Ceftriaxone 000 mg Injection

CEFTRIAXONE PHARMA-Q 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 meningitides, or Streptococcus pneumoniae.
• Intra-abdominal infections caused by: Escherichia coli, Klebsiella pneumoniae, 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 gonorrhea, including both beta-lactamase-, and non-beta-lactamase - producing strains, and pharyngeal gonorrhea caused by non-beta-lactamase - producing strains of Neisseria gonorrhea.
• Peri-operative infection prophylaxis.

Posology

Standard dosage

Adults and children over 12 years: The usual dosage is 1 - 2 g CEFTRIAXONE PHARMA-Q once daily. 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 - 50 mg/kg body weight 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 - 80 mg/kg once daily. For children with bodyweights of 50 kg or more, the usual adult dose should be used. Intravenous doses of 50 mg/kg bodyweight should be given by infusion over at least 30 minutes.

Elderly patients: No dose modification is needed in the elderly.

Duration of therapy

The duration of therapy varies according to the course of the disease. Administration of CEFTRIAXONE PHARMA-Q 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 4 000 mg) 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 4 000 mg once daily.
• Gonorrhoea: For the treatment of uncomplicated gonorrhoea (both beta-lactamase-producing and non- beta-lactamase-producing strains), a single intramuscular (IM) dose of 125 mg CEFTRIAXONE is recommended.
• Peri-operative infection prophylaxis: A single dose of 1 - 2 g CEFTRIAXONE PHARMA-Q administered 30 - 90 minutes prior to surgery. In colorectal surgery, administration of CEFTRIAXONE PHARMA-Q with or without a 5-nitroimidazole, e.g. metronidazole, has been proven effective, (separate administration: see Method of administration).
• Impaired renal and hepatic function: In patients with impaired renal function, there is no need to reduce the dosage of CEFTRIAXONE PHARMA-Q provided that hepatic function is intact. In cases of severe renal failure (creatinine clearance < 10 ml/min) the CEFTRIAXONE PHARMA-Q dosage should not exceed 2 000 mg daily. In patients with liver damage, there is no need for the dosage to be reduced, provided that renal function is intact.

Method of administration

CEFTRIAXONE PHARMA-Q 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 medicine.

Intramuscular injection: For IM injection, CEFTRIAXONE PHARMA-Q 250 mg or 500 mg is dissolved in 2 ml and CEFTRIAXONE PHARMA-Q 1 000 mg in 3,5 ml of water for injection. CEFTRIAXONE PHARMA-Q 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 1 000 mg is injected at one site. Reconstitution with 1 % lignocaine (without adrenaline) has no effect on the absorption or elimination of CEFTRIAXONE PHARMA-Q.

Intravenous injection: The lignocaine solution must never be administered intravenously. For IV injection CEFTRIAXONE PHARMA-Q 250 mg or 500 mg is dissolved in 5 ml, and CEFTRIAXONE PHARMA-Q 1 000 mg in 10 ml sterile water for injection. The intravenous administration should be given over 2 to 4 minutes.

Incompatibilities: See section 6.2

• Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients of CEFTRIAXONE PHARMA-Q (see section 6.1).
• History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial medicines (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, 4.8 and 6.2).
• Contraindications to lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See the contraindications section in the professional information of lidocaine.
• Ceftriaxone solutions containing lidocaine should never be administered intravenously.

* 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.

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). In case of severe hypersensitivity reactions, treatment with CEFTRIAXONE PHARMA-Q 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 medicine. Caution should be used if CEFTRIAXONE PHARMA-Q is given to patients with a history of non-severe hypersensitivity to other beta-lactam medicines.

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).

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 PHARMA-Q 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 PHARMA-Q 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 PHARMA-Q is considered necessary in patients requiring continuous nutrition, TPN solutions and CEFTRIAXONE PHARMA-Q 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 PHARMA-Q 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 PHARMA-Q in neonates, infants and children have been established for the dosages described under Posology (see section 4.2). Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. CEFTRIAXONE PHARMA-Q 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 PHARMA-Q (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during CEFTRIAXONE PHARMA-Q treatment in both adults and children. If a patient develops anaemia while on CEFTRIAXONE PHARMA-Q, the diagnosis of a cephalosporin-associated anaemia should be considered and CEFTRIAXONE PHARMA-Q 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 PHARMA-Q, 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 PHARMA-Q (see section 4.8). Discontinuation of therapy with CEFTRIAXONE PHARMA-Q and the administration of specific treatment for Clostridium difficile should be considered. 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 PHARMA-Q may lead to false-positive test results. CEFTRIAXONE PHARMA-Q 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 PHARMA-Q should be done enzymatically (see section 4.8). The presence of CEFTRIAXONE PHARMA-Q 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 PHARMA-Q 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 PHARMA-Q, the administration of an additional antibiotic should be considered.

