoxication

Typical signs of overdose can be expected to correspond to the adverse reaction profile. In the case of overdose nausea, vomiting and diarrhoea can occur.

Colics occurred very rarely in the presence of nephropathy or cholelithiasis when using high doses administered more frequently and more rapidly than recommended.

Therapy of intoxication

Excessive serum concentration of ceftriaxone cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Symptomatic therapeutic measures are indicated.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

General properties

Pharmacotherapeutic group

Third-generation cephalosporins, ATC code: J01DD04 Mode of action

Ceftriaxone has bactericidal activity that results from the inhibition of bacterial cell wall synthesis.

Ceftriaxone has a high degree of stability in the presence of P-lactamases produced by Gram-negative and Gram-positive bacteria.

Synergistic effects of ceftriaxone and aminoglycosides on certain Gramnegative bacteria have been noted in vitro.

Mechanism of resistance

Ceftriaxone is active against organisms producing some types of beta-lactamase, for example TEM-1.

However, it is inactivated by beta-lactamases that can efficiently hydrolyse cephalosporins, such as many of the extended-spectrum beta-lactamases and chromosomal cephalosporinases, such as AmpC type enzymes. Ceftriaxone cannot be expected to be active against the majority of bacteria with penicillinbinding proteins that have reduced affinity for beta-lactam medicinal products. Resistance may also be mediated by bacterial impermeability or by bacterial drug efflux pumps. More than one of these four means of resistance may be present in the same organism.

Breakpoints

Clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens according to EUCAST are:

-    Enterobacteriaceae: S<1 mg/l and R>2 mg/l

-    Haemophilus influenzae: S<0.12 mg/l and R>0.12 mg/l

-    Neisseria gonorrhoea: S<0.12 mg/l and R>0.12 mg/l

-    Neisseria meningitides: S<0.12 mg/l and R>0.12 mg/l

-    Streptococcus A,B,C,G: S<0.5 mg/l and R>0.5 mg/l

-    Streptococcus pneumonia: S<0.5 mg/l and R>2 mg/l

-    Non-species related breakpoints: S<1 mg/l and R>2 mg/l

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.

5.2 Pharmacokinetic properties

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

After a dose of 1 to 2 g, concentrations have been shown to remain above the MIC values for most infection-causing pathogens for over 24 hours in over 60 different tissues (including lungs, heart, bile ducts, liver, tonsils, middle ear, nasal mucosa, bones) and in many tissue fluids (including cerebrospinal fluid, pleural fluid as well as prostatic and synovial fluid).

Absorption

Ceftriaxone is completely absorbed following intramuscular administration with peak plasma concentrations (about 80 mg/l) occurring between 2 and 3 hours after dosing.

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.

Ceftriaxone is reversibly bound to albumin. The binding is 95% at plasma concentrations less than 100 mg/l with the binding percentage decreasing as the concentration increases (to 85% at ceftriaxone plasma concentrations of 300 pg/ml).

Serum levels

Following an the intravenous infusion of 1 g of ceftriaxone for 30 minutes, serum levels immediately after cessation of the infusion process were at 123.2 pg/ml, and at 94.81, 57.8, 20.2 and 4.6 pg/ml, respectively, 1.5, 4, 12 and 24 hours after the onset of infusion.

Subsequent to an intramuscular injection of 1 g of ceftriaxone the serum concentration amounted to 79.2pg/ml after 1.5 hours, and afterwards 58.2, 35.5 and 7.8 pg/ml at the respective time-points 4, 12 and 24 hours after injection.

Ceftriaxone penetrates the inflamed meninges of newborn, infants and children. In CSF the peak concentrations of 18 mg/l are achieved, after a 50-100 mg/kg intravenous dose, in about four hours. In adult patients with meningitis, therapeutic concentrations are achieved within 2-24 hours with the dose of 50 mg/kg.

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.

