Fraxone 250 mg and 1 g Powder for Injection,

FRAXONE 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 meningitidis 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 FRAXONE may reduce the incidence of post-operative infections.

Posology

Adults and children over 12 years:

The usual dosage is 1-2 g of FRAXONE 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 therapy: The duration of therapy varies according to the course of the disease. Administration of FRAXONE 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 therapy: Synergy between FRAXONE 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 FRAXONE and aminoglycosides, the two medicines must be administered separately at the recommended dosages. Chemical incompatibility with FRAXONE has also been observed with IV administration of amsacrine, vancomycin and fluconazole.

Special dosage instructions:

Children: 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. FRAXONE is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age) (see section 4.3 contraindications). FRAXONE 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 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.

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

Elderly: The dosages recommended for adults require no modification in geriatric patients provided there is no severe renal and hepatic impairment.

Patients with hepatic impairment: In patients with liver damage there is no need for the dosage to be reduced provided renal function is not impaired.

Patients with renal impairment: In patients with impaired renal function there is no need to reduce the dosage of FRAXONE, provided hepatic function is not impaired. In cases of severe renal failure (creatinine clearance < 10 mL/min) the FRAXONE 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: FRAXONE 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.

Patients with 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 neonates and children, treatment begins with doses of 100 mg per kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dosage can be reduced accordingly.

Gonorrhoea: For the treatment of gonorrhoea (penicillinase-producing and non-penicillinase-producing strains), a single IM dose of 250 mg ceftriaxone is recommended.

Perioperative prophylaxis: A single dose of 1-2 g ceftriaxone administered 30-90 minutes prior to surgery.

Method of administration: FRAXONE must be reconstituted prior use. 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, Fraxone 250 should be dissolved in 2 ml and Fraxone 1 g in 3.5 ml of water for injection. In adults, intramuscular administrations of some cephalosporins, including FRAXONE, cause pain at the injection site. This can be reduced greatly by administering in combination with a local anaesthetic. FRAXONE dissolved in a 1% lignocaine (lidocaine) solution can reduce pain at the site of injection. FRAXONE must be injected well within the body of a relatively large muscle. It is recommended that not more than 1 g be injected on one side. Reconstitution with 1% lidocaine (without adrenaline) has no effect on the absorption or the elimination of Ceftriaxone. The lidocaine solution must never be administered intravenously.

Intravenous Injection: For IV injection, FRAXONE 250 is dissolved in 5 ml water for injection and FRAXONE 1 g dissolved in 10 ml water for injection. The intravenous administration should be given over two (2) to four (4) minutes.

Intravenous infusion: The infusion should be given over a period of at least 30 minutes. For IV infusion, 2 g of FRAXONE is dissolved in approximately 40 ml of sterile water for injection. Ceftriaxone solutions should not be mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, owing to possible incompatibility.

Incompatibilities: See section 6.2

Hypersensitivity: FRAXONE 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).

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

Premature Neonates: FRAXONE 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 FRAXONE. In vitro studies have shown that FRAXONE 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: FRAXONE 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-FRAXONE precipitates in the lungs and kidneys have been reported at autopsy in both term and preterm neonates receiving FRAXONE and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both FRAXONE 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 FRAXONE 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).

FRAXONE must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. FRAXONE and IV calcium-containing solutions or products must not be administered within 48 hours of each other. Precipitation of ceftriaxone-calcium may occur when FRAXONE is mixed with calcium-containing solutions in the same IV administration line.

FRAXONE 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 FRAXONE and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both FRAXONE 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 FRAXONE 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 FRAXONE. 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, FRAXONE 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, FRAXONE 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 FRAXONE and oral calcium-containing products or interaction between intramuscular FRAXONE and calcium-containing products (IV or oral).

Hypersensitivity: Serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). In case of severe hypersensitivity reactions, treatment with FRAXONE 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 hypersensitivity reactions to ceftriaxone, to other cephalosporins, or to any other type of beta-lactam medicine. Caution should be used if FRAXONE is given to patients with a history of hypersensitivity to other beta-lactam medicines.

Haemolytic anaemia: An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterial including FRAXONE. Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anaemia while on FRAXONE, the diagnosis of cephalosporin associated anaemia should be considered and FRAXONE discontinued until the aetiology is determined.

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

Superinfection with non-susceptible micro-organisms may occur as with other antibacterial agents. Calcium-ceftriaxone precipitates in the gallbladder have been observed on ultrasound scan in patients receiving FRAXONE, particularly at doses of 1 g per day and above. The probability of such precipitates appears to be greatest in paediatric patients. Precipitates disappear after discontinuation of FRAXONE therapy and are rarely symptomatic. In symptomatic cases, conservative nonsurgical management is recommended, and discontinuation of FRAXONE treatment should be considered by the medical practitioner based on an individual benefit-risk assessment.

Pancreatitis: Cases of pancreatitis, possible of biliary obstruction aetiology, have been rarely reported in patients treated with FRAXONE. 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 FRAXONE-related biliary precipitation cannot be ruled out.

Paediatrics: Safety and efficacy of FRAXONE in neonates, infants and children have been established for the dosages described under section 4.2. Studies have shown that FRAXONE can displace bilirubin from serum albumin. FRAXONE should not be used in neonates (especially prematures) at risk of developing bilirubin encephalopathy (see section 4.3).

Blood monitoring: During prolonged treatment a complete blood count should be carried out at regular intervals.

Special groups: Patients with reduced renal and liver function: Refer to section 4.2. The elderly: Refer to section 4.2. Children: Refer to section 4.2.

No impairment of renal function has been observed after concurrent administration of large doses of FRAXONE and potent diuretics (e.g., furosemide). There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins including FRAXONE. 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 FRAXONE. FRAXONE 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 FRAXONE.

Influence on diagnostic tests: In patients treated with FRAXONE the Coombs test may become false-positive. Treatment with FRAXONE 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 FRAXONE should be done enzymatically. The presence of FRAXONE 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: FRAXONE should not be added to solutions containing calcium. Do not use diluents containing calcium such as Ringeru2019s lactate solution or Hartmannu2019s solution to reconstitute FRAXONE vials, or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when FRAXONE is mixed with calcium-containing solutions in the same IV administration line. FRAXONE 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 FRAXONE 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 FRAXONE (see section 4.8).

Pregnancy: Safety in human pregnancy has not been established.

Lactation: FRAXONE crosses the placental barrier. FRAXONE is excreted in the breast milk. Safety in lactation has not been established.

Fertility: Safety in human lactation has not been established.

During treatment with FRAXONE, 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.

Infections and Infestations: Less Frequent: Genital fungal infection, pseudo-membranous colitis.

Blood and lymphatic system disorders: Frequent: Eosinophilia, leucopenia, thrombocyte penia. Less frequent: Granulocytopenia, anemia, coagulopathy.

Nervous system disorders: Less frequent: Headache, vomiting.

Respiratory, thoracic and mediastinal disorders: Less frequent: Bronchospasm.

Gastrointestinal disorders: Frequent: Diarrhoea. Less frequent: Nausea, vomiting.

Hepatobiliary disorders: Frequent: Hepatic enzyme increased. Unknown frequency: Hepatotoxicity.

Skin and subcutaneous tissue disorders: Frequent: Rash. Less frequent: Pruritus, urticaria.

Renal and urinary disorders: Less frequent: Haematuria, glycosuria.

General disorders and administration site conditions: Less frequent: Phlebitis, injection site pain, pyrexia, oedema, chills.

Investigations: Less frequent: Blood creatinine increased.

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: hppts://www.sahpra.or.za/Publications/Index/8

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