Document: spc-doc_PL 24598-0007 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.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1g vial contains 1g of Ceftriaxone as 1.19g hydrated disodium ceftriaxone. For excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

A white to pale yellow 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 susceptible micro-organisms (see section 5.1), and when parenteral therapy is required:

•    Pneumonia

•    Meningitis

•    Septicaemia

•    Bone, skin and soft tissue infections

•    Infections in neutropenic patients

•    Gonorrhoea

•    Peri-operative prophylaxis of infections associated with surgery

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

4.2 Posology and method of administration

Posology

The dose of ceftriaxone should be determined by the severity of the infection, the susceptibility of the causative organism and the patient’s condition. 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.

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).

Adults and children 12 years and over

Standard therapeutic dose: 1 g once daily.

Severe infections: 2 - 4 g daily, normally as a single dose every 24 hours.

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 or by slow intravenous injection or by intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.

Elderly

The recommended adult doses 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 doses are recommended for once daily administration.

Neonates

A daily dose of 20 - 50 mg/kg body weight, 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 Special warnings and special precautions for use).

Infants and children of up to 12 years

Standard therapeutic dose: 20 - 50 mg/kg body weight once daily.

In severe infections up to 80 mg/kg body weight daily may be given. For children with body weights of 50 kg or more, the usual adult dose should be used. Doses of 50 mg/kg or over should be given by 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 impairment

In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance < 10 ml per minute) should the daily dosage be limited to 2 g or less.

In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of ceftriaxone should be determined at regular intervals and dosage adjusted.

In patients undergoing dialysis, no additional supplementary dosing is required following the dialysis. Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

Hepatic impairment

In patients with hepatic impairment there is no need for the dose to be reduced provided renal function is intact.

Method of Administration

Ceftriaxone may be administered by deep intramuscular injection, by slow intravenous injection or as an intravenous infusion after reconstitution. See section 6.6 for directions for reconstitution. Intramuscular doses greater than 1g should be divided so that no more than 1g is injected at any one site.

4.3 Contraindications

Hypersensitivity to ceftriaxone or to any of the cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin, or to any other type of beta-lactam drug.

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

o 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 recommended doses 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, any other cephalosporin, or to any penicillin or other beta-lactam drug.

Ceftriaxone is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug.

Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to any penicillin or to any other beta-lactam drug.

Ceftriaxone should be given with caution to patients who have other allergic diatheses or asthma.

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under Posology and method of administration.

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).

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.

Ceftriaxone may precipitate in the gall bladder and then be detectable as shadows on ultrasound (see section 4.8 undesirable effects). 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, and conservative management of ceftriaxone precipitate in the gall bladder is recommended.

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.

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.

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug Therefore in patients treated with ceftriaxone, the Coombs' test may rarely become false-positive and they may occasionally develop a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

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

Each gram of ceftriaxone contains approximately 3.6mmol sodium. This 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 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.

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.

In vitro, chloramphenicol has been shown to be antagonistic with respect to ceftriaxone and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ceftriaxone with chloramphenicol is proposed, the possibility of antagonism should be considered.

In patients treated with ceftriaxone, the Coombs test may become false-positive. Ceftriaxone, like other antibiotics, may also result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

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

4.6 Pregnancy and lactation

Ceftriaxone has not been associated with adverse effects 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 clearly needed.

Only minimal amounts of ceftriaxone are excreted in breast milk. However, caution is advised when ceftriaxone is administered to 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

The following adverse reactions have been observed in association with ceftriaxone use:

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).

General disorders and administration site conditions:

Pain or discomfort at the injection site can occur with intravenous or intramuscular administration.

Rare (> 0.01% - <0.1%): Phlebitis following intravenous administration. This can be minimised by slow injection (over 2-4 minutes).

An intramuscular injection without lidocaine is painful.

Infections and infestations:

Rare (>0.01% - 0.1%): Mycosis of the genital tract. Other superinfections of various sites are possible.