Elimination

Over a 0.15 to 3 g dose range, the values of elimination half-life range from 6 to 9 hours, total plasma clearance from 0.6-1.4 l/h and renal clearance from 0.3-0.7 l/h.

50-60% of ceftriaxone is eliminated as an unchanged active substance in the urine whilst the remainder is excreted via the bile into the faeces as microbiologically inactive metabolites.

Ceftriaxone concentrates in the urine. The urine concentrations are 5-10 times higher than those found in the plasma.

Ceftriaxone cannot be removed by dialysis. This applies to both haemodialysis and peritoneal dialysis.

Urinary excretion is via glomerular filtration. No tubular secretion takes place. For this reason, no increase in the serum levels is to be expected in coincident administration of probenecid and is actually - even at higher dosage e.g. with 1-2 g probenecid - not found.

Non-Linearity

The pharmacokinetics of ceftriaxone is non-linear with respect to the dose. This nonlinearity 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% accumulation above single dose values

Special _patient groups

Elderly above 75 years

The plasma elimination half-life of ceftriaxone is about 2-3 fold increased compared to young adults.

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.

Patients with impaired renal and/or liver function

Patients with an impaired renal function have an increased excretion of ceftriaxone into the bile.

Patients with an impaired liver function have an increased renal excretion of ceftriaxone. The plasma elimination half-life of ceftriaxone is almost not increased in these patient groups. Patients with an impaired renal function, as well as an impaired liver function, may have an increased ceftriaxone plasma elimination half-life.

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

5.3 Preclinical safety data

The adverse reactions (e.g. gastrointestinal disturbances and nephrotoxicity) associated with high parenteral doses of cephalosporins have been shown to be reversible in animals during repeat dosing.

After high doses of ceftriaxone diarrhoea, formation of biliary caliculi in the gallbladder and nephropathy were observed in monkeys and dogs.

Ceftriaxone has no effect on fertility or reproduction. It has not been shown to possess any mutagenic activity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Solutions containing ceftriaxone should not be mixed with or added to 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 IV administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calciumcontaining 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.

6.3 Shelf life

Unopened: 2 years.

Opened and after reconstitution:

Chemical and physical in-use stability has been demonstrated for 6 hours at 25°C and 24 hours at 2 to 8°C.

From a microbiological point of view, 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 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the vial(s) 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

2 g powder for solution for injection/infusion

20 ml or 100 ml vials of clear type I glass closed with grey siliconated, bromobutyl rubber stopper with white coloured flip-off seal.

Pack sizes (both 20 ml and 100 ml): 1, 2, 4 and 5 vials. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Instructions for use and handling

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

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.

Ceftriaxone should not be mixed in the same syringe with any medicinal product other than 1% lidocaine hydrochloride solution (for intramuscular injection only).

Intravenous injection

Ceftriaxone 2g powder for solution for injection or infusion should be dissolved in 20 ml of water for injections.

The injection should be administered over at least 2 to 4 minutes directly into the vein (see section 4.2).

Intravenous infusion

Ceftriaxone 2g powder for solution for injection or infusion should be dissolved in 40 ml of one of the following calcium-free infusion solutions: Sodium chloride 0.9%, sodium chloride 0.45% and glucose 2.5%, glucose 5% or 10%, dextran 6% in glucose 5%, hydroxyethyl starch 6-10% infusions. See also the information included in section 6.2.

The infusion should be administered immediately as a short time infusion over at least 30 minutes.

Intramuscular injection

Ceftriaxone 2g powder for solution for injection or infusion should be dissolved in

7.2 ml of 1% lidocaine hydrochloride injection solution.

The solution should be administered by deep intramuscular injection. Doses greater than 1 g should be divided and injected on more than one site (see section 4.2).

Solutions in lidocaine should not be administered intravenously.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegur 76-78 IS-220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0181

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 25/10/2010

10 DATE OF REVISION OF THE TEXT

29/08/2012