Ceftriaxone

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

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

In patients with both severe hepatic dysfunction, close clinical monitoring for safety and efficacy is advised.

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 must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid.

In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium.

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

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 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 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 must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing 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.

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 drug adjusted accordingly, both during and after treatment with ceftriaxone.

There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases.

In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown.

In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test results.

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of haemolytic anaemia, including fatalities, have been reported during ceftriaxone treatment in both adults 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.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor of ceftriaxone-related biliary precipitation cannot be ruled out.

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, 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. Discontinuation of therapy with ceftriaxone and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

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

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

When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of ceftriaxone treatment should be considered by the physician based on specific benefit risk assessment.

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone. In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment.

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.

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 diarrhoea 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.

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.

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

Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials.

The following convention has been used for the classification of frequency: Very common (≥1/10), Common (≥1/100 - <1/10), Uncommon (≥1/1000 - <1/100), Rare (≥1/10000 - <1/1000), Not known (cannot be estimated from the available data)

Infections and infestations

Uncommon: Genital fungal infection

Rare: Pseudomembranous colitis

Not Known^a: Superinfection

Blood and lymphatic system disorders

Common: Eosinophilia, Leucopenia, Thrombocytopenia

Uncommon: Granulocytopenia, Anaemia, Coagulopathy

Not Known^a: Haemolytic anaemia, Agranulocytosis

Immune system disorders

Not Known^a: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction, Hypersensitivity

Nervous system disorders

Uncommon: Headache, Dizziness

Not Known^a: Convulsion

Ear and labyrinth disorders

Not Known^a: Vertigo

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm

Gastrointestinal disorders

Common: Diarrhoea, Loose stools

Uncommon: Nausea, Vomiting

Not Known^a: Pancreatitis, Stomatitis, Glossitis

Hepatobiliary disorders

Common: Hepatic enzyme increased

Not Known^a: Gall bladder precipitation, Kernicterus

Skin and subcutaneous tissue disorders

Common: Rash

Uncommon: Pruritus

Rare: Urticaria

Not Known^a: Stevens Johnson Syndrome, Toxic epidermal necrolysis, Erythema multiforme, Acute generalised exanthematous pustulosis

Renal and urinary disorders

Rare: Haematuria, Glycosuria

Not Known^a: Oliguria, Renal precipitation (reversible)

General disorders and administration site conditions

Uncommon: Phlebitis, Injection site pain, Pyrexia

Rare: Oedema, Chills

Investigations

Uncommon: Blood creatinine increased

Not Known^a: Coombs test false positive, Galactosaemia test false positive, Non enzymatic methods for glucose determination false positive

^a Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

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.

Ceftriaxone-calcium salt precipitation

Rarely, 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.

Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. ≥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.

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily 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 – above 30% in some studies. The incidence appears to be lower with slow infusion (20-30 minutes). 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.