Ceftriaxone Ipharma 500 mg, 1 000 mg, Intravenous (IV) injection

CEFTRIAXONE iPHARMA 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 that 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, Morgonella morganii or Klebsiella pneumoniae.
• Respiratory tract infections caused by Streptococcus pneumoniae, Methicillin Sensitive Staphylococcus aureus (MSSA), Haemophilus influenzae, Haemophilus para-influenzae, 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 influenza (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 CEFTRIAXONE iPHARMA may reduce the incidence of post-operative infections.
• In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside should be administered concomitantly.

Prescribers must adhere to the principles of antibiotic stewardship.

Posology

Standard dosage

Adults and children over the age of 12 years: The usual dosage is 1 to 2 g CEFTRIAXONE iPHARMA 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 of age: The following dosage schedules are recommended for once daily administration.

• Neonates (up to 14 days of age): 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 geriatric patients.

Duration of therapy

The duration of therapy varies according to the course of the disease. Administration of CEFTRIAXONE iPHARMA 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.

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 dosage can be adjusted 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 intramuscular dose of 125 mg CEFTRIAXONE iPHARMA IM is recommended.

Peri-operative prophylaxis: A single dose of 1 to 2 g CEFTRIAXONE iPHARMA administered 30 - 90 minutes prior to surgery. In colorectal surgery, administration of CEFTRIAXONE iPHARMA 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 CEFTRIAXONE iPHARMA, provided that the hepatic function is intact. In cases of severe renal failure (creatinine clearance <10 ml/min) the CEFTRIAXONE iPHARMA 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

CEFTRIAXONE iPHARMA 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 2 u2013 8 u221eC). 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 medicine.

Intramuscular administration

CEFTRIAXONE iPHARMA can be administered by deep intramuscular injection. Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 1 g should be injected at one site. For IM injection, CEFTRIAXONE iPHARMA 500 mg is dissolved in 2 ml and CEFTRIAXONE iPHARMA 1 000 mg in 3,5 ml, of water for injection. CEFTRIAXONE iPHARMA dissolved in a 1 % lidocaine solution instead of water for injection can reduce pain at the site of injection. If the solvent used is lidocaine (lignocaine), the resulting solution should never be administered intravenously (see section 4.3)

Intravenous administration

For IV injection, CEFTRIAXONE iPHARMA 500 mg is dissolved in 5 ml, and CEFTRIAXONE iPHARMA 1 000 mg in 10 ml sterile water for injection. The intravenous administration should be given over 2 - 4 minutes.

Intravenous Infusion

The infusion should be given over a period of at least 30 minutes. For incompatibilities, see section 6.2. For instructions on reconstitution of the CEFTRIAXONE iPHARMA before administration, see section 6.6.

• Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients listed in section 6.1.
• History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial medicine (penicillins, monobactams and carbapenems).
• 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, 4.5 and 4.8)

* In-vitro studies have shown that ceftriaxone 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 CEFTRIAXONE iPHARMA IM reconstituted with lidocaine (lignocaine) is given to patients (see section 4.4). Lidocaine (lignocaine) is contraindicated in patients with:

• hypersensitivity to lidocaine (lignocaine) or amide-type local anaesthetics
• hypovolaemia, heart block, other conduction disturbances, bradycardia, cardiac decompensation or hypotension
• sino-atrial disorders
• all grades of atrioventricular block
• severe myocardial depression
• patients with porphyria
• CEFTRIAXONE iPHARMA IM solutions containing lidocaine (lignocaine) should never be administered intravenously.

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 CEFTRIAXONE iPHARMA 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 contained in CEFTRIAXONE iPHARMA, to other cephalosporins or to any other type of beta-lactam medicine. Caution should be used if CEFTRIAXONE iPHARMA 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 (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected CEFTRIAXONE iPHARMA 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 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 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 CEFTRIAXONE iPHARMA 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 CEFTRIAXONE iPHARMA 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 professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of CEFTRIAXONE iPHARMA is considered necessary in patients requiring continuous nutrition, TPN solutions and CEFTRIAXONE iPHARMA 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 iPHARMA 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 iPHARMA 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, like some other cephalosporins, can displace bilirubin from serum albumin. CEFTRIAXONE iPHARMA 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 contained in CEFTRIAXONE iPHARMA (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment with ceftriaxone, as contained in CEFTRIAXONE iPHARMA in both adults and children.

If a patient develops anaemia while on CEFTRIAXONE iPHARMA, the diagnosis of a cephalosporin-associated anaemia should be considered and CEFTRIAXONE iPHARMA 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, 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 ceftriaxone (see section 4.8). Discontinuation of therapy with CEFTRIAXONE iPHARMA and the administration of specific treatment for Clostridium difficile should be considered. Medicines that inhibit peristalsis should not be given.

Superinfections with non-susceptible microorganisms 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 iPHARMA may lead to false-positive test results. CEFTRIAXONE iPHARMA 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 CEFTRIAXONE iPHARMA 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.

Sodium

Each gram of CEFTRIAXONE iPHARMA contains 3,6 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet.

Antibacterial spectrum

Ceftriaxone as contained in CEFTRIAXONE iPHARMA 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. In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone, administration of an additional antibiotic should be considered.

