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4.3 Contraindications
Hypersensitivity to ceftriaxone or to any of the cephalosporins. Rocephin is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics.
Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug. 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.
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).
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.
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 (see Section 4.3). Ceftriaxone should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.
Ceftriaxone should be given with caution to patients who have other allergic diatheses.
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. Rocephin 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.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Rocephin, 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.
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.
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.
As with other cephalosporins, prolonged use of ceftriaxone may result in the overgrowth of non-susceptible organisms, such as enterococci and Candida spp.
In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under section 4.2. In severe renal and hepatic insufficiency, dosage should be reduced according to given recommendations (see section 4.2).
Rocephin may precipitate in the gallbladder 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 Rocephin 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 Rocephin. As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are not normally indicated.
Shadows, which have been mistaken for gallstones are however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of Rocephin therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended.
Discontinuation of Rocephin treatment in symptomatic cases should be at the discretion of the physician.
Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug to produce a positive Coombs’ test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Rocephin. 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 Rocephin-related biliary precipitation can not be ruled out.
Safety and effectiveness of Rocephin in neonates, infants and children have been established for the dosages described under Dosage and administration. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.
During prolonged treatment a 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.
The stated dosage should not be exceeded.
Each gram of Rocephin contains approximately 3.6mmol sodium. To 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 so far been observed in man after simultaneous administration of Rocephin with diuretics. after concurrent administration of large doses of Rocephin and potent diuretics (e.g. furosemide).
No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with Rocephin.
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. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Rocephin. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins. The elimination of Rocephin is not altered by probenecid.
In vitro, chloramphenicol has been shown to be antagonistic with respect to ceftriaxone and other cephalosporins. 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, but caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.
Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Rocephin is mixed with calcium-containing solutions in the same IV administration line. Rocephin 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, Rocephin 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.
Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.
In patients treated with Rocephin, the Coombs’ test may rarely become false-positive. Rocephin, like other antibiotics, may 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 Rocephin 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.
4.7 Effects on ability to drive and use machines
Not applicable Since Rocephin sometimes induces dizziness the ability to drive and use machines can be impaired.
4.8 Undesirable effects
Gastrointestinal disorders
Common (³ 1% - < 10%): Loose stools or diarrhoea, nausea, vomiting.
Rare (³ 0.01% - < 0.1%): Stomatitis, glossitis. These side effects are usually mild and commonly disappear during treatment or after discontinuation of treatment.
Very rare (< 0.01%) including isolated reports: Pseudomembranous colitis (mostly caused by Clostridium difficile), pancreatitis (possibly caused by obstruction of bile ducts). Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use.
An intramuscular injection without lidocaine solution is painful.
4.9 Overdose
In the case of overdose nausea, vomiting, diarrhoea, can occur.In the case of overdosage, drug Ceftriaxone concentrations would can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment should be is symptomatic.
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