Auroxon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AURIOXON (AUROXONE)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium, calculated as ceftriaxone – 500 mg or
1000 mg or 2000 mg;

Excipients: none.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical characteristics: crystalline powder ranging from white to yellowish-orange in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other β-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone.

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action.

Mechanism of action.

The bactericidal activity of ceftriaxone is due to inhibition of bacterial cell wall synthesis. Ceftriaxone is active in vitro against a broad spectrum of Gram-positive and Gram-negative microorganisms. Ceftriaxone is highly stable against most β-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria. Ceftriaxone is generally active in vitro against the following microorganisms and in clinical infections (see section "Indications"):

Gram-positive aerobes.

Staphylococcus aureus (methicillin-susceptible), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B),
β-hemolytic streptococci (groups neither A nor B), Streptococcus viridans, Streptococcus pneumoniae.

Note. Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes are also resistant to ceftriaxone.

Gram-negative aerobes.

Acinetobacter lwoffii, Acinetobacter anitratus (mainly A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alcaligenes-like bacteria, Borrelia burgdorferi, Burkholderia cepacia, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (others)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris, Pseudomonas fluorescens**, Pseudomonas spp. (others)*, Providencia rettgeri, Providencia spp. (others), Salmonella typhi, Salmonella spp. (enteritidis group), Serratia marcescens, Serratia spp. (others), Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others).

* Some isolates of these species are resistant to ceftriaxone, mainly due to chromosomally-mediated β-lactamase production.

** Some isolates of Klebsiella pneumoniae are resistant to ceftriaxone due to plasmid-mediated β-lactamases.

Note. Many strains of the above-mentioned microorganisms, which are multidrug-resistant to antibiotics such as aminopenicillins, ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain susceptible to ceftriaxone. Treponema pallidum is susceptible to ceftriaxone in vitro and in animal models. Clinical trials have shown that ceftriaxone is effective in the treatment of primary and secondary syphilis. With rare exceptions, clinical isolates of P. aeruginosa are resistant to ceftriaxone.

Anaerobes.

Bacteroides spp. (bile-sensitive)*, Clostridium spp. (except C. perfringens group), Fusobacterium nucleatum, Fusobacterium spp. (others), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococci.

* Some isolates of Bacteroides spp. are resistant to ceftriaxone.

Note. Many strains of Bacteroides spp. that produce β-lactamases (particularly B. fragilis) are resistant to ceftriaxone. Clostridium difficile is resistant.

Susceptibility to ceftriaxone can be determined by the disk diffusion method or by agar or broth dilution methods using standardized procedures similar to those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). For ceftriaxone, the NCCLS has established the following criteria for interpreting susceptibility test results:

	Susceptible	Intermediate	Resistant
Dilution method Inhibitory concentration, mg/l	≤ 8	16–32	≥ 64
Disc method (disc with 30 µg ceftriaxone) Diameter of inhibition zone, mm	≥ 21	20–14	≤ 13

To determine microbial susceptibility, disks containing ceftriaxone should be used, since in vitro studies have shown that ceftriaxone is active against certain strains resistant to disks designed for the entire cephalosporin group.

Instead of NCCLS standards for determining microbial susceptibility, other well-standardized guidelines such as DIN and ICS may also be used, allowing adequate assessment of the susceptibility level.

Pharmacokinetics.

The pharmacokinetics of ceftriaxone are nonlinear. All major pharmacokinetic parameters based on total drug concentrations (free and protein-bound ceftriaxone), except for the elimination half-life, are dose-dependent.

Absorption.

Maximum plasma concentration after intramuscular administration of 1 g of the drug is 81 mg/L and is achieved within 2–3 hours after administration. Single intravenous infusions of 1 g and 2 g result in concentrations of 168.1 ± 28.2 mg/L and 256.9 ± 16.8 mg/L, respectively, after 30 minutes. The area under the plasma concentration-time curve after intravenous administration is equivalent to that after intramuscular administration. This indicates that the bioavailability of ceftriaxone after intramuscular injection is 100%.

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. After intravenous administration, ceftriaxone rapidly penetrates into interstitial fluid, where bactericidal concentrations against susceptible microorganisms are maintained for 24 hours.

After administration of 1–2 g doses, ceftriaxone penetrates well into tissues and body fluids. For over 24 hours, its concentrations exceed the minimum inhibitory concentrations for most pathogens by more than 60-fold in various tissues and fluids (including lungs, heart, biliary tract, liver, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions).

Ceftriaxone reversibly binds to albumin, with the extent of binding decreasing as concentration increases—for example, declining from 95% at plasma concentrations below 100 mg/L to 85% at 300 mg/L. Due to lower albumin concentrations in tissue fluid, the fraction of free ceftriaxone is higher in tissue fluid than in plasma.

