Ceftriaxone Fksa 500 mg/1 g/2 g Solution

CEFTRIAXONE FKSA is indicated for the treatment of the following infections when caused by susceptible organisms:

• Bacterial septicaemia caused by methicillin sensitive Staphylococcus aureus (MSSA), Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.
• Meningitis caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae.
• Intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.
• Skin and skin structure infections caused by Methicillin Sensitive Staphylococcus aureus (MSSA), Streptococcus pyogenes, Streptococcus viridans group, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa, Serratia marcescens, or Peptostreptococcus species.
• Bone- and joint infections caused by Methicillin Sensitive Staphylococcus aureus (MSSA), Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.
• Renal and urinary tract infections (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.
• Respiratory tract infections caused by Streptococcus pneumoniae, methicillin sensitive Staphylococcus aureus (MSSA), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.
• Ear, nose and throat infections (acute bacterial otitis media) caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).
• Uncomplicated gonorrhoea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and non-penicillinase-producing strains, and pharyngeal gonorrhoea caused by non-penicillinase-producing strains of Neisseria gonorrhoeae.
• Surgical prophylaxis: The pre-operative administration of a single 1 g dose of CEFTRIAXONE FKSA may reduce the incidence of post-operative infections. In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside should be administered concomitantly.

Posology

Adults and children over 12 years: The usual dosage is 1-2 g of CEFTRIAXONE FKSA once daily (every 24 hours). In severe cases or in infections caused by moderately sensitive organisms, the dosage may be raised to 4 g, once daily.

Neonates, infants and children up to 12 years: The following dosage schedules are recommended for once daily administration.

• Neonates (up to 14 days): 20-50 mg/kg bodyweight once daily. The daily dose should not exceed 50 mg/kg. It is not necessary to differentiate between premature and term infants.
• Infants and children (15 days to 12 years): 20-80 mg/kg once daily. For children with bodyweights of 50 kg or more, the usual adult dosage should be used.

Intravenous doses of u2265 50 mg/kg bodyweight should be given by infusion over at least 30 minutes.

Elderly patients: The dosages recommended for adults require no modification in elderly patients.

Duration of therapy: The duration of therapy varies according to the course of the disease. Administration of CEFTRIAXONE FKSA should be continued for a minimum of 48-72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Special dosage instructions

Meningitis: In bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (up to a maximum of 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly. For bacterial meningitis in adults, the recommended dose is 4 g daily.

Gonorrhoea: In the treatment of uncomplicated gonorrhoea (penicillinase-producing and non-penicillinase-producing strains) a single IM dose of 125 mg is recommended.

Perioperative prophylaxis: A single dose of 1 to 2 g, depending on the risk of infection of 30 to 90 minutes prior to surgery. In colorectal surgery, administration of CEFTRIAXONE FKSA with or without a 5-nitroimidazole, e.g. ornidazole (separate administration: see u201cMethod of administrationu201d below) has been proven effective.

Impaired renal and hepatic function

In patients with impaired renal function, there is no need to reduce the dosage of CEFTRIAXONE FKSA, provided hepatic function is intact. In cases of severe renal failure (creatinine clearance < 10 mL/min) the CEFTRIAXONE FKSA dosage should not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced provided renal function is intact.

Method of administration

CEFTRIAXONE FKSA must be reconstituted prior to use. Reconstituted solutions retain their physical and chemical stability for 6 hours at room temperature (or 24 hours in the refrigerator at u00b1 5 u00b0C). As a general, however, the solutions should be used immediately after preparation. The solutions range in colour from pale yellow to amber, depending on the concentration and length of storage. The colouration of the solutions is of no significance for the efficacy or tolerance of the medicine.

Intramuscular injection. For IM injection, CEFTRIAXONE FKSA 500 mg is dissolved in 2 mL, and CEFTRIAXONE FKSA 1 g in 3,5 mL, of water for injection or 1 % lidocaine (lignocaine) hydrochloride solution (to reduce pain at the site of injection). CEFTRIAXONE FKSA must be injected well within the body of a relatively large muscle. It is recommended that not more than 1 g be injected at one site. Reconstitution with 1 % lidocaine (lignocaine) (without epinephrine (adrenaline)) has no effect on the absorption or the elimination of CEFTRIAXONE FKSA. The lidocaine solution should never be administered intravenously.

Intravenous injection. For IV injection, CEFTRIAXONE 500 mg FKSA is dissolved in 5 mL, and CEFTRIAXONE 1 g FKSA in 10 mL sterile water for injection. The intravenous administration should be given over 2 to 4 minutes.

