Inoxiphin 250 mg/500 mg/1 g/2 g Solution

INOXIPHIN 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 INOXIPHIN may reduce the incidence of post-operative infections.
• In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside should be concomitantly.

Adults and children over twelve years: The usual dosage is 1 - 2 g INOXIPHIN 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: The dosages recommended for adults require no modification in the case of elderly patients.

Duration of therapy: The duration of therapy varies according to the course of the disease. Administration of INOXIPHIN 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.

Meningitis: In bacterial meningitis in neonates, infants 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. For bacterial meningitis in adults, the recommended dose is 4 g daily.

Gonorrhoea: For the treatment of uncomplicated gonorrhoea (penicillinase- producing and non-penicillinase-producing strains), a single IM dose of 125 mg INOXIPHIN is recommended.

Peri-operative prophylaxis: A single dose of 1 to 2 g INOXIPHIN administered 30 - 90 minutes prior to surgery. In colorectal surgery, administration of INOXIPHIN with or without a 5-nitroimidazole, e.g. ornidazole, (separate administration: see Method of administration below) has been proven effective.

Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage of INOXIPHIN, provided that the hepatic function is intact. In cases of severe renal failure (creatinine clearance < 10 L /min) the INOXIPHIN dosage should not exceed 2 g daily. In patients with liver damage, there is no need for the dosage to be reduced, provided renal function is intact.

Method of administration: INOXIPHIN must be reconstituted prior to use. As a general rule, however, the solutions should be used immediately after preparation.

Intramuscular injection: INOXIPHIN must be injected well within the body of a relatively large muscle. It is recommended that not more than 1 g be injected at one site (see section 6.6).

Intravenous injection: The intravenous administration should be given over 2 - 4 minutes (see section 6.6).

Intravenous infusion: The infusion should be given over a period of at least 30 minutes (see section 6.6).

Hypersensitivity to ceftriaxone or any other cephalosporin or any of the ingredient excipients of INOXIPHIN listed in section 6.1. History of hypersensitivity to any other type of beta-lactam antibacterial medicine (penicillins, monobactams and carbapenems), the possibility of allergic cross-reactions should be borne in mind.

INOXIPHIN is contraindicated in:

• Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age)
• Full-term neonates (up to 28 days of age):
• with hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired
• if they require (or are expected to require) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone-calcium salt (see sections 4.4, 4.8 and 6.2).

* In vitro studies have shown that INOXIPHIN can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients.

Contraindications to lidocaine (lignocaine) must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See information in the professional information of lidocaine (lignocaine), especially contraindications.

INOXIPHIN solutions containing lidocaine (lignocaine) should never be administered intravenously.

Prescribers should adhere to the principles of antibiotic stewardship.

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

Severe cutaneous adverse reactions (SCAR) such as (Stevens Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) and generalised exanthematous pustulosis (AGEP) which can be life-threatening or fatal have been reported in association with beta-lactam antibiotics such as INOXIPHIN treatment; however, the frequency of these events is not known (see section 4.8). When SCAR is suspected INOXIPHIN should be discontinued.

Interaction with calcium containing products: Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described. At least one of them had received ceftriaxone as in INOXIPHIN and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than neonates, treated with ceftriaxone as in INOXIPHIN and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age INOXIPHIN must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age INOXIPHIN and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare provider may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of INOXIPHIN is considered necessary in patients requiring continuous nutrition, TPN solutions and INOXIPHIN can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2).

Paediatric population: Safety and effectiveness of ceftriaxone as in INOXIPHIN in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that ceftriaxone as in INOXIPHIN, like some other cephalosporins, can displace bilirubin from serum albumin. INOXIPHIN is contraindicated in premature and full-term neonates 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 ceftriaxone as in INOXIPHIN (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during INOXIPHIN treatment in both adults and children. If a patient develops anaemia while on INOXIPHIN, the diagnosis of a cephalosporin - associated anaemia should be considered and INOXIPHIN discontinued until the aetiology is determined.

Long term treatment: During prolonged treatment complete blood count should be performed at regular intervals.

Colitis/Overgrowth of non-susceptible microorganisms: Antibacterial medicine-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial medicines, including ceftriaxone as in INOXIPHIN, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of INOXIPHIN (see section 4.8). Discontinuation of therapy with INOXIPHIN and the administration of specific treatment for Clostridium difficile should be considered. Appropriate fluid and electrolyte management should be instituted. Medicines that inhibit peristalsis should not be given.

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 ceftriaxone as in INOXIPHIN may lead to false-positive test results. Ceftriaxone as in INOXIPHIN 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 INOXIPHIN should be done enzymatically (see section 4.8). The presence of ceftriaxone as in INOXIPHIN 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.

Antibacterial spectrum: Ceftriaxone as in INOXIPHIN has a limited spectrum of antibacterial activity and may not be suitable for use as a single medicine for the treatment of some types of infections unless the pathogen has already been confirmed (see section 4.2). In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone as in INOXIPHIN, administration of an additional antibiotic should be considered.

