APR TEXCEF-ADVANCE

AB-11B:

INFORMATION FOR THE USER
Ceftriaxone and Sulbactam Injection

Read all of this information carefully before you start taking this medicine because it contains important information for you.
• Keep this information. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine is prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this information.

1. COMPOSITION:
Eachvial contains:
Ceftriaxone sodium eq. to ann. Ceftriaxone – 1gm
Sulbactam – 500mg

For IV/IM use only.

2. DESCRIPTION:
Ceftriaxone is a 3rd generation cephalosporin antibacterial and helps to kill infection causing bacteria. Sulbactam is an irreversible inhibitor of the enzyme beta lactamase and helps to enhance the spectrum of ceftriaxone.

3. PHARMACOLOGICAL ACTION:
Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis & death.

Sulbactam is a synthetic beta-lactamase inhibitor. It binds to the beta lactamase enzyme and blocks it irreversibly. A feature that distinguishes sulbactam from other available beta-lactamase inhibitors is its direct antimicrobial activity. Its mechanism of antimicrobial activity against is related to its intrinsic affinity for the essential penicillin-binding proteins of these organisms, and for altering the permeability of the outer membrane of Gram-negative bacilli, resulting in the leakage of beta-lactamases & thus, better penetration by other antibacterial agents.

4. CLINICAL PHARMACOKINETICS:
After IV bolus administration of ceftriaxone 500 mg & 1g, mean peak plasma levels are approx. 120 & 200 mg/l resp. After IV infusion of ceftriaxone 500 mg, 1g & 2g, the plasma levels are approx. 80, 150 & 250 mg/l resp. Following IM injection, mean peak plasma levels are approx. half those observed after IV administration of an equivalent dose. The max plasma conc. after a single IM dose of 1g is about 81 mg/l & is reached in 2-3 hrs after administration. The area under the plasma concentration-time curve after IM administration is equivalent to that after IV administration of an equivalent dose. The volume of distribution is 7–12L. Conc. well above the MIC of most relevant pathogens are detectable in tissue including lung, heart, biliary tract/liver, tonsil, middle ear & nasal mucosa, bone & in cerebrospinal, pleural, prostatic & synovial fluids. An 8-15 % increase in mean peak plasma concentration (Cmax) is seen on repeated administration; steady state is reached in most cases within 48-72 hrs depending on the route of administration. It penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak conc. in CSF in patients with bacterial meningitis are reported to be up to 25% of plasma levels compared to 2% of plasma levels in patients with uninflamed meninges. Peak conc. in CSF are reached approx. 4-6 hrs after IV injection. It crosses the placental barrier & is excreted in the breast milk at low conc. It is reversibly bound to albumin. Plasma protein binding is ~95 % at plasma conc. below 100 mg/l. Binding is saturable & the bound portion decreases with rising concentration (~85 % at a plasma conc. of 300 mg/l). It is not metabolised systemically; but is converted to inactive metabolites by the gut flora.Plasma clearance (bound & unbound) is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40-50% is excreted unchanged in the bile. The elimination half-life in adults is about 8 hrs.
After a 30-minute infusion of 1g of sulbactam, a peak conc. of approx. 43 mcg/mL is obtained.Multiple dosing at rates as high as 500mg every 6 hrs (IM) or 1g twice a day (1-hour infusions/IV bolus) does not appear to lead to accumulation of the drug as indicated by an increase in the peak serum conc. or the AUCs.The binding to human serum proteins is approx. 38%. In a 2-compartment pharmacokinetic model, the apparent volume of distribution of the central compartment of 9-16 L is in the range of total extracellular fluid in humans (approx. 15 litres) & suggests that sulbactam is widely distributed in the extracellular fluid.The total apparent volume of distribution of between 19-28 L is over half that of the total body fluid, approx. 40L in a 70kg human, suggesting it may be widely distributed into the tissues. 1 hr after IV administration of 1g sulbactam (at its peak conc. in serum) in 8 patients with bacterial respiratory infections, a penetration ratio (alveolar lavage fluid versus serum) of 61% has been reported. In patients with inflamed meninges; the CSF penetration is reported to be 2-32% of serum levels, which are approx. 42-60 mg/L after a 1g IV dose. After 500mg of a parenteral dose, appreciable conc. were observed in peritoneal fluid (14 mg/L), intestinal mucosa (0-28 mg/g), prostate (7mg/g) & pus (12.7 mg/L).The mean serum half-life is approx. 1 hr in healthy volunteers. Approx. 70% of a parenteral dose was excreted in the urine between 0-6 hrs, with an additional recovery of 5% between 6-12 hours post-dose. The renal clearance is approx. 204 ml/min & was not dose-dependent. The total clearance of drug from the serum was 266 mL/min. The non-renal clearance was 65 mL/min.An additional similarity to the beta-lactam antibiotics is the increase in the half-life of sulbactam of approx. 40% in humans due to a prior dose of probenecid.
5. INDICATIONS:
Ceftriaxone and sulbactam injection is indicated for the treatment of:
– Bacterial meningitis
– Community acquired pneumonia
– Hospital acquired pneumonia
– Acute otitis media
– Intra-abdominal infections
– Complicated urinary tract infections (including pyelonephritis)
– Infections of the bones and joints
– Complicated skin and skin structure infections
– Gonorrhoea
– Syphilis
– Bacterial endocarditis
– Acute exacerbations of chronic obstructive pulmonary disease in adults
– Disseminated Lyme borreliosis
– Pre-operative prophylaxis of surgical site infections
– Management of neutropenic patients with fever and suspected bacterial infection
– MDR and ESBL infections
– Lower respiratory tract infections
– Sepsis

6. CONTRAINDICATIONS:
– Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients.
– History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams & carbapenems).
– Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age)*
– Full-term neonates (up to 28 days of age):
1) with hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic.
2) if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone calcium salt.
– Contraindications to lidocaine must be excluded before IM injection of ceftriaxone when lidocaine solution is used as a solvent.
– Ceftriaxone solutions containing lidocaine should never be administered IV.