Intravenous infusion. The infusion should be given over at least 30 minutes. For IV infusion, CEFTRIAXONE 2 g FKSA is dissolved in 40 mL of one of the following calcium-free infusion solutions: Sodium chloride 0,9 %, sodium chloride 0,45 % + dextrose 2,5 %, dextrose 5 %, dextrose 10 %, dextran 6 % in dextrose 5 %, hydroxy ethyl starch 6-10 % infusion; sterile water for injection. CEFTRIAXONE FKSA solutions should not be mixed with or piggybacked into solutions containing other antimicrobial medicines or into diluent solutions other than those listed above, owing to possible incompatibility. Incompatibilities: See section 6.2

• Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients of CEFTRIAXONE FKSA listed in section 6.1.
• History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial medicine (penicillins, monobactams and carbapenems).
• CEFTRIAXONE FKSA is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age) *.
• CEFTRIAXONE FKSA is also contraindicated in full-term neonates (up to 28 days of age):
• with hyperbilirubinaemia, 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) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a CEFTRIAXONE FKSA calcium salt (see sections 4.4, 4.8 and 6.2).
• * CEFTRIAXONE FKSA can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients. See section 4.4.
• Contraindications to lidocaine (lignocaine) should be excluded before intramuscular injection of CEFTRIAXONE FKSA when lidocaine (lignocaine) solution is used as a solvent (see section 4.4). See information in the Professional Information of lidocaine (lignocaine), especially contraindications.
• CEFTRIAXONE FKSA solutions containing lidocaine (lignocaine) should never be administered intravenously.

Prescribers should adhere to the principles of antibiotic stewardship.

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions have been reported with beta-lactam antibiotics (see section 4.8). Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). In case of severe hypersensitivity reactions, treatment with CEFTRIAXONE FKSA must be discontinued immediately and adequate emergency measures should be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone as in CEFTRIAXONE FKSA, to other cephalosporins or to any other type of beta-lactam medicine. Caution should be used if CEFTRIAXONE FKSA is given to patients with a history of non-severe hypersensitivity to other beta-lactam medicines.

Severe cutaneous adverse reactions (SCAR) such as Stevens Johnson syndrome (SJS), or Lyell's syndrome/toxic epidermal necrolysis (TEN), u201cdrug reaction with eosinophilia and systemic symptomsu201d (DRESS) and generalised exanthematous pustulosis (AGEP) which can be life-threatening or fatal have been reported in association with beta-lactam antibiotics such as CEFTRIAXONE FKSA treatment. The frequency of these events is not known (see section 4.8). When SCAR is suspected CEFTRIAXONE FKSA should be discontinued.

Interaction with calcium-containing products

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described. At least one of them had received ceftriaxone as in CEFTRIAXONE FKSA 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 neonates, treated with ceftriaxone as in CEFTRIAXONE FKSA and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups. In patients of any age CEFTRIAXONE FKSA must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. See section 4.3.

However, in patients older than 28 days of age CEFTRIAXONE FKSA 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 total parenteral nutrition (TPN) solutions, healthcare providers may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of CEFTRIAXONE FKSA is considered necessary in patients requiring continuous nutrition, TPN solutions and CEFTRIAXONE FKSA can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of a TPN solution could be stopped for the period of CEFTRIAXONE FKSA infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2).

Paediatric population

Safety and effectiveness of ceftriaxone as in CEFTRIAXONE FKSA in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that ceftriaxone as in CEFTRIAXONE FKSA, like some other cephalosporins, can displace bilirubin from serum albumin. CEFTRIAXONE FKSA is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section 4.3).

Immune mediated haemolytic anaemia

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterial medicines, including ceftriaxone as in CEFTRIAXONE FKSA (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during ceftriaxone treatment in both adults and children. If a patient develops anaemia while on CEFTRIAXONE FKSA, the diagnosis of a cephalosporin-associated anaemia should be considered and CEFTRIAXONE FKSA discontinued until the aetiology is determined.

Long term treatment

During prolonged treatment complete blood count should be performed at regular intervals.

Colitis/Overgrowth of non-susceptible microorganisms

Antibacterial medicine-associated colitis and pseudo-membranous colitis have been reported and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of CEFTRIAXONE FKSA (see section 4.8). Discontinuation of therapy with CEFTRIAXONE FKSA and the administration of specific treatment for Clostridium difficile should be considered. Medicines that inhibit peristalsis should not be given.

Superinfection with non-susceptible microorganisms may occur as with other antibacterial medicines.

Severe renal and hepatic insufficiency

In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2).

Interference with serological testing

Interference with Coombs tests may occur, as ceftriaxone as in CEFTRIAXONE FKSA may lead to false-positive test results. Ceftriaxone as in CEFTRIAXONE FKSA can also lead to false-positive test results for galactosaemia (see section 4.8). The presence of ceftriaxone as in CEFTRIAXONE FKSA may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute CEFTRIAXONE FKSA 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 FKSA is mixed with calcium-containing solutions in the same intravenous administration line. CEFTRIAXONE FKSA 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 FKSA and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. It has been reported that in vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2).

