Roche Rocephin Ceftriaxone Injection

Rocephin®

Ceftriaxone

Composition

Active ingredient: ceftriaxone (as the disodium salt).

Rocephin contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone.

Pharmaceutical form and quantity of active substance per unit

250mg i.v.

Dry substance: ceftriaxone 250 mg as disodium ceftriaxone per vial.

Solvent: water for injection 5 ml.

250 mg i.m.

Dry substance: ceftriaxone 250 mg as disodium ceftriaxone per vial.

Solvent: lidocaine hydrochloride 20 mg, water q.s. 2 ml of solution.

500 mg i.v.

Dry substance: ceftriaxone 500 mg as disodium ceftriaxone per vial.

Solvent: water for injection 5 ml.

500mg i.m.

Dry substance: ceftriaxone 500 mg as disodium ceftriaxone per vial.

Solvent: lidocaine hydrochloride 20 mg, water q.s. 2 ml of solution.

1 g i.v.

Dry substance: ceftriaxone 1 g as disodium ceftriaxone per vial.

Solvent: water for injection 10 ml.

1 g i.m.

Dry substance: ceftriaxone 1 g as disodium ceftriaxone per vial.

Solvent: lidocaine hydrochloride 35 mg, water q.s. 3.5 ml of solution.

2 g i.v.

Dry substance: ceftriaxone 2 g as disodium ceftriaxone per vial.

Indications and potential uses

Infections caused by pathogens which are susceptible to ceftriaxone, e.g.:

– Respiratory tract infections, particularly pneumonia, and ear, nose and throat infections.

– Abdominal infections (peritonitis, infections of the biliary and gastrointestinal tracts).

– Renal and urinary tract infections.

– Infections of the genital organs, including gonorrhea.

– Sepsis.

– Infections of the bones, joints, soft tissue and skin, and wound infections.

– Infections in patients with impaired immune response.

– Meningitis.

– Disseminated Lyme borreliosis (stages II and III). Perioperative prophylaxis of infections in operations on the gastrointestinal tract, biliary tract and urogenital tract and in gynecological procedures, but only in cases of potential or known contamination.

Official recommendations on appropriate use of antibiotics should be observed, in particular recommendations on how to prevent increased antibiotic resistance.

Dosage and administration

Dosage

Adults and children over 12 years

The usual dosage is 1-2 g of Rocephin once daily (every 24 hours). In severe cases or in infections caused by only moderately sensitive organisms, the dosage may be increased to 4 g once daily.

Neonates, infants and children up to 12 years

The following dosage guidelines are recommended for once-daily administration:

Neonates (up to 14 days)

A daily dose of 20-50 mg/kg bodyweight; 50 mg/kg should not be exceeded. It is not necessary to differentiate between premature infants and those born at term.

Rocephin is contraindicated in neonates (28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as in parenteral nutrition, because of the risk of calcium ceftriaxone precipitation (see Contraindications).

Infants and children (15 days to 12 years)

A daily dose of 20-80 mg/kg.

For children with a body weight of 50 kg or more, the usual adult dosage should be used.

Intravenous doses of 50 mg or more per kg body weight should be given by slow infusion over at least 30 minutes.

Elderly patients

The dosages recommended for adults require no modification in the case of geriatric patients.

Duration of therapy

The duration of therapy varies with the indication and the course of the disease.

Combination therapy

Synergy between Rocephin and aminoglycosides has been demonstrated with many gram-negative bacteria under experimental conditions. Although enhanced activity of such combinations is not always predictable, combination should be considered in severe, life-threatening infections due to microorganisms such as Pseudomonas aeruginosa. Because of physical incompatibility, the two drugs must be administered separately at the recommended dosages.

Special dosage instructions

Meningitis

In the case of bacterial meningitis in infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 g) once daily. Once the pathogen has been identified and its sensitivity determined, the dosage can be reduced accordingly. Best results have been achieved with the following durations of therapy:

Neisseria meningitidis 4 days
Haemophilus infiuenzae 6 days
Streptococcus pneumoniae 7 days

Lyme borreliosis

The dosage in Lyme borreliosis is 50 mg/kg up to a maximum of 2 g in children and adults, administered once daily for 14 days.

Gonorrhea

For the treatment of gonorrhea (penicillinase-producing and non-penicillinase-producing strains), a single i.m. dose of 0.25 g Rocephin is recommended.

Perioperative prophylaxis

To prevent postoperative infection in contaminated or potentially contaminated operations, a single dose of 1-2 g Rocephin – depending on the risk of infection – is recommended for administration 30-90 minutes prior to surgery. In colorectal surgery, simultaneous administration of Rocephin and a 5-nitroimidazole, e.g. ornidazole, has proven effective.

Impaired renal and hepatic function

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

In dialysis patients no additional administration is required following dialysis. Rather, plasma concentrations in these patients should be monitored, as the elimination rate may be reduced.

The daily dose should not exceed 2 g in dialysis patients. In patients with liver damage there is no need to reduce the dosage of Rocephin, provided renal function is not impaired. In concomitant severe renal and hepatic dysfunction, plasma concentrations of ceftriaxone should be determined at regular intervals. Dose adjustments may become necessary, as the elimination rate in these patients may be reduced.

Administration instructions: see Additional information / Instructions for use and handling.

Contraindications

Known hypersensitivity to cephalosporin antibiotics. Patients with penicillin hypersensitivity may also have allergic reactions to Rocephin.

Neonates in the case of:

• Hyperbilirubinemia, because ceftriaxone displacement of bilirubin from its binding to serum albumin causes a risk of bilirubin encephalopathy.

• Parenteral calcium therapy, because precipitation of ceftriaxone calcium salts causes a risk of fatal organ damage to kidneys and lungs.

Premature infants:

• Because ceftriaxone displacement of bilirubin from its binding to serum albumin causes a risk of bilirubin encephalopathy.

A small number of cases with fatal outcome in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Rocephin and calcium-containing solutions. In some of these cases the same infusion line was used for Rocephin and calcium-containing solutions, and in some a precipitate was found in the infusion line. At least one fatality has been reported in a neonate to whom Rocephin and calcium-containing solutions were administered at different time points and via different infusion lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates (see Undesirable effects).

Warnings and precautions

As with other cephalosporins, anaphylactic reactions with fatal outcome have been reported, even in patients not known to be allergic or previously exposed. Should allergic reactions occur, Rocephin must be discontinued immediately and appropriate therapy initiated. Ceftriaxone may prolong prothrombin time. Prothrombin time should therefore be checked if vitamin K deficiency is suspected.

An immune-mediated hemolytic anemia has been observed in patients receiving cephalosporin-class antibiotics including Rocephin. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of cephalosporin-associated anemia should be considered and ceftriaxone discontinued until the etiology has been determined.

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 up to 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. Antiperistaltic drugs are contraindicated in this case. During long-term use of Rocephin, non-susceptible microorganisms may become difficult to control. Close patient supervision is therefore essential.

Appropriate measures must be taken if superinfection occurs during treatment. Shadows that may be mistaken for gallstones have been detected in ultrasound scans of the gallbladder. Such shadows generally consist of precipitates of the calcium salt of ceftriaxone. These precipitates usually occur following doses higher than the recommended dose. The shadows disappear on completion or discontinuation of Rocephin therapy.

Rarely, these findings have been associated with symptoms. In symptomatic cases conservative, nonsurgical management is recommended. Discontinuation of Rocephin in symptomatic cases should be at the discretion of the doctor. Rare cases of pancreatitis possibly due to cholestasis have been reported in patients treated with Rocephin. At interview most of the patients concerned were found to have risk factors for cholestasis and biliary sludge, e.g. extensive previous treatment, serious disease or total parenteral nutrition. The possibility that gallbladder precipitates due to Rocephin may act as triggers or cofactors cannot be ruled out. Ceftriaxone can displace bilirubin from its binding to serum albumin. Treatment of hyperbilirubinemic neonates is therefore contraindicated (see Contraindications). Blood counts should be performed at regular intervals during prolonged treatment.