7. WARNINGS AND PRECAUTIONS:
Hypersensitivity reactions: As with all beta-lactam antibacterial agents, serious & occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment must be discontinued immediately & 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 agent. Caution should be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.Severe cutaneous adverse reactions (Stevens Johnson syndrome or toxic epidermal necrolysis) have been reported; however, the frequency of these events is not known.
Interaction with calcium containing products:Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs & kidneys in premature & full-term neonates aged less than 1 month have been described. Neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.
In patients of any age ceftriaxone must not be mixed/administered simultaneously with any calcium-containing IV solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone & 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 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 is considered necessary in patients requiring continuous nutrition, TPN solutions & ceftriaxone 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 & the infusion lines flushed between solutions.
Paediatric population:Safety & effectiveness in neonates, infants & children have been established for the dosages described under Posology & Method of Administration. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.It is contraindicated in premature & full-term neonates at risk of developing bilirubin encephalopathy.
Immune mediated haemolytic anaemia:An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Ceftriaxone. Severe cases of haemolytic anaemia, including fatalities, have been reported during Ceftriaxone treatment in both adults & children.If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin- associated anaemia should be considered & ceftriaxone 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 agent-associated colitis & pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, & may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftriaxone. Discontinuation of therapy with ceftriaxone & the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents.
Severe renal and hepatic insufficiency:In severe renal & hepatic insufficiency, close clinical monitoring for safety & efficacy is advised.
Interference with serological testing:Interference with Coombs tests may occur, as Ceftriaxone may lead to false-positive test results. It can also lead to false-positive test results for galactosaemia.Non-enzymatic methods for glucose determination in urine may give false- positive results. Urine glucose determination during therapy with Ceftriaxone should be done enzymatically.
Sodium:Each gram of ceftriaxone contains 3.6 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet.
Antibacterial spectrum:It has a limited spectrum of antibacterial activity & may not be suitable for use as a single agent 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:In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for IM injection. Contraindications to lidocaine, warnings & other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use. The lidocaine solution should never be administered IV.
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 & have been observed more frequently at ceftriaxone doses of 1g per day & above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended & discontinuation of ceftriaxone should be considered by the physician based on specific benefit risk assessment.
Biliary stasis:Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Ceftriaxone. Most patients presented with risk factors for biliary stasis & biliary sludge e.g. preceding major therapy, severe illness & 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. In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment.
Treatment with antibacterial agents alters the normal flora of the colon, leading to the overgrowth of C.difficile. If C.difficile-associated diarrhoea is suspected or confirmed, ongoing antibiotic use not directed against C.difficile may need to be discontinued. Appropriate fluid & electrolyte management, protein supplementation, antibiotic treatment of C.difficile, & surgical evaluation should be instituted as clinically indicated.

As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes the renal, hepatic & haematopoietic systems. This is particularly important in neonates, especially when premature& other infants.

8.ADVERSE EFFECTS:
Common side effects include: Eosinophelia, Leucopenia, Thrombocytopenia, Diarrhea, Increased hepatic enzymes, Rash
Uncommon side effects include: Coagulopathy, Headache, Dizziness, Nausea, Vomiting, Pruritis, Pain at injection site, Increased blood creatinine
Rare side effects include: Pseudomembranous colitis, Urticaria, Brinchospasm, oedema, Hemolyticanemia, Anaphylaxis, Steven Johnsons syndrome, Toxic epidermal necrolysis

9. DRUG INTERACTIONS:
Calcium-containing diluents, such as Ringer’s solution/Hartmann’s solution, should not be used to reconstitute Ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. It must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone & calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid.
Concomitant use with oral anticoagulants may increase the anti-vitamin K effect & the risk of bleeding. It is recommended that the INR is monitored frequently & the posology of the anti-vitamin K drug adjusted accordingly, both during & after treatment with ceftriaxone.
There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (& renal function) in clinical practice should be closely adhered to in such cases.
Antagonistic effects have been observed with the combination of chloramphenicol & ceftriaxone.
Coombs’ test may lead to false-positive test results.
May result in false-positive tests for galactosaemia.
Non-enzymatic methods for glucose determination in urine may yield false- positive results. For this reason, glucose level determination in urine during therapy should be carried out enzymatically.
No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone & potent diuretics (e.g. furosemide).
Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone.
Probenecid decreases the renal tubular secretion of sulbactam. Concurrent use of probenecid may result in increased & prolonged blood levels of sulbactam.

10.DOSAGE:
Paediatrics: 50-75mg/kg ceftriaxone given once daily (or in equally divided doses twice a day). Max 2g/day.
Adults: 1-2g ceftriaxone given once a day (or in equally divided doses twice a day). Max 4g/day.

11.ADMINISTRATION:
For IV/IM use only.
Administration to be done by a registered medical practitioner/nurse in a proper sterile and hospital setting only.
12. STORAGE:
Do not store above 25°C. Store in the original package. Keep away from children. Do not expose to direct sunlight.

13.MANUFACTURED BY:
14.MARKETED BY:

Last revised on August 2020.