Blood and lymphatic system disorders:

A positive Coomb’s test is possible.

Rare (>0.01% - < 0.1%): Eosinophilia, leucopenia, neutropenia, anaemia (including haemolytic anaemia), thrombocytopenia, prolongation of prothrombin time.

Very rare (<0.01%): Coagulation disorders.

Agranulocyctosis (<500/mm³). Most of the cases occurred 10 days after the beginning of the therapy or after a total dose of 20g or more.

Immune system disorders:

Rare (>0.01% - <0.1%): Anaphylactic or anaphylactoid reactions (see section 4.4 special warnings and precautions for use), drug fever, shivering, chills. See also skin reactions for other allergic manifestations.

Nervous system disorders:

Rare (>0.01% - <0.1%): Headache, dizziness.

Gastrointestinal disorders:

Common (>1% - < 10%): Diarrhoea, loose stools, nausea, vomiting,

Rare (>0.01% - <0.1%): stomatis, glossitis.

Very rare (<0.01%): Pseudomembranous enterocolitis (see section 4.4 special warnings and precautions for use), pancreatitis, gastrointestinal haemorrhage.

Hepato-biliary disorders:

Rare (>0.01% - <0.1%): increase in serum activities of liver-derived enzymes (AST, ALT, ALP)

Symptomatic precipitation of ceftriaxone calcium salt in the gall bladder (see also section 4.4)

Skin and subcutaneous tissue disorders:

Uncommon (>0.1% -<1%): Exanthema, allergic dermatitis, pruritus, rash, oedema, urticaria, erythema multiforme.

Very rare (<0.01%): Stevens-Johnson syndrome, toxic epidermal necrolysis

Renal and urinary disorders:

Rare (>0.01% - <0.1%): Oligurua, haematuria, glycosuria, increase in serum creatinine.

Very rare (<0.01%): Precipitates in the kidneys of calcium ceftriaxone, particularly in paediatric patients and those who are immobilised or dehydrated. Anuria and renal impairment have been reported in association.

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cephalosporins and related substances.

ATC code: J01D D04

Mechanism of action

Like other beta-lactam drugs, ceftriaxone exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes, namely the penicillin binding proteins. This results in the interruption of cell wall (peptidoglycan) biosynthesis, which can lead to bacterial cell lysis and death.

Mechanism of resistance

Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms:

-    Hydrolysis by beta-lactamases. Ceftriaxone may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably derepressed in certain aerobic gram-negative bacterial species.

-    Reduced affinity of penicillin-binding proteins for ceftriaxone.

-    Outer membrane impermeability, which restricts access of ceftriaxone to penicillin binding proteins in Gram-negative organisms.

-    Drug efflux pumps.

According to EUCAST, the following clinical MIC breakpoints have been defined for ceftriaxone:

Breakpoints

	Susceptible (mg/L)	Resistant (mg/L)
Enterobacteriaceae (1)	<1	>1
Haemophilus influenzae (2)	<0.12	>0.12
Neisseria gonorrhoea (2)	<0.12	>0.12
Neisseria meningitides (2)	<0.12	>0.12
Streptococcus A,B,C,G (2)	<0.5	>0.5
Streptococcus pneumonia (2)	<0.5	>2
Non-species related (3)	<1	>2

(1)    Some ESBL-producing strains may exhibit different breakpoints

(2)    The identification and antimicrobial susceptibility tests on any isolate with MIC results above the S/I breakpoint must be repeated and it the result is confirmed then the isolate should be sent to a reference laboratory.

(3)    Non-species related breakpoints are for use only with species that have not been given a species-specific breakpoint.

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 common Gram-positive and Gram-negative bacterial species is presented in the table below:

5.2 Pharmacokinetic properties

The pharmacokinetics of ceftriaxone are largely determined by its concentration-dependent binding to serum albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Plasma concentrations:

Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg ceftriaxone in 1.06% Lidocaine produces mean peak plasma concentrations of 40 - 70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.

