Kocef 250 mg, 500 mg, 1000 mg, INJECTION

KOCEF 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, Haemophilus influenzae, Escherichia coli, or Klebsiella pneumoniae.
• Meningitis caused by: Haemophilus influenzae, Neisseria meningitidis, or Streptococcus pneumoniae.
• Intra-abdominal infections caused by: Escherichia coli, Klebsiella pneumonia, 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 KOCEF may reduce the incidence of post-operative infections.

Posology

Standard dosage

Adults and children over 12 years. The usual dosage is 1 u2013 2 g KOCEF 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 u201cSpecial dosage instructionsu201d for other patient populations.

Duration of treatment

The duration of treatment varies according to the course of the disease. Administration of KOCEF 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.

Combination treatment

Synergy between KOCEF 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 KOCEF and aminoglycosides, the two medicines must be administered separately at the recommended dosages. Chemical incompatibility with KOCEF has also been observed with IV administration of amsacrine, vancomycin and fluconazole.

Special dosage instructions

Paediatric population

Neonates, infants and children up to 12 years. The following dosage schedules are recommended for once daily administration:

• Neonates (up to 14 days): 20 u2013 50 mg/kg bodyweight once daily. The daily dose should not exceed 50 mg/kg. KOCEF is contraindicated in premature neonates up to corrected age of 41 weeks (gestational age + chronological age) (see section 4.3). KOCEF 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 u2013 80 mg/kg once daily. For children with bodyweights of 50 kg or more, the usual adult dose 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 dose can be adapted accordingly. For children with bodyweights of 50 kg or more, the usual adult dosage should be used.

Elderly population

No dose adjustment of KOCEF 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 KOCEF, provided hepatic function is not impaired. In cases of severe renal failure (creatinine clearance < 10 mL/min) the KOCEF dosage should not exceed 2 g daily.

Dialysis

KOCEF is not removed by peritoneal- or hemo-dialysis. 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, the plasma concentrations of ceftriaxone should be determined at regular intervals and if necessary, the dose should be adjusted. Clinical monitoring for safety and efficacy is advised in these patients.

Meningitis For bacterial meningitis in adults, the recommended dose is 4 g daily. For dosages recommended in children see section u201cPaediatric population: Meningitisu201d above.

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.

Peri-operative infection prophylaxis A single dose of 1 to 2 g, depending on the risk of infection, 30 to 90 minutes prior to surgery. In colorectal surgery, administration of KOCEF with or without a 5-nitroimidazole, e.g. ornidazole (separate administration, see u201cMethod of administrationu201d below) has been proven effective.

Method of administration

Ceftriaxone must be reconstituted prior to use and can be administered by intramuscular or intravenous injection. As a general rule the solutions should be used immediately after preparation. 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.

For instructions on dilution of the product before administration, see section 6.6. For storage instructions after dilution, see section 6.3. If the solvent used for dilution is lidocaine (lignocaine), this solution must never be administered intravenously (see section 4.3).

• Hypersensitivity: known hypersensitivity to ceftriaxone or to any other cephalosporins. 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).
• Lidocaine/lignocaine: contraindications to lidocaine/lignocaine must be excluded before intramuscular injection of KOCEF when lidocaine/lignocaine solution is used as a solvent (see section 4.2). See the contraindications section in the professional information of lidocaine. KOCEF solutions containing lidocaine (lignocaine) should never be administered intravenously.
• Premature neonates: KOCEF is contraindicated in premature neonates up to adjusted age of 41 weeks (gestational age + chronological age).
• Hyperbilirubinemic newborns: hyperbilirubinaemic newborns, should not be treated with KOCEF. In vitro studies have shown that KOCEF 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: KOCEF 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-ceftriaxone precipitates in the lungs and kidneys have been reported at autopsy in both term and preterm neonates receiving KOCEF and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone 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 KOCEF 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).

Interaction with calcium containing products

KOCEF must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. KOCEF and IV calcium-containing solutions or products must not be administered within 48 hours of each other. Precipitation of ceftriaxone-calcium may occur when KOCEF is mixed with calcium-containing solutions in the same IV administration line. KOCEF 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 KOCEF and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both KOCEF 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 KOCEF 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 KOCEF. 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, KOCEF 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, KOCEF 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 data are available on potential interaction between KOCEF and oral calcium-containing products or interaction between intramuscular KOCEF and calcium-containing products (IV or oral).

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). In case of severe hypersensitivity reactions, treatment with KOCEF 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 KOCEF 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 and drug reaction with eosinophilia and systemic symptoms (DRESS)) which can be life-threatening or fatal have been reported in association of ceftriaxone treatment; however, the frequency of these events is not known (see section 4.8).

Paediatric population

Safety and effectiveness of KOCEF in neonates, infants and children have been established for the dosages described under section 4.2. Studies have shown that KOCEF, like some other cephalosporins, can displace bilirubin from serum albumin. KOCEF is contraindicated in neonates (especially prematures) at risk of developing bilirubin encephalopathy (see section 4.3).

Immune mediated haemolytic anaemia

An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including KOCEF (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during KOCEF 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.

Use of lidocaine (lignocaine)

In case a lidocaine (lignocaine) solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Contraindications to lidocaine (lignocaine), warnings and other relevant information as detailed in the professional information of lidocaine (lignocaine) must be considered before use (see section 4.3). The lidocaine (lignocaine) solution should never be administered intravenously.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of KOCEF, and may range in severity from mild diarrhoea to fatal colitis. Treatment with KOCEF 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. Toxin hyperproducing 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 diarrhoea following KOCEF use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial medicines, such as KOCEF.

If CDAD is suspected or confirmed, on-going 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

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

Severe renal and hepatic insufficiency

In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2).

Interference with serological testing

Interference with Coombs tests may occur, as KOCEF may lead to false-positive test results. KOCEF can also lead to false-positive test results for galactosaemia (see section 4.8). Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with KOCEF should be done enzymatically (see section 4.8). 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.

Interaction with calcium-containing products

KOCEF should not be added to solutions containing calcium. Do not use diluents containing calcium such as Ringeru2019s lactate solution or Hartmannu2019s solution to reconstitute KOCEF vials, or to further dilute a reconstituted vial for IV administration because a precipitate can form (see sections 4.3, 4.4 and 6.2). Precipitation of ceftriaxone-calcium can also occur when KOCEF is mixed with calcium-containing solutions in the same IV administration line. KOCEF 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 4.3, 4.4 and 4.8).

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).

Anticoagulants

Concomitant use of KOCEF 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 KOCEF (see section 4.8).

Aminoglycosides

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

Laboratory tests

In patients treated with KOCEF the Coombsu2019 test and tests for galactosaemia may become false-positive. Non-enzymatic methods for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with KOCEF should be done enzymatically. The presence of KOCEF 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.

Chloramphenicol

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

Probenecid

The elimination of KOCEF is not altered by probenecid.

Diuretics

Renal function impairment has not been observed after concurrent administration of KOCEF and diuretics (e.g. furosemide).

Alcohol

No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of KOCEF. KOCEF does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems.

Pregnancy

Ceftriaxone crosses the placental barrier. Safety in pregnancy has not been established. Reproductive studies in animals have shown no evidence of embryotoxicity, fetotoxicity, teratogenicity, birth or perinatal and postnatal development. In primates, no embryotoxicity or teratogenicity has been observed.

Breastfeeding

Low concentrations of ceftriaxone is excreted in human breast milk. Caution should be exercised when KOCEF is administered to a breastfeeding woman.

Fertility

Reproductive studies in animals have shown no evidence of adverse effects on male or female fertility.

During treatment with KOCEF, 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.

b) Tabulated list of adverse reactions

The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with ceftriaxone.

System Organ Class Frequency Frequent Less Frequent Not known a Infections and infestations Genital fungal infection, pseudo-membranous colitis b Superinfection b Blood and lymphatic system disorders Eosinophilia, leucopenia, thrombocytopenia Granulocytopenia, anaemia, coagulopathy Haemolytic anaemia b, agranulocytosis Immune system disorders Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity b, Jarisch-Herxheimer reaction b Nervous system disorders Headache, dizziness, encephalopathy Convulsion Ear and labyrinth disorders Vertigo Respiratory, thoracic and mediastinal disorders Bronchospasm Gastrointestinal disorders Diarrhoea, loose stools Nausea, vomiting Pancreatitis b, stomatitis, glossitis Hepatobiliary disorders Hepatic enzyme increased Gall bladder precipitation b, kernicterus, hepatitis c, hepatitis cholestatic b,c Skin and subcutaneous tissue disorders Rash Pruritus, urticaria Stevens Johnson Syndrome b, toxic epidermal necrolysis b, erythema multiforme, acute generalised exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS) b Renal and urinary disorders Haematuria, glycosuria Oliguria, renal precipitation (reversible) General disorders and administration site conditions Phlebitis, injection site pain, pyrexia, edema, chills Investigations Blood creatinine increased Coombs test false positive b, galactosaemia test false positive, non-enzymatic methods for glucose determination false positive b 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. b See section 4.4 c Usually reversible upon discontinuation of ceftriaxone.

c. Description of selected adverse reactions

Interaction with calcium Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. u2265 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 KOCEF. Reports of diarrhoea following the use of ceftriaxone may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted (see section 4.4).

Blood and lymphatic system disorders

Isolated cases of agranulocytosis (< 500/mm 3) 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.

Renal and urinary disorders

Renal precipitation has been reported, mostly in children older than 3 years who have been treated with either high daily doses (e.g. u2265 80 mg/kg/day) or total doses exceeding 10 g and presenting with other risk factors (e.g. fluid restrictions, confinement to bed). This event may be symptomatic or asymptomatic, may lead to renal insufficiency, and is reversible upon discontinuation of KOCEF.

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