Use of lidocaine (lignocaine): In case a lidocaine (lignocaine) solution is used as a solvent, ceftriaxone as in INOXIPHIN 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 must be considered before use (see section 4.3). The lidocaine (lignocaine) solution should never be administered intravenously.

Biliary lithiasis: When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium-ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone as in INOXIPHIN doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of INOXIPHIN therapy. Precipitates of calcium ceftriaxone have been associated with symptoms in a few cases. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of INOXIPHIN treatment should be considered by the medical practitioner based on specific benefit risk assessment (see section 4.8).

Biliary stasis: Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with ceftriaxone as in INOXIPHIN (see section 4.8). 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 of ceftriaxone - related biliary precipitation cannot be ruled out.

Renal lithiasis: Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone as in INOXIPHIN (see section 4.8). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the medical practitioner based on specific benefit risk assessment.

Jarisch-Herxheimer reaction (JHR): Some patients with spirochete infections may experience a Jarisch-Herxheimer reaction (JHR) shortly after ceftriaxone as in INOXIPHIN treatment is started. JHR is usually a self-limiting condition or can be managed by symptomatic treatment. INOXIPHIN treatment should not be discontinued if such reaction occurs.

Sodium: Each gram of INOXIPHIN contains 3.6 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute INOXIPHIN vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when INOXIPHIN is mixed with calcium-containing solutions in the same intravenous administration line. INOXIPHIN must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, INOXIPHIN and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. It has been reported that in vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2).

Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently, and the posology of the anti-vitamin K medicine adjusted accordingly, both during and after treatment with INOXIPHIN (see section 4.8).

No impairment of renal function has been observed after concurrent administration of large doses of INOXIPHIN and potent diuretics (e.g. furosemide). There is no evidence that INOXIPHIN increases renal toxicity of aminoglycosides. It was reported that in an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone as in INOXIPHIN.

There have been no reports of an interaction between ceftriaxone as in INOXIPHIN and oral calcium-containing products or interaction between intramuscular ceftriaxone as in INOXIPHIN and calcium-containing products (intravenous or oral). In patients treated with ceftriaxone as in INOXIPHIN, the Coombs' test may lead to false-positive test results. Ceftriaxone as in INOXIPHIN like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may yield false-positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone as in INOXIPHIN should be carried out enzymatically.

Simultaneous administration of probenecid does not reduce the elimination of INOXIPHIN ceftriaxone. No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of INOXIPHIN. Ceftriaxone as in INOXIPHIN does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems.

Pregnancy: Safety in human pregnancy has not been established. Ceftriaxone crosses the placental barrier.

Breast feeding: Ceftriaxone as in INOXIPHIN is excreted into human milk in low concentrations, caution is advised in breastfeeding mothers. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from INOXIPHIN therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility: Reproductive studies have shown no evidence of adverse effects on male or female fertility.

INOXIPHIN may cause dizziness, which may influence the ability to drive and use machines. Patients should not drive or operate machines until they know how INOXIPHIN affects them.

Infections and infestation:

• Less frequent: Genital fungal infection, pseudomembranous colitis.
• Frequency not known: Superinfection

Blood and lymphatic system disorders:

• Frequent: Eosinophilia, leucopenia, thrombocytopenia, hematoma
• Less frequent: Granulocytopenia, anaemia, coagulopathy
• Frequency not known: Haemolytic anaemia, agranulocytosis

Immune system disorders:

• Frequency not known: Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, Jarisch-Herxheimer reaction

Nervous system disorders:

• Less frequent: Headache, dizziness.
• Frequency not known: Convulsion

Ear and labyrinth disorders:

• Frequency not known: Vertigo

Respiratory, thoracic and mediastinal disorders:

• Less frequent: Bronchospasm

Gastrointestinal disorders:

• Frequent: Diarrhoea, loose stools
• Less frequent: Nausea.
• Frequency not known: Pancreatitis, stomatitis, and glossitis

Hepatobiliary disorders:

• Frequent: Hepatic enzyme increased
• Frequency not known: Gall bladder precipitation of ceftriaxone, kernicterus, Hepatotoxicity.

Skin and subcutaneous tissue disorders:

• Frequent: Rash, pruritis, petechiae, purpura, diaphoresis, flushing, urticaria, allergic dermatitis, exanthema.
• Frequency not known: Stevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalised exanthematous pustulosis (AGEP), oedema, drug reaction with eosinophilia and systemic symptoms (DRESS) and exfoliative dermatitis.

Renal and urinary disorders:

• Less frequent: Haematuria, glycosuria.
• Frequency not known: Oliguria, renal precipitation (reversible)

General disorders and administration site conditions:

• Less frequent: Phlebitis, injection site pain, pyrexia, oedema, chills (shivering)

Investigations:

• Less frequent: Blood creatinine increased.
• Frequency not known: Coombu2019s test false positive, galactosaemia test false positive, non-enzymatic methods for glucose determination false positive

In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Plasma concentrations of ceftriaxone as in INOXIPHIN cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic.