Triaxiphin 1 g, 250 mg, 500 mg Injection

TRIAXIPHIN is indicated for the treatment of the following infections:

• Bacterial septicemia 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 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, 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 beta-lactamase-, and non-beta-lactamase-producing penicillinase- and non-penicillinase-producing strains, and pharyngeal gonorrhoea caused by non-beta-lactamase-producing strains of Neisseria gonorrhoeae.
• Surgical prophylaxis: The pre-operative administration of a single 1 g dose of TRIAXIPHIN 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 TRIAXIPHIN 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.

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. It is not necessary to differentiate between premature and term infants.
• 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 should be given by infusion over at least 30 minutes.

Elderly patients. No dose modification is needed in the elderly. 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 TRIAXIPHIN 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 therapy: Synergy between TRIAXIPHIN 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 TRIAXIPHIN and aminoglycosides, the two medicines must be administered separately at the recommended dosages. Chemical incompatibility with TRIAXIPHIN has also been observed with IV administration of amsacrine, vancomycin and fluconazole.

Special dosage instructions

Meningitis: In bacterial meningitis in neonates, infants and children, treatment begins with doses of 100 mg/kg (not to exceed 4 g) once daily. As soon as the causative organism has been identified and its sensitivity determined, the dose can be adapted accordingly.

For bacterial meningitis in adults, the recommended dose is 4 g once daily.

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 u2013 2 g TRIAXIPHIN administered 30 u2013 90 minutes prior to surgery.

In colorectal surgery, administration of TRIAXIPHIN with or without a 5-nitroimidazole, e.g. metronidazole, has been proven effective, (separate administration: see 'Method of administration')

Method of administration

Ceftriaxone must be reconstituted prior to use. Reconstituted solutions retain their physical and chemical stability for 6 hours at room temperature or 24 hours in the refrigerator at +5 u00b0C. As a general rule, however, 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 drug (medicine).

Intramuscular injection

For i.m. injection, TRIAXIPHIN 250 mg or 500 mg is dissolved in 2 ml and TRIAXIPHIN 1 g in 3.5 ml, of water for injection. TRIAXIPHIN dissolved in a 1 % lignocaine solution instead of water for injection can reduce pain at the site of injection. It is recommended that not more than 1 g be injected at one site. Reconstitution with 1 % lignocaine (without adrenaline) has no effect on the absorption or the elimination of TRIAXIPHIN.

Intravenous injection

The lignocaine solution must never be administered intravenously. For i.v. injection, TRIAXIPHIN 250 mg or 500 mg is dissolved in 5 ml, and TRIAXIPHIN 1 g in 10 ml sterile water for injection. The intravenous administration should be given over 2 to 4 minutes.

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

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

• Hypersensitivity TRIAXIPHIN 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 u2013 Hypersensitivity).
• Lidocaine/Lignocaine Contraindications to lidocaine/lignocaine must be excluded before intramuscular injection of TRIAXIPHIN when lidocaine solution is used as a solvent (see section 4.2). TRIAXIPHIN solutions containing lidocaine should never be administered intravenously.
• Premature Neonates TRIAXIPHIN 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 TRIAXIPHIN. In vitro studies have shown that TRIAXIPHIN 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 TRIAXIPHIN 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-TRIAXIPHIN precipitates in the lungs and kidneys have been reported at autopsy in both term and preterm neonates receiving TRIAXIPHIN and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both TRIAXIPHIN 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 TRIAXIPHIN 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).

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

TRIAXIPHIN 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 TRIAXIPHIN and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both TRIAXIPHIN 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 TRIAXIPHIN 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 TRIAXIPHIN. Precipitate formation can result.

Interaction with Calcium-Containing Products: 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, TRIAXIPHIN and calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age even via different infusion lines at different sites. As a further theoretical consideration and based on 5 half-lives of ceftriaxone (TRIAXIPHIN) 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 ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

Hypersensitivity: Serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8 Undesirable effects). In case of severe hypersensitivity reactions, treatment with TRIAXIPHIN 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 TRIAXIPHIN 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 antibacterials including TRIAXIPHIN. Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anaemia while on TRIAXIPHIN, the diagnosis of cephalosporin associated anaemia should be considered and TRIAXIPHIN discontinued until the aetiology is determined.

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

Superinfections: Superinfections 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 TRIAXIPHIN, 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 TRIAXIPHIN therapy and are rarely symptomatic. In symptomatic cases, conservative nonsurgical management is recommended, and discontinuation of TRIAXIPHIN 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 TRIAXIPHIN. 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 TRIAXIPHIN-related biliary precipitation cannot be ruled out.

Paediatrics: Safety and efficacy of TRIAXIPHIN in neonates, infants and children have been established for the dosages described under section 4.2. Studies have shown that TRIAXIPHIN can displace bilirubin from serum albumin. TRIAXIPHIN 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. Sodium: This medicine contains less than 1 mmol sodium (23 mg) per the maximum recommended dose, that is to say essentially u2018sodium-free.

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

Influence on diagnostic tests: In patients treated with TRIAXIPHIN the Coombs test may become false-positive. Treatment with TRIAXIPHIN 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 TRIAXIPHIN should be done enzymatically.

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

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

During treatment with TRIAXIPHIN, 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.

System Organ Class

Frequent

Less frequent

Frequency unknown

Infections and infestations

Genital fungal infection, pseudo-membranous colitis

Superinfections

Blood and lymphatic system disorders

Eosinophilia

Leucopenia

Thrombocytopenia

Granulocytopenia

Anaemia

Coagulopathy

Blood and lymphatic system disorders, Coagulation disorders

Haemolytic Anaemia

Agranulocytosis

Immune system disorders: Anaphylactic shock

Anaphylactic reaction

Anoranaphylactoid reactions

Hypersensitivity

Jarisch-Herxheimer reaction

Nervous system disorders

Headach, dizziness

Encephelopathy

Convulsion

Ear and Labyrinth disorders

Vertigo

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Gastrointestinal disorders

Diarrhoea

Loose stools

Nausea, vomiting

Pancreatitis, stomatitis, glossitis. Pseudomembranous enterocolitis

Hepatobiliary disorders

Hepatic enzyme increased

Risk

Symptomatic precipitation of ceftriaxone-calcium salt in the gallbladder, kernicterus

Hepatitis*

Hepatitis* cholestatic

Skin and subcutaneous tissue disorders

Rash

Pruritus, urticaria

Acute generalised exanthematous pustulosis (AGEP), cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome or Lyellu2019s Syndrome/toxic epidermal necrolysis).

Toxic epidermalnecrolysis

Drug reaction with eosinophilia and systemic symptoms (Dress)

Renal and urinary disorders

Haematuria

Glycosuria

Oliguria.

Renal Precipition (reversible)

General disorders and administration site conditions

Phlebitis, injection site pain, pyrexia, oedema, chills

Phlebitis reactions after IV administration

Investigations

Blood creatinine increased

Coombs test false positive, galactosemia test false positive, non-enzymatic methods for glucose determination false positive (see section 4.5).

* Usually reversible upon discontinuation of ceftriaxone

c. Description of selected adverse reactions from clinical trials

Interaction with calcium: Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. 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 TRIAXIPHIN.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the 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: https://www.sahpra.org.za/Publications/Index/8

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