Excretion:

Ceftriaxone is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10 -22ml/min. The renal clearance is 5 ~ 12ml/min. The elimination half-life in adults is about 8 hours. The half-life is not significantly affected by the dose, the route of administration or by repeated administration.

Pharmacokinetics in special clinical situations

In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adults. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.

In elderly persons aged over 75 years: the average elimination half-life is usually 2 to 3 times longer than in the young adult group. As with all cephalosporins, a decrease in renal function in the elderly may lead to an increase in half-life. Evidence gathered to date with ceftriaxone however, suggests that no modification of the dosage regimen is needed.

In patients with renal or hepatic dysfunction: the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

Cerebrospinal fluid: Ceftriaxone crosses non-inflamed and inflamed meninges, attaining concentrations 4 - 17% of the simultaneous plasma concentration.

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 SmPC.

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 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.

6.3 Shelf life

Unopened vial: Three years.

Reconstituted solution: Chemical and physical stability has been demonstrated for ceftriaxone reconstituted with Water for Injections Ph. Eur. or 1.06% Lidocaine Hydrochloride BP Solution, for 6 hours at 25 °C and 24 hours at 2-8°C. Protect from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, the 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 opening, reconstitution, and dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Unopened vial:

Store below 25°C. Keep the vial in the outer carton

Reconstituted solution:

See section 6.3 and section 6.6 for further information.

6.5    Nature and contents of container

Type III Ph. Eur. glass vials with Type I stopper and aluminium cap, containing a sterile white to pale yellow crystalline powder. Packs of 1, 5, 10, 20 and 50 vials are available.

6.6 Special precautions for disposal

Single use only, whereby any unused solution should be discarded.

The use of freshly prepared solutions is recommended. These maintain potency for at least 6 hours at or below 25^oC, or 24 hours at 2-8^oC (see section 6.3). Protect from light.

The reconstituted solution should be clear. Do not use if particles are present.

Ceftriaxone when reconstituted with Water for Injections is a light to dark yellow solution. Variations in the intensity of the colour will not affect the potency of the drug.

Ceftriaxone should not be mixed in the same syringe with any drug other than 1.06% Lidocaine Hydrochloride BP Solution (for intramuscular injection only).

The reconstituted solution should be shaken for approximately 90 seconds to ensure complete dissolution of the ceftriaxone. The user should then allow the solution to stand in order to ensure that there are no bubbles in the solution.

Intramuscular injection:

250mg Ceftriaxone should be dissolved in 1ml of 1.06% Lidocaine Hydrochloride BP solution, or 1 g in 3.5 ml of 1.06% Lidocaine Hydrochloride BP. The solution should be administered by deep intramuscular injection. Dosages greater than 1g should be divided and injected at more than one site.

Solutions in Lidocaine should not be administered intravenously.

Intravenous injection:

250mg of Ceftriaxone should be dissolved in 5ml or 1g 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.

Intravenous Infusion:

2g of Ceftriaxone should be dissolved in 40ml of one of the following calcium-free solutions: Dextrose injection BP 5% or 10%, Sodium Chloride Injection BP, Sodium Chloride and Dextrose Injection BP (0.45% sodium Chloride and 2.5% dextrose), dextran 6% in Dextrose Injection BP 5%, hydroxyethyl starch 6-10% infusions. The infusion should be administered over at least 30 minutes.

The displacement value of 250mg of Ceftriaxone is 0.194ml.

7 MARKETING AUTHORISATION HOLDER

Noridem Enterprises Ltd., (trading as Fannin)

Evagorou & Makariou,

Mitsi Building 3, Suit.115,

1065 Nicosia,

Cyprus.

8    MARKETING AUTHORISATION NUMBER(S)

PL 24598/0007

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/02/2013

10    DATE OF REVISION OF THE TEXT

15/02/2016