Use of lidocaine (lignocaine)

In case a lidocaine (lignocaine) solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. The lidocaine (lignocaine) solution should never be administered intravenously. Facilities for resuscitation should be available when administering lidocaine (lignocaine). Lidocaine (lignocaine) should be used with caution in patients with epilepsy, shock, myasthenia gravis, congestive cardiac failure or respiratory depression, including where medicines are known to interact with lidocaine (lignocaine) either to increase its availability or additive effects e.g., phenytoin or prolong its elimination e.g., hepatic or end renal insufficiency where the metabolites of lidocaine (lignocaine) may accumulate. The effect of lidocaine (lignocaine) may be reduced if the injection is made into an inflamed or infected area. Intramuscular lidocaine (lignocaine) may increase creatinine phosphokinase concentrations which can interfere with the diagnosis of acute myocardial infarction.

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 doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of CEFTRIAXONE iPHARMA therapy. Precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of CEFTRIAXONE iPHARMA 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 contained in CEFTRIAXONE iPHARMA, (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 iPHARMA-related biliary precipitation cannot be ruled out.

Renal lithiasis

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of CEFTRIAXONE iPHARMA (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 iPHARMA treatment is started. JHR is usually a self-limiting condition or can be managed by symptomatic treatment. The antibiotic treatment should not be discontinued if such reaction occurs.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute CEFTRIAXONE iPHARMA vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when CEFTRIAXONE iPHARMA is mixed with calcium-containing solutions in the same intravenous administration line. CEFTRIAXONE iPHARMA 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, CEFTRIAXONE iPHARMA and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. 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 4.3, 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 CEFTRIAXONE iPHARMA (see section 4.8).

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

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

In patients treated with CEFTRIAXONE iPHARMA, the Coombs' test may lead to false-positive test results. CEFTRIAXONE iPHARMA 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 iPHARMA should be carried out enzymatically.

No impairment of renal function has been observed after concurrent administration of large doses of CEFTRIAXONE iPHARMA and potent diuretics (e.g. furosemide). Simultaneous administration of probenecid does not reduce the elimination of CEFTRIAXONE iPHARMA.

Pregnancy

Safety in human pregnancy has not been established. CEFTRIAXONE iPHARMA, and the solvent lidocaine (lignocaine), crosses the placental barrier.

Breastfeeding

CEFTRIAXONE iPHARMA, and the solvent lidocaine (lignocaine), is excreted into human milk in low concentrations. Caution is advised in nursing mothers.

Fertility

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

During treatment with CEFTRIAXONE iPHARMA, 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.

The most frequently reported adverse reactions for ceftriaxone as contained in CEFTRIAXONE iPHARMA are eosinophilia, leukopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased. Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials.

System Organ Class

Infections and infestations: Genital fungal infection, Pseudomembranous colitis; Superinfection

Blood and lymphatic system disorders: Eosinophilia, leukopenia, thrombocytopenia; Granulocytopenia, anaemia, coagulopathy; Haemolytic anaemia, Agranulocytosis

Immune system disorders: Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity; Jarisch-Herxheimer reaction

Nervous system disorders: Headache, dizziness; Convulsion

Ear and labyrinth disorders: Vertigo

Respiratory, thoracic and mediastinal disorders: Bronchospasm

Gastrointestinal disorders: Diarrhoea, loose stools; Nausea, vomiting; Pancreatitis, stomatitis, glossitis

Hepato-biliary disorders: Increased hepatic enzyme; Gall bladder precipitation, Kernicterus, hepatotoxicity

Skin and subcutaneous tissue disorders: Rash; Pruritus, urticaria; Stevens Johnson Syndrome, toxic epidermal necrolysis (TEN), erythema multiforme, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), petechiae, purpura, diaphoresis, flushing, urticaria, exfoliative dermatitis

Renal and urinary disorders: Haematuria, glycosuria; Oliguria, renal precipitation (reversible)

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

Investigations: Increased blood creatinine; Coombs test false positive, galactosaemia test false positive, non-enzymatic methods for glucose determination false positive

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

Adverse events reported for lidocaine (lignocaine) solvent: Adverse reactions reported for lidocaine (lignocaine) are usually the result of raised plasma concentrations due to accidental intravascular injection, excessive dosage or rapid absorption from highly vascular areas, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient.

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

Lidocaine (lignocaine) used as solvent for intramuscular injection

Symptoms of acute systemic toxicity: Central nervous system toxicity presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness followed by sedation, hyperacusis and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anaesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, dysrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome.

Recovery occurs as a consequence of redistribution of the local anaesthetic medicine from the central nervous system, and of metabolism and may be rapid unless large amounts of lignocaine (lidocaine) have been injected.

Treatment of acute toxicity: If signs of acute systemic toxicity appear, the injection should be stopped immediately. Treatment will be required if convulsions and CNS depression occurs. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. A patent airway should be established and oxygen should be administered, together with assisted ventilation (mask and bag) if necessary. The circulation should be maintained with infusions of plasma or intravenous fluids. Where further supportive treatment of circulatory depression is required, use of a vasopressor type of medicine may be considered although this involves a risk of central nervous system excitation. If the convulsions do not stop spontaneously in 15 u2013 20 seconds, they may be controlled by the intravenous administration of diazepam or thiopentone sodium, bearing in mind that anticonvulsant medicines may also depress respiration and the circulation. Prolonged convulsions may jeopardise the patient's ventilation and oxygenation and early endotracheal intubation should be considered. If cardiac arrest should occur, standard cardiopulmonary resuscitation procedures should be instituted. Continual optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine (lignocaine).