Rocephin Range 250 mg. 500 mg. 1 g. 2 g Injection

Rocephin 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 meningitides 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 Rocephin may reduce the incidence of post-operative infections.

Posology

Standard 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 moderately sensitive organisms, the dosage may be raised to 4 g, once daily. Refer below to Special dosage instructions for other patient populations.

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

Combination treatment

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, it should be considered in severe, life threatening infections due to microorganisms such as Pseudomonas aeruginosa. Due to chemical incompatibility between Rocephin and aminoglycosides, the two medicines must be administered separately at the recommended dosages. Chemical incompatibility with Rocephin has also been observed with IV administration of amsacrine, vancomycin and fluconazole.

Special dosage instructions

Pediatric use

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. Rocephin is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age) (see section 4.3 contraindications). Rocephin is contraindicated in neonates (u2264 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see sections 4.3, 4.4 and 4.8). For neonates, 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, in infants and children up to 12 years of age should be given by infusion over at least 30 minutes. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy.

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 children with bodyweights of 50 kg or more, the usual adult dosage should be used.

Geriatric use

No dose adjustment of Rocephin is required in patients u2265 65 years of age provided there is no severe renal and hepatic impairment.

Hepatic impairment: No dose adjustment is required, provided renal function is not impaired.

Renal impairment: In patients with impaired renal function there is no need to reduce the dosage of Rocephin, No dose adjustment of Rocephin is required, provided hepatic function is not impaired. In cases of severe renal failure (creatinine clearance < 10 mL/min) the Rocephin dosage should not exceed 2 g daily. In patients with both severe renal and hepatic dysfunction, the plasma concentrations of ceftriaxone should be determined at regular intervals and if necessary the dose should be adjusted.

Dialysis: Rocephin is not removed by peritoneal- or hemodialysis. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Plasma concentrations should however be monitored, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be altered.

Severe renal and hepatic impairment

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

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.

Lyme borreliosis: 50 mg/kg to a maximum of 2 g in children and adults, once daily for 14 days.

Gonorrhoea: In the treatment of uncomplicated gonorrhoea (penicillinase-producing and non-penicillinase-producing strains) a single IM dose of 250 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 Rocephin with or without a 5-nitroimidazole, e.g. ornidazole (separate administration, see Method of administration below) has been proven effective.

Method of administration: Rocephin must be reconstituted prior to use. As a general rule the solutions should be used immediately after preparation. Reconstituted solutions retain their physical and chemical stability for 6 hours at room temperature (or 24 hours in the refrigerator at 2 - 8 u00b0C). 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, Rocephin 250 mg and 500 mg is dissolved in 2 mL; Rocephin 1 g in 3,5 mL of water for injections. In adults, intramuscular administrations of some cephalosporins, including Rocephin, cause pain at the injection site. This can be reduced greatly by administering in combination with a local anaesthetic. Rocephin dissolved in 3,5 mL of a 1 % lignocaine (lidocaine) solution instead of water for injections can reduce pain at the site of injection, in adults. It is recommended that no more than 1 g of Rocephin be injected at one site. Safe dose of 1 % lignocaine (lidocaine) has not been established.

Reconstitution with 1 % lignocaine/lidocaine (without adrenaline) has no effect on the absorption or the elimination of Rocephin. The lignocaine (lidocaine) solution should never be administered intravenously (see section 4.3 contraindications).

Intravenous injection: For IV injection, Rocephin 250 mg or 500 mg is dissolved in 5 mL, and Rocephin 1 g in 10 mL water for injections. 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, 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 % + dextrose 2,5 %, dextrose 5 %, dextrose 10 %, dextran 6 % in dextrose 5 %, water for injections. Rocephin 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

Rocephin is contraindicated in patients with known hypersensitivity to ceftriaxone, any of its excipients or to any other cephalosporin. Patients with previous hypersensitivity reactions to penicillin and other beta lactam medicines may be at greater risk of hypersensitivity to ceftriaxone (see section 4.4 Special warnings and precautions for useu2013 Hypersensitivity).

Lidocaine/Lignocaine

Contraindications to lidocaine/lignocaine must be excluded before intramuscular injection of Rocephin when lidocaine solution is used as a solvent (see section 4.2). See the contraindications section in the professional information of lidocaine. Rocephin solutions containing lidocaine should never be administered intravenously.

Premature Neonates

Rocephin is contraindicated in premature neonates up to postmenstrual age of 41 weeks (gestational age + chronological age).

Hyperbilirubinemic newborns

Hyperbilirubinaemic newborns, should not be treated with Rocephin. In vitro studies have shown that Rocephin can displace bilirubin from its binding to serum albumin leading to a possible risk of bilirubin encephalopathy in these patients.

Neonates and Calcium Containing IV Solutions

Rocephin is contraindicated in neonates (u2264 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium. A small number of cases of fatal outcomes with calcium-Rocephin precipitates in the lungs and kidneys have been reported at autopsy in both term and preterm neonates receiving Rocephin and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Rocephin and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate to whom Rocephin and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates, (see sections 4.2, 4.4 and 4.8).

Rocephin must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. Rocephin and IV calcium-containing solutions or products must not be administered within 48 hours of each other.

Precipitation of ceftriaxone-calcium may 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. Fatal outcomes have been reported in neonates receiving Rocephin and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Rocephin and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom Rocephin and calcium-containing fluids were administered at different time points via different intravenous lines. In some cases times of administration of ceftriaxone and calcium-containing solutions differed (see sections 4.2, 4.3, 4.5 and 4.8). Do not use diluents containing calcium, such as Ringeru2019s lactate solution or Hartmannu2019s solution to reconstitute Rocephin. Precipitate formation can result.

There are no reports to date of intravascular or pulmonary precipitations in patients, other than neonates, treated with ceftriaxone and calcium-containing IV solutions. However, the theoretical possibility exists for an interaction between ceftriaxone and IV calcium-containing solutions in patients other than neonates. Therefore, Rocephin and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patients irrespective of age even via different infusion lines at different sites. As a further theoretical consideration and based on 5 half-lives of ceftriaxone, Rocephin and IV calcium-containing solutions should not be administered within 48 hours of each other in any patient (see sections 4.2, 4.3, 4.5 and 4.8).

No impairment of renal function has been observed after concurrent administration of large doses of Rocephin and potent diuretics (e.g. furosemide).

There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins including Rocephin. The recommended monitoring of aminoglycoside levels and renal function in clinical practice should be closely adhered to in such cases. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Rocephin. Rocephin does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems. In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and Rocephin.

Influence on diagnostic tests

In patients treated with Rocephin the Coombs test may become false-positive. Treatment with Rocephin may result in false-positive test for galactosemia. Likewise, non-enzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Rocephin should be done enzymatically. The presence of Rocephin 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.

Interaction with calcium-containing products: Rocephin should not be added to solutions containing calcium. Do not use diluents containing calcium such as Ringeru2019s lactate solution or Hartmannu2019s 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 (see sections 4.2, 4.3, 4.4 and 4.8). Concomitant use of Rocephin with Vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with Rocephin (see section 4.8 Undesirable Effects).

Safety in human pregnancy has not been established. Rocephin crosses the placental barrier. Rocephin is excreted in the breast-milk. Safety in lactation has not been established.

Pregnancy

Rocephin crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity or adverse effects on male or female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.

Lactation

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Rocephin is administered to a nursing woman.

During treatment with Rocephin, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8). Patients should be cautious when driving or operating machinery.

a. Summary of the safety profile: 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.

Tabulated summary of adverse drug reactions from clinical trials

Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (u22651/10), common (u22651/100 to <1/10), uncommon (u22651/1,000 to <1/100), rare (u22651/10,000 to <1/1000).

Table 1 Summary of adverse reactions occurring in patients treated with Rocephin in clinical trials

Adverse reactions Frequency category

• Blood and lymphatic system disorders
• Eosinophilia Common
• Leucopenia Common
• Thrombocytopenia Common
• Granulocytopenia Uncommon
• Anaemia Uncommon
• Coagulopathy Uncommon
• Gastrointestinal disorders
• Diarrhoea Common
• Loose stools Common
• Nausea Uncommon
• Vomiting Uncommon
• General disorders and administration site conditions
• Phlebitis Uncommon
• Injection site reactions Uncommon
• Pyrexia Uncommon
• Oedema Rare
• Chills Rare
• Hepatobiliary disorders
• Hepatic enzyme increased Common
• Infections and infestations
• Genital fungal infection Uncommon
• Pseudo-membranous colitis Rare
• Investigations
• Blood creatinine increased Uncommon
• Nervous system disorders
• Headache Uncommon
• Dizziness Uncommon
• Renal and urinary disorders
• Haematuria Rare
• Glycosuria Rare
• Respiratory, thoracic and mediastinal disorders
• Bronchospasm Uncommon
• Skin and subcutaneous tissue disorders
• Rash Common
• Pruritus Uncommon
• Urticaria Rare

Post Marketing Experience

The following adverse drug reactions have been identified from post marketing experience with Rocephin. Infections and infestations: Superinfection Blood and lymphatic system disorders: Isolated cases of agranulocytosis (< 500/mm3) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more. Coagulation disorders have been reported. Immune system disorders: Anaphylactic or anaphylactoid reactions. Nervous system disorders: Convulsion encephalopathy Reversible encephalopathy has been reported with the use of cephalosporins, including ceftriaxone, particularly when high doses are administered in patients with renal impairment and additional predisposing factors such as older age, pre-existing central nervous system disorders. Gastrointestinal disorders: Pancreatitis, stomatitis, glossitis. Pseudomembranous enterocolitis has been reported. Hepato-biliary disorders: Symptomatic precipitation of ceftriaxone-calcium salt in the gallbladder, kernicterus Skin and subcutaneous tissue disorders: Acute generalised exanthematous pustulosis (AGEP), and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome or Lyellu2019s Syndrome/toxic epidermal necrolysis) have been reported.

In the case of overdosage, plasma concentration would not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.