Ceftriaxone penetrates through inflamed meninges in children, including newborns. Maximum concentration in cerebrospinal fluid is reached approximately 4 hours after intravenous administration and averages 18 mg/L at doses of 50–100 mg/kg. In bacterial meningitis, the average concentration of ceftriaxone in cerebrospinal fluid is 17% of plasma concentration; in aseptic meningitis, it is 4%. Twenty-four hours after intravenous administration of Auraxon at 50–100 mg/kg, ceftriaxone concentrations in cerebrospinal fluid exceed 1.4 mg/L. In adults with meningitis, administration of a 50 mg/kg dose results in cerebrospinal fluid concentrations of ceftriaxone 2–24 hours later that are many times higher than the minimum inhibitory concentrations for the most common causative agents of meningitis.

Ceftriaxone crosses the placental barrier and penetrates into breast milk in small concentrations (3–4% of maternal plasma concentration 4–6 hours after administration).

Metabolism.

Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.

Excretion.

Total plasma clearance of ceftriaxone is 10–22 mL/min. Renal clearance is 5–12 mL/min. 50–60% of ceftriaxone is excreted unchanged by the kidneys and 40–50% unchanged via bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours.

Pharmacokinetics in special populations.

In newborn infants, approximately 70% of the dose is excreted by the kidneys. In children during the first 8 days of life, as well as in patients aged 75 years and older, the elimination half-life is on average 2–3 times longer than in younger adults.

In patients with mild to moderate impairment of renal and hepatic function, the pharmacokinetics of ceftriaxone are altered only slightly, with only a minor increase in plasma elimination half-life observed. When only renal function is impaired, biliary excretion increases; when hepatic function is impaired, renal excretion increases.

Clinical characteristics.

Indications.

Auroxon is indicated for the treatment of the following infections in adults and children, including full-term newborns (from birth):

• bacterial meningitis;
• community-acquired pneumonia;
• hospital-acquired pneumonia;
• acute otitis media;
• intra-abdominal infections;
• complicated urinary tract infections (including pyelonephritis);
• bone and joint infections;
• complicated skin and soft tissue infections;
• gonorrhea;
• syphilis;
• bacterial endocarditis.

Auroxon may be used for:

• treatment of acute exacerbations of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme borreliosis (early stage II and late stage III) in adults and children, including newborns from day 15 of life;
• surgical prophylaxis of surgical site infections;
• management of neutropenic patients who develop fever and are suspected of having a bacterial infection;
• patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections are suspected.

Auroxon should be administered in combination with other antibacterial agents if the potential spectrum of bacterial pathogens is not covered by its antibacterial spectrum (see section "Special precautions").

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated:

in preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

in full-term newborns (aged ≤ 28 days):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired in these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone calcium salt (see sections "Special precautions" and "Adverse reactions").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin encephalopathy in such patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the lidocaine prescribing information, particularly contraindications.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Auroxon in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including calcium-containing parenteral nutrition solutions, via a Y-type infusion system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone calcium salt precipitate formation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

Concomitant use of the drug with oral anticoagulants may enhance the anti-vitamin K effect and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be adjusted appropriately during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

No cases of interaction between ceftriaxone and orally administered calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration) have been reported.

Patients receiving ceftriaxone may exhibit false-positive Coombs' test results.

Like other antibiotics, ceftriaxone may cause false-positive results in galactosemia testing.

Similarly, false-positive results may occur when testing for glucose in urine using non-enzymatic methods. For this reason, urine glucose levels should be determined using enzymatic methods during ceftriaxone therapy.

No renal function impairment has been observed following concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions.

As with all β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to DRESS syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to ascertain whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of β-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other β-lactam drugs.

Cases of severe skin reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS), associated with ceftriaxone use, have been reported; however, the frequency of these events is unknown (see section "Adverse reactions").

Jarisch-Herxheimer reaction.

Shortly after initiating ceftriaxone therapy, some patients with spirochetal infections may experience a Jarisch-Herxheimer reaction (JHR). This reaction usually resolves spontaneously or may be managed symptomatically. Antibiotic treatment should not be discontinued if such reactions occur.

Interaction with calcium-containing medicinal products.

In preterm and term neonates up to 1 month of age, cases of precipitates of ceftriaxone calcium salt in the lungs and kidneys, some fatal, have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitates have been observed only in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that neonates are at higher risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or administered simultaneously with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents that do not carry such precipitation risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines should be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").

Children.

The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

Ceftriaxone is contraindicated in preterm and term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated haemolytic anaemia.