Use of lidocaine

In case a lidocaine solution is used as a solvent, CEFTRIAXONE PHARMA-Q solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Professional information of lidocaine must be considered before use (see section 4.3). The lidocaine 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 doses of 1 g per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Less frequently precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of CEFTRIAXONE PHARMA-Q 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 PHARMA-Q (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 PHARMA-Q -related biliary precipitation cannot be ruled out.

Renal lithiasis

Cases of renal lithiasis have been reported, which is reversible upon discontinuation of CEFTRIAXONE PHARMA-Q (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 PHARMA-Q treatment is started. JHR is usually a self u2013 limiting condition or can be managed by symptomatic treatment. The antibiotic treatment should not be discontinued if such reaction occurs.

Encephalopathy

Encephalopathy has been reported with the use of ceftriaxone (see section 4.8), particularly in elderly patients with severe renal impairment (see section 4.2) or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g. decreased level of consciousness, altered mental state, myoclonus, convulsions), discontinuation of CEFTRIAXONE PHARMA-Q should be considered.

Sodium

CEFTRIAXONE 250 PHARMA-Q sterile powder for injection contains 48,42 mg sodium per vial. CEFTRIAXONE 500 PHARMA-Q sterile powder for injection contains 96,85 mg sodium per vial. CEFTRIAXONE 1000 PHARMA-Q sterile powder for injection contains 193,70 mg sodium per vial.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute CEFTRIAXONE PHARMA-Q 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 PHARMA-Q is mixed with calcium-containing solutions in the same intravenous administration line. CEFTRIAXONE PHARMA-Q 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 PHARMA-Q 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 4.2, 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 drug adjusted accordingly, both during and after treatment with CEFTRIAXONE PHARMA-Q (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.

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).

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

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

Safety in pregnancy and lactation has not been established.

Pregnancy

Ceftriaxone crosses the placental barrier. There are limited amounts of data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development.

Breastfeeding

Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. 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 breastfeeding or to discontinue/abstain from CEFTRIAXONE PHARMA-Q therapy.

Fertility

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

During treatment with CEFTRIAXONE PHARMA-Q, 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, leukopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.

b. Tabulated summary of adverse reactions

The adverse reactions have been grouped according to system organ class and with the following frequency classifications: frequent, less frequent and frequency unknown.

System organ class Frequency Adverse reactions

Infections and infestations Less frequent Genital fungal infection, pseudo-membranous colitis (see section 4.4) Frequency unknown Superinfection (see section 4.4)

Blood and lymphatic system disorders Frequent Eosinophilia, leukopenia, thrombocytopenia Less frequent Granulocytopenia, anaemia, coagulopathy Frequency unknown Haemolytic anaemia, agranulocytosis (see section 4.4)

Immune system disorders Frequency unknown Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, Jarisch-Herxheimer reaction (see section 4.4)

Nervous system disorders Less frequent Headache, dizziness, encephalopathy Frequency unknown Convulsion

Ear and labyrinth disorders Frequency unknown Vertigo

Cardiac disorders Frequency unknown Kounis syndrome

Respiratory, thoracic and mediastinal disorders Less frequent Bronchospasm

Gastrointestinal disorders Frequent Diarrhoea, loose stools (see section 4.4) Less frequent Nausea, vomiting Frequency unknown Pancreatitis (see section 4.4), stomatitis, glossitis

Hepato-biliary disorders Frequent Hepatic enzyme increased Frequency unknown Gall bladder precipitation, kernicterus, hepatitis, hepatitis cholestatic (see section 4.4)

Skin and subcutaneous tissue disorders Frequent Rash Less frequent Pruritus, urticaria Frequency unknown Stevens Johnson Syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalised exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4), linear IgA disease

Renal and urinary disorders Less frequent Haematuria, glycosuria Frequency unknown Oliguria, renal precipitation (reversible)

General disorders and administration site conditions Less frequent Phlebitis, injection site reactions, pyrexia, oedema, chills

Investigations Less frequent Blood creatinine increased Frequency unknown Coombs test false positive, galactosaemia test false positive, non enzymatic methods for glucose determination false positive (see section 4.4)

c. Description of selected adverse reactions

Infections and infestations 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).

Ceftriaxone-calcium salt precipitation Less frequently, severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (aged < 28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in neonates is a result of their low blood volume and the longer half-life of ceftriaxone compared with adults (see sections 4.3, 4.4, and 5.2).

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 CEFTRIAXONE PHARMA-Q (see section 4.4).

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application - above 30 % in some studies. The incidence appears to be lower with slow infusion (20 - 30 minutes). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of CEFTRIAXONE PHARMA-Q (see section 4.4).

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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

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.