Caution is advised in patients with impaired renal function receiving concomitant treatment with aminoglycosides and diuretics.

Ceftriaxone must not be mixed or administered concurrently with calcium-containing solutions, even if the solutions are given via different infusion lines. Cases of fatal reactions due to calcium ceftriaxone precipitates in lungs and kidneys have been described in neonates, even when different infusion lines and times of administration were used for ceftriaxone and the calcium-containing solutions. For this reason intravenous calcium-containing solutions must not be administered to neonates for at least 48 hours after the last dose of Rocephin (see Contraindications).

Cases of intravascular ceftriaxone calcium precipitation after concomitant use of ceftriaxone with intravenous calcium- containing solutions have not been reported in other age groups. Nevertheless, co-administration should be avoided in all patients.

Interactions

No impairment of renal function has been observed after simultaneous administration of large doses of Rocephin and potent diuretics such as furosemide. No disulfiram-like effect has been demonstrated following administration of Rocephin and ingestion of alcohol. Ceftriaxone does not contain the N-methylthiotetrazole moiety that has been associated with ethanol intolerance and bleeding problems with use of certain other cephalosporins.

Probenecid does not influence the elimination of ceftriaxone. There is no evidence that Rocephin increases the renal toxicity of aminoglycosides. Nevertheless, the two products must be administered separately (see Additional information / Incompatibilities).

Bacteriostatic drugs can interfere with the bactericidal action of cephalosporins.
Antagonistic effects were observed in an in vitro study of ceftriaxone in combination with chloramphenicol.

Diluents containing calcium (e.g. Ringer’s solution or Hartmann’s solution) must not be used to reconstitute Rocephin vials or to further dilute a reconstituted vial for intravenous administration because precipitates may form. Calcium ceftriaxone precipitates may also form when Rocephin is mixed with calcium-containing solutions in the same infusion line. Rocephin must not be administered simultaneously with calcium-containing infusion solutions, including continuous calcium-containing infusions such as in parenteral nutrition via a Y-site. However, in patients other than neonates, Rocephin and calcium-containing solutions may be administered consecutively if the infusion lines are thoroughly flushed between infusions with a compatible solution. In vitro studies using plasma from adults and neonatal cord blood demonstrated that neonates have an increased risk of calcium ceftriaxone precipitation (see Dosage and administration and Contraindications).

There are no reports of interactions between ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (intravenous or oral).

Pregnancy and lactation

Pregnancy

Ceftriaxone crosses the placental barrier (see Pharmacokinetics /Distribution). No controlled clinical studies are available. Although no evidence of teratogenicity was detected in the relevant preclinical studies, Rocephin should only be used in pregnancy, particularly in the first three months, if there is a compelling indication for its use.

Lactation

As ceftriaxone is excreted – albeit in low concentrations – in breast milk, the product should not be used by nursing mothers. Where treatment is absolutely essential, breastfeeding should be stopped.

Effects on ability to drive and use machines

No relevant studies have been performed.

Because of possible side effects such as dizziness, the ability to drive motor vehicles and operate machines may be impaired by Rocephin.

Undesirable effects

The following side effects, which subsided either spontaneously or after withdrawal of the drug, have been observed during the use of Rocephin:

Infections

Rare

Mycosis of the genital tract, superinfection with non- susceptible organisms.

Blood and lymphatic system

Common

Eosinophilia, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, prolongation of prothrombin time.

Rare

Elevation of serum creatinine.

Very rare

Coagulation disorders.

Very rarely, cases of agranulocytosis (< 500/mm3) have been observed, mostly following a total dose of 20 g or more.

Blood counts should be performed at regular intervals during prolonged treatment. Slight prolongation of prothrombin time has been reported.

Gastrointestinal disturbances

Common

Loose stools/diarrhea, nausea, vomiting, stomatitis, glossitis.

Rare

Pancreatitis, possibly due to bile duct obstruction. Most of the patients concerned had risk factors for cholestasis and biliary sludge, e.g. preceding major surgery, serious disease or total parenteral nutrition. The possibility that Rocephin may act as a trigger or cofactor in the formation of gallbladder precipitates cannot be ruled out.

Very rare

Pseudomembranous enterocolitis.

Liver and gallbladder

Very common

Symptomatic precipitation of ceftriaxone calcium salt in the gallbladder of children, reversible cholelithiasis in children.

This disorder occurs rarely in adults (see Warnings and Precautions).

Common

Increase in serum liver enzymes (AST [SGOT], ALT [SGPT], alkaline phosphatase).

Skin

Common

Rash, allergic dermatitis, pruritus, urticaria, edema.

Very rare

Severe skin reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis).

Kidneys and urinary tract

Rare

Oliguria.

Very rare

Renal precipitates have been reported, mostly in children aged over 3 years who were treated with either high daily doses (e.g. ≥ 80 mg/kg/day) or total doses in excess of 10 g and who had additional risk factors (e.g. reduced fluid intake, confinement to bed, etc.). This side effect may or may not give rise to clinical manifestations, can lead to renal failure, and is reversible upon discontinuation of Rocephin.

General disturbances and administration site reactions

Rare

Headache, dizziness, fever, chills. Anaphylactic or anaphylactoid reactions.

Vein wall inflammatory reactions after i.v. administration. These may be minimized by slow (2-4 minutes) injection of the substance.

Intramuscular injection without lidocaine solution is painful.

Interactions with calcium

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood, have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dl). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dl) or higher in adult plasma or 4 mM (16 mg/dl) or higher in neonatal plasma. This may be reflective of calcium ceftriaxone precipitation.

A small number of cases with fatal outcome in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Rocephin and calcium-containing solutions. In some of these cases the same infusion line was used for Rocephin and calcium- containing solutions, and in some a precipitate was found in the infusion line. At least one fatality has been reported in a neonate to whom Rocephin and calcium-containing solutions were administered at different time points and via different infusion lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates (see Warnings and precautions).

Overdosage

Excessive plasma concentrations of ceftriaxone cannot be reduced by hemodialysis or peritoneal dialysis. Symptomatic measures are recommended for the treatment of patients following overdosage.

Properties and effects

ATC code: J01DD04

Mechanism of action/Pharmacodynamics

The bactericidal efficacy of ceftriaxone results from inhibition of cell wall synthesis.

Ceftriaxone exerts broad-spectrum activity in vitro against gram-negative and gram-positive microorganisms. Ceftriaxone is highly stable to most β-lactamases – both penicillinases and cephalosporinases – of gram-positive and gram-negative bacteria.

Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see Indications and potential uses):

Gram-positive aerobes Median values
MIC50* (in mg/l) MIC90**
(in mg/l)
Staphylococcus aureus (methicillin-sensitive) 4 4
Staphylococci, coagulase-negative 4 16
Streptococcus pyogenes (beta-hemolytic, group A) 0.03 0.03
Streptococcus agalactiae (beta-hemolytic, group B) ≤ 0.06 0.06
Streptococci, beta-hemolytic (non group A or B) ≤ 0.06 0.06
Streptococcus viridans 0.125 0.5
Streptococcus pneumoniae ≤ 0.06 0.06

* MIC50 = Minimum inhibitory concentration for 50% of tested strains
** MIC90 = Minimum inhibitory concentration for 90% of tested strains

Gram-negative aerobes Median values
MIC50* (in mg/l) MIC90**
(in mg/l)
Acinetobacter iwoffii 2 8
Acinetobacter anitratus1 (mostly A. baumanii) 8 34
Aeromonas hydrophila 0.25 4
Alcaligenes faecalis 1 8
Alcaligenes odorans ≤ 0.25 0.5
Alcaligenes-like bacteria ≤ 0.25 0.5
Borrelia burgdorferi ≤ 0.06 ≤ 0.06
Burkholderia cepacia 2 16
Capnocytophaga spp. ≤ 0.06 4
Citrobacter diversus (including C. amalonaticus) 0.125 0.125
Citrobacterfreundii1 0.125 16
Escherichia coli ≤ 0.06 0.125
Enterobacter aerogenes1 2 16
Enterobacter cloacae1 0.5 16
Enterobacter spp. (other)1 0.25 32
Haemophilus ducreyi 0.004 0.004
Haemophilus influenza ≤ 0.008 0.06
Haemophilus parainfluenzae 0.016 0.06
Hafnia alvei 0.125 2
Kiebsiella oxytoca ≤ 0.06 0.125
Kiebsiella pneumoniae2 ≤ 0.06 0.125
Moraxella catarrhalis (formerly Branhamella catarr.) 0.125 0.5
Moraxella osloensis ≤ 0.25 ≤ 0.25
Moraxella spp. (other) ≤ 0.25 ≤ 0.25
Morganella morganii 0.06 1
Neisseria gonorrhoeae ≤ 0.008 0.06
Neisseria meningitides ≤ 0.008 0.008
Pasteurella multocida ≤ 0.06 0.06
Plesiomonas shigelloides ≤ 0.06 0.06
Proteus mirabilis ≤ 0.06 0.06
Proteus penneri1 1 64
Proteus vulgaris ≤ 0.06 2
Pseudomonas fluorescens1 16 64
Pseudomonas spp. (other)1 8 16
Providencia rettgeri ≤ 0.06 2
Providencia spp. (other) ≤ 0.06 0.5
Salmonella typhi ≤ 0.06 0.125
Salmonella spp. (enteritidis group) ≤ 0.06 0.06
Serratia marcescens 0.5 2
Serratia spp. (other) 0.25 16
Shigella spp. 0.03 0.25
Vibrio spp. ≤ 0.06 0.25
Yersinia enterocolitica ≤ 0.125 0.125
Yersinia spp. (other) 0.25 2
Anaerobes Median values
MIC50
(in mg/l)
MIC90
(in mg/l)
Bacteroides spp.3 (bile-sensitive) 2 16
Clostridium spp. (excluding the C. perfringens group) 2 16
Fusobacterium nucleatum 1 2
Fusobacterium spp. (other) 0.125 0.25
Gaffkia anaerobica (formerly Peptococcus) 0.125 1
Peptostreptococci 0.125 1

Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardized techniques for susceptibility testing such as those recommended by the Clinical and Laboratory Standards Institute (CLSI). The CLSI issued the following interpretative breakpoints for tests with ceftriaxone:

Susceptible Moderately susceptible Resistant
Dilution test Inhibitory concentrations in mg/l ≤ 8 16-32 ≥ 64
Dffusion test
(disk with 30 µg
ceftriaxone) ≤Inhibition zone diameter in mm
≥ 21 20-14 ≤ 13

Microorganisms should be tested with the ceftriaxone disk, since in vitro tests have shown ceftriaxone to be active against certain strains resistant to cephalosporin class disks. Instead of CLSI recommendations, alternative standardized guidelines such as those issued by DIN or ICS can be used to determine resistance.

Resistances

1) Some isolates of these species are resistant to ceftriaxone due to derepression of chromosomal β-lactamase.

2) Some isolates of Klebsiella pneumoniae are resistant to ceftriaxone due to plasmid-dependent β-lactamase production.

3) Some isolates of Bacteroides spp. are resistant to ceftriaxone.
Many strains of β-lactamase-producing Bacteroides spp. (notably B. fragilis) are resistant.

Clostridium difficile is resistant.

Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. In general, Enterococcus faecalis, Enterococcus faecium and Listeria monocytogenes are resistant.

Many strains of gram-negative aerobes that possess multiple resistance to other antibiotics, e.g. aminopenicillins and ureidopeniciliins, older cephalosporins and aminoglycosides, are susceptible to ceftriaxone. Treponema pallidum is sensitive in vitro and in animal experiments. Clinical trials indicate that primary and secondary syphilis respond well to ceftriaxone therapy.

With few exceptions, clinical isolates of Pseudomonas aeruginosa are resistant to ceftriaxone.

Pharmacokinetics

The pharmacokinetics of ceftriaxone are nonlinear. All pharmacokinetic parameters other than elimination half-life are dose-dependent if referred to total concentration (free and protein-bound ceftriaxone).

Absorption

After a single i.m. injection of 1 g ceftriaxone, a peak plasma concentration of 81 mg/l was reached after 2-3 h. After a single i.v. infusion of 1 g, a concentration of
168.1 ± 28.2 mg/l was reached after 30 mm. After a single i.v. infusion of 2 g, a concentration of 256.9 ± 16.8 mg/l was reached after 30 mm.

The areas under the plasma concentration-time curves after i.v. and i.m. administration are identical. This means that the bioavailability of intramuscularly administered ceftriaxone is 100%.

Distribution

The distribution volume is between 7 and 121.

On intravenous administration ceftriaxone diffuses rapidly into interstitial body fluid, where bactericidal concentrations against susceptible organisms are maintained for 24 hours. After a dose of 1-2 g, ceftriaxone shows good penetration into tissue and body fluids. Concentrations above the minimal inhibitory concentrations for most pathogens are maintained for more than 24 hours in over 60 tissues or body fluids, including lung, heart, biliary tract, liver, middle ear, nasal mucosa and bone as well as cerebrospinal, pleural, synovial and prostatic fluid.

Ceftriaxone is reversibly bound to albumin, the degree of binding decreasing with increasing concentration. Thus, binding decreases from 95% at a plasma concentration of <100 mg/i to 85% at 300 mg/i. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Cefiriaxone penetrates the inflamed meninges of neonates, infants and children. Peak concentration in CSF is reached about 4 hours after i.v. injection and on average is 18 mg/l with a dose of 50-100 mg/kg. The average concentration in CSF during bacterial meningitis is 17% of the plasma concentration; in aseptic meningitis it is 4%.

24 hours after i.v. injection of Rocephin in doses of 50-100 mg/kg bodyweight, ceftriaxone concentrations > 1.4 mg/l were measured in CSF.

In adult patients with meningitis, administration of 50 mg/kg leads within 2-24 hours to CSF concentrations several times higher than the minimum inhibitory concentrations required for the most common causative organisms of meningitis.

Ceftriaxone crosses the placental barrier. Ceftriaxone is excreted in breast milk at low concentrations (3-4% of maternal plasma concentrations after 4-6 hours).

Metabolism

Ceftriaxone is not metabolized in the organism itself. Only following biliary excretion into the intestinal lumen does the intestinal flora transform the active ingredient into inactive metabolites.

Elimination

Plasma clearance is 10-22 ml/min.

Renal clearance is 5-12 ml/min.

50-60% of ceftriaxone is excreted unchanged via the kidneys, while 40-50% is excreted unchanged in the bile.

The plasma half-life in adults is about 8 hours.

Pharmacokinetics in special patient groups

In neonates, renal elimination accounts for about 70% of the dose.

In infants aged less than 8 days and in persons aged over 75 years, the average plasma half-life is approximately 2-3 times that in healthy young adults.

In patients with mild to moderate renal failure or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only slightly altered. The plasma half-life is minimally increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased, whereas if liver function alone is impaired, renal elimination is increased.

Preclinical data

Teratogenicity

No embryotoxic or teratogenic effects of Rocephin were found in studies in mice, rats and monkeys.

Additional information

Incompatibilities

Rocephin should not be added to calcium-containing solutions such as Hartmann’s solution or Ringer’s solution. Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

Rocephin may be mixed only with the medicines specified in Instructions for use and handling.

Influence on diagnostic methods

During treatment with Rocephin the Coombs’ test may rarely become false-positive. Rocephin, like other antibiotics, may result in false-positive tests for galactosemia.
Likewise, non-enzymatic methods for the determination of glucose in urine may give false-positive results. For this reason, urinary glucose determination during therapy with Rocephin should be done enzymatically.

Stability

This medicine must not be used after the expiry date (EXP) shown on the pack.

Reconstituted solutions retain their physical and chemical stability for 6 hours at room temperature (or 24 hours in the refrigerator at 2-8°C).

Special precautions for storage

Do not store above 30°C. Keep the container in the outer carton to protect the contents from light.

Instructions for use and handling

Reconstituted solutions must be used immediately after preparation. They range in colour from pale yellow to yellow-brown, depending on the concentration. This characteristic of the active ingredient is of no significance for the efficacy or tolerability of the drug.

Special precautions for storage

Do not store above 30°C. Keep the container in the outer carton to protect the contents from light.

Instructions for use and handling

Reconstituted solutions must be used immediately after preparation. They range in colour from pale yellow to yellow-brown, depending on the concentration. This characteristic of the active ingredient is of no significance for the efficacy or tolerability of the drug.

Intramuscular injection

For i.m. injection, Rocephin 0.25 g is dissolved in 2 ml, and Rocephin 1 g in 3.5 ml, of 1% lidocaine solution and injected well within a relatively large mass of muscle. It is recommended that not more than 1 g be injected at one site. The lidocaine-containing solution must never be administered intravenously.

Intravenous injection

For i.v. injection, Rocephin 0.5 g is dissolved in 5 ml, and Rocephin 1 g in 10 ml, water for injections and injected intravenously over a period of 2-4 minutes.

Intravenous infusion

The infusion should last at least 30 minutes. For i.v. infusion, 2 g Rocephin is dissolved in 40 ml of one of the following calcium-free infusion solutions: sodium chloride 0.9%, sodium chloride 0.45% + glucose 2.5%, glucose 5%, glucose 10%, dextran 6% in glucose 5%, hydroxyethyl starch 6-10%, water for injections.

Owing to possible incompatibility, Rocephin solutions should not be mixed with or piggy-backed into solutions containing other antibiotics. Similarly, they must not be added to diluent solutions other than those listed above. Nevertheless, 2 g ceftriaxone and 1 g ornidazole are physically and chemically compatible in 250 ml
physiological sodium chloride or glucose solution.

Diluents containing calcium (e.g. Ringer’s solution or Hartmann’s solution) must not be used to reconstitute Rocephin vials or to further dilute a reconstituted vial for intravenous administration because precipitates may form. Calcium ceftriaxone precipitates may also form when Rocephin is mixed with calcium-containing solutions in the same infusion line. Rocephin must not be administered simultaneously with calcium-containing infusion solutions, including continuous calcium-containing infusions such as in parenteral nutrition via a Y-site. However, in patients other than neonates, Rocephin and calcium-containing solutions may be administered consecutively if the infusion lines are thoroughly flushed between infusions with a compatible solution (see Interactions, for interactions with other medicinal products and other forms of interaction).

Disposal of unused or expired medicinal products

The release of pharmaceutical preparations into the environment should be reduced to a minimum. Medicinal products should not be disposed of via the wastewater system and disposal in domestic waste should be avoided. Any medicinal products unused after the end of treatment or by the expiry date should be returned in their original packaging to the place of supply (physician or pharmacist) for proper disposal.

Packs

Packs for i.m. injection containing:

1 vial with active ingredient dry substance equivalent to 0.25 g, 0.5 g or 1 g ceftriaxone, and 1 ampoule of 2 ml or 3.5 ml 1% lidocaine solution

0.25 g vials 1,5,50

0.5 g vials 1,5,50

1 g vials 1,5,50

Packs for i.v. injection containing:

1 vial with active ingredient dry substance equivalent to 0.25 g, 0.5 g or 1 g ceftriaxone, and 1 ampoule of 5 ml or 10 ml water for injections

0.25 g vials 1,5,50

0.5 g vials 1,5,50

1 g vials 1,5,50

Packs for i.v. infusion containing:

1 vial with active ingredient dry substance equivalent to 2 g ceftriaxone

2 g vials 1,50

This is a medicament

A medicament is a product which affects your health, and its consumption contrary to instructions is dangerous for you. Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist who sold the medicament.

The doctor and the pharmacist are experts in medicine, its benefits and risks.

Do not by yourself interrupt the period of treatment prescribed for you.

Do not repeat the same prescription without consulting your doctor.

Medicine: keep out of reach of children

Council of Arab Health Ministers Union of Arab Pharmacists

Current at February 2010

Made in Switzerland by F. Hoffmann-La Roche Ltd, Basel manufacturing site Kaiseraugst