There have been no reports of an interaction between ceftriaxone as in CEFTRIAXONE FKSA and oral calcium-containing products or interaction between intramuscular ceftriaxone as in CEFTRIAXONE FKSA and calcium-containing products (intravenous or oral).

Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently, and the posology of the anti-vitamin K medicine adjusted accordingly, both during and after treatment with CEFTRIAXONE FKSA (see section 4.8).

There is no evidence that ceftriaxone as in CEFTRIAXONE FKSA increases renal toxicity of aminoglycosides. In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone as in CEFTRIAXONE FKSA. No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone as in CEFTRIAXONE FKSA and potent diuretics (e.g. furosemide). Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of ceftriaxone as in CEFTRIAXONE FKSA. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems. The elimination of CEFTRIAXONE FKSA is not altered by probenecid.

Pregnancy

Safety in human pregnancy has not been established. Ceftriaxone crosses the placental barrier. Adequate data on the use of CEFTRIAXONE FKSA in pregnant women are not available. CEFTRIAXONE FKSA should therefore not be used pregnancy.

Breastfeeding

As ceftriaxone as in CEFTRIAXONE FKSA is excreted in the breast milk at low concentrations, caution is advised in breastfeeding mothers.

Fertility

Reproductive studies have shown no evidence of adverse effects on male or female fertility.

CEFTRIAXONE FKSA may cause dizziness which may influence the ability to drive and use machines (see section 4.8). Patients should not drive or operate machines until they know how CEFTRIAXONE FKSA affects them.

Summary of the safety profile

The most frequently reported adverse reactions for CEFTRIAXONE FKSA are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.

Tabulated list of adverse events

System Organ Class Frequent Less frequent Not known a

Infections and infestations Genital fungal infection, pseudo-membranous colitis b Superinfection b

Blood and lymphatic system disorders Eosinophilia, leucopenia, thrombocytopenia Granulocytopenia, anaemia, coagulopathy Haemolytic anaemia b, agranulocytosis, neutropenia, haematoma or bleeding

Immune system disorders Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity b, Jarisch-Herxheimer reaction b

Nervous system disorders Headache, dizziness, encephalopathy Convulsion

Ear and labyrinth disorders Vertigo

Cardiac disorders Kounis syndrome

Respiratory, thoracic and mediastinal disorders Bronchospasm

Gastrointestinal disorders Diarrhoea b, loose stools Nausea, vomiting Pancreatitis b, stomatitis, glossitis

Hepatobiliary disorders Hepatic enzyme increased Gall bladder precipitation b, kernicterus, hepatitis c, cholestatic hepatitis b,c

Skin and subcutaneous tissue disorders Rash Pruritus, urticaria Stevens Johnson syndrome b, toxic epidermal necrolysis b, erythema multiforme, acute generalised exanthematous pustulosis, DRESS b, exfoliative dermatitis, petechiae, purpura, diaphoresis, flushing

Renal and urinary disorders Haematuria, glycosuria Oliguria, renal precipitation (reversible)

General disorders and administration site conditions Phlebitis, injection site pain, pyrexia, oedema, chills

Investigations Blood creatinine increased False-positive Coombs test b, false-positive galactosaemia test b, false-positive non-enzymatic methods for glucose determination b

Description of selected adverse reactions

Infections and infestations Reports of diarrhoea following the use of ceftriaxone may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted (see section 4.4).

Ceftriaxone-calcium salt precipitation Severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (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 neonates is a result of their low blood volume and the longer half-life of ceftriaxone compared with adults (see sections 4.3, 4.4, and 5.2).

Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g., u2265 80 mg/kg/day or total doses exceeding 10 grams) and who have other risk factors (e.g., dehydration, confinement to bed). This event may be asymptomatic or symptomatic and may lead to ureteric obstruction and postrenal acute renal failure but is usually reversible upon discontinuation of ceftriaxone (see section 4.4).

Precipitation of ceftriaxone-calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. It has been reported in children, prospective studies have shown a variable incidence of precipitation with intravenous application - above 30 % in some studies. The incidence appears to be lower with slow infusion (20 - 30 minutes) (see section 4.2). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone (see section 4.4).

In overdose, symptoms of nausea, vomiting and diarrhoea can occur. There is no specific antidote. Plasma concentrations of ceftriaxone as in CEFTRIAXONE FKSA cannot be reduced by haemodialysis or peritoneal dialysis. Treatment of overdose should be symptomatic.