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ALCEF 500 (Ceftriaxone for Injection USP 500mg)

Pharmacotherapeutic group: Antibacterials for systemic use, Third-generation Cephalosporins

ATC Code: J01DD04

Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

Therapeutic indications

Ceftriaxone sodium is a broad-spectrum bactericidal cephalosporin antibiotic. Ceftriaxone is active in vitro against a wide range of Gram-positive and Gram negative organisms, which β-lactamase producing strains. Ceftriaxone is indicated in the treatment of the following infections either before the infecting organism has been identified or when known to be caused by bacteria of established sensitivity.

Pneumonia
Septicaemia
Meningitis
Skin and soft tissue infections
Infections in neutropenic patients
Gonorrhea

Peri-operative prophylaxis of infections associated with surgery. Treatment may be started before the results of susceptibility tests are known. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Resistance

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

hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases and Amp C enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacteria species.
reduced affinity of penicillin-binding proteins for ceftriaxone.
outer membrane impermeability in Gram-negative organisms.
bacterial efflux pumps.

Posology and method of administration Posology

Adults and children 12 years and over: Standard therapeutic dosage: 1g once daily. Severe infections: 2-4 g daily, normally as a once daily dose.

The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Acute, uncomplicated gonorrhoea: One dose of 250mg intramuscularly should be administered.

Simultaneous administration of probenecid is not indicated.

Peri-operative prophylaxis: Usually one dose of 1g given by intramuscular or slow intravenous injection. In colorectal surgery, 2g should be given intramuscularly (in divided doses at different injection sites), by slow intravenous injection or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.

Elderly: These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory.

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.

Paediatric Population

Children under 12 years

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

Up to 80mg/kg body-weight daily may be given in severe infections, except in premature neonates where a daily dosage of 50mg/kg should not be exceeded. For children with body weights of 50kg or more, the usual dosage should be used. Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.

Hepatic impairment: Available data do not indicate the need for dose adjustment in mild or moderateliverfunction impairment provided renal function is not impaired.There are no study data in patients with severe hepatic impairment.

Renal impairment: In patients with impaired renal function, there is no need to reduce the dosage ofceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renalfailure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not exceed 2 gdaily.

In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Ceftriaxone is not removed by peritoneal- or haemodialysis. Close clinical monitoring for safety and efficacy is advised.

Patients with severe hepatic and renal impairment: In patients with both severe renal and hepatic dysfunction, close clinical monitoring forsafety and efficacy is advised.

Contraindications

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

History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of betalactam antibacterial agent (penicillins, monobactams and carbapenems).

Ceftriaxone is contraindicated in:

Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
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 calciummcontaining infusions due to the risk of precipitation of a ceftriaxone-calcium salt.

In vitro studies have shown that ceftriaxone can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients.

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

Ceftriaxone solutions containing lidocaine should never be administered intravenously

Special warnings and precautions for use

Hypersensitivity reactions: As with all beta-lactam antibacterial agents, serious and occasionally fatalhypersensitivity reactions have been reported. In case of severe hypersensitivityreactions, treatment with ceftriaxone must be discontinued immediately and adequateemergency measures must be initiated. Before beginning treatment, it should beestablished whether the patient has a history of severe hypersensitivity reactions toceftriaxone, to other cephalosporins or to any other type of beta-lactam agent. Cautionshould be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of these events is not known.

Interaction with calcium containing products: Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys inpremature and full-term neonates aged less than 1 month have been described. At leastone of them had received ceftriaxone and calcium at different times and throughdifferent intravenous lines. In the available scientific data, there are no reports ofconfirmed intravascular precipitations in patients, other than neonates, treated withceftriaxone andcalcium-containing solutions or any other calcium-containing products. In vitro studiesdemonstrated that neonates have an increased risk of precipitation of ceftriaxonecalciumcompared 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 o avoid precipitation.

In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the 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 and the infusion lines flushed between solutions.

Paediatric population: Safety and effectiveness of Ceftriaxone in neonates, infants and children have beenestablished for the dosages described under Posology and Method of Administration.

Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy.

Immune mediated haemolytic anaemia: An immune mediated haemolytic anaemia has been observed in patients receivingcephalosporin class antibacterials including Ceftriaxone. Severe cases of haemolyticanaemia, including fatalities, have been reported during Ceftriaxone treatment in bothadults and children.

If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin associated anaemia should be considered and ceftriaxone 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 agent-associated colitis and pseudo-membranous colitis have beenreported with nearly all antibacterial agents, including ceftriaxone, and may range inseverity from mild to life- threatening. Therefore, it is important to consider this diagnosisin patients who present with diarrhoea during or subsequent to the administration ofceftriaxone.

Discontinuation of therapy with ceftriaxone and the administration ofspecific treatment for Clostridium difficile should be considered. Medicinal products thatinhibit peristalsis should not be given.

Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.

Severe renal and hepatic insufficiency: In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacyis advised.

Interference with serological testing: Interference with Coombs tests may occur, as Ceftriaxone may lead to false-positive testresults. Ceftriaxone can also lead to false-positive test results for galactosaemia.

Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with Ceftriaxone should be done enzymatically.

The presence of ceftriaxone 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.

Sodium: Each gram of ceftriaxone sodium contains approximately 3.6 mmol sodium. Thisshould be taken into consideration in patients on a controlled sodium diet.

Antibacterial spectrum: Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable foruse as a single agent for the treatment of some types of infections unless the pathogenhas already been confirmed. In polymicrobial infections, where suspected pathogensinclude organisms resistant to ceftriaxone, administration of an additional antibioticshould be considered.

Use of lidocaine: In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only beused for intramuscular injection. Contraindications to lidocaine, warnings and otherrelevant information as detailed in the Summary of Product Characteristics of lidocainemust be considered before use. The lidocaine solution should never be administeredintravenously.

Interaction with other medicinal products and other forms of interaction

Calcium-containing diluents, such as 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.

Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.

Likewise, non-enzymatic methods for glucose determination in urine may yield false positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone should be carried out enzymatically. No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g. furosemide). Simultaneous administration of probenecid does not reduce the elimination of Ceftriaxone.

Fertility, pregnancy and lactation

Pregnancy: Ceftriaxone crosses the placental barrier. There are limited amounts of data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development.

Ceftriaxone should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk.

Breastfeeding: Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a risk of diarrhea and fungal infection of the mucous membranes cannot be excluded.

The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

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

Effects on ability to drive and use machines

During treatment with ceftriaxone, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines. Patients should be cautious when driving or operating machinery.

Undesirable effects

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

Overdose

In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

ALCEF 500 (Ceftriaxone for Injection USP 500mg)

ALCEF 500 (Ceftriaxone for Injection USP 500mg)