Cases of immune-mediated haemolytic anaemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Adverse reactions"). Severe cases of haemolytic anaemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.

If a patient develops anaemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated anaemia should be considered, and ceftriaxone should be discontinued until the aetiology is determined.

Prolonged treatment.

During prolonged treatment, a complete blood count should be performed regularly.

Colitis/overgrowth of resistant microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported with the use of nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhoea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant to ceftriaxone may occur.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended (see section "Dosage and administration").

Effect on serological test results.

When using the medicinal product Auroxson, the Coombs test may yield false-positive results. Auroxson may also cause false-positive results in galactosaemia screening tests (see section "Adverse reactions").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During ceftriaxone therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Adverse reactions").

Sodium.

Each gram of the medicinal product contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inadequate as monotherapy for certain types of infections, except when the causative pathogen has been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant organisms are suspected, additional antibiotics should be considered.

Use of lidocaine.

If lidocaine solution is used as a solvent, ceftriaxone may be administered only intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine medicinal product instructions must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Gallstone disease.

When shadows are observed on ultrasound, the possibility of ceftriaxone calcium salt precipitates should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, ceftriaxone calcium salt precipitates have been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on a benefit-risk assessment for the individual case (see section "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly due to biliary obstruction, have been reported in patients receiving ceftriaxone (see section "Adverse reactions"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, and total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone use cannot be excluded as a triggering or contributing factor.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). In symptomatic cases, ultrasound examination should be performed. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment for the individual case.

Encephalopathy.

Encephalopathy has been reported during ceftriaxone use (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of the medicinal product.

Environmental contamination by the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Any unused medicinal product or waste material after treatment completion or expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Limited data are available on the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects on embryonic/foetal, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the potential risk.

Breastfeeding.

Ceftriaxone is excreted in breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhoea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

Reproductive function studies have not shown any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. Due to the possible occurrence of adverse reactions such as dizziness, Auroxson may affect the ability to drive or operate machinery.

Method of administration and dosage.

Dosage

The dosage of the medicinal product depends on the severity, sensitivity, localization and type of infection, as well as on the patient's age and liver and kidney function.

Recommended dosages for specific indications are listed below. In particularly severe cases, the highest dose within the recommended range should be used.

Adults and children aged 12 years and older (≥ 50 kg)

Ceftriaxone dose*	Frequency of administration**	Indications
1–2 g	Once daily	Community-acquired pneumonia. Acute exacerbation of chronic obstructive pulmonary disease. Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis).
2 g	Once daily	Hospital-acquired pneumonia. Complicated skin and soft tissue infections. Bone and joint infections.
2–4 g	Once daily	Management of patients with neutropenia who develop fever and are suspected of having a bacterial infection. Bacterial endocarditis. Bacterial meningitis.

* In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens.

Acute otitis media

A single intramuscular dose of 1–2 g of ceftriaxone may be administered.

Some data suggest that in cases of severe clinical condition or when prior therapy has been ineffective, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.

Prophylaxis of surgical site infections

A single dose of 2 g prior to surgery.

Gonorrhea

500 mg as a single intramuscular dose.

Syphilis

The recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily in cases of neurosyphilis, for 10–14 days. Dose recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.

Disseminated Lyme borreliosis [early (Stage II) and late (Stage III)]

2 g once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be considered.

Children

Neonates, infants and children aged 15 days to 12 years (<50 kg)

Children with body weight of 50 kg or more should receive the standard adult doses.

Ceftriaxone dose*	Dosing frequency**	Indications
50–80 mg/kg	Once daily	Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia.
50–100 mg/kg (maximum 4 g)	Once daily	Complicated skin and soft tissue infections. Bone and joint infections. Management of febrile neutropenic patients suspected of bacterial infection.
80–100 mg/kg (maximum 4 g)	Once daily	Bacterial meningitis
100 mg/kg (maximum 4 g)	Once daily	Bacterial endocarditis

* In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

Indications in newborns, infants, and children aged 15 days to 12 years (< 50 kg) requiring special dosage regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has failed, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg once daily for 3 days.

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

The recommended dose is 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

Disseminated Lyme borreliosis [early (Stage II) and late (Stage III)]

50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Newborns aged 0–14 days

Ceftriaxone is contraindicated in preterm newborns up to 41 weeks of postmenstrual age (gestational age + postnatal age).

Ceftriaxone dose*	Frequency of administration	Indications
20–50 mg/kg	Once daily	Intra-abdominal infections. Complicated skin and soft tissue infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia. Bone and joint infections. Management of febrile neutropenic patients suspected of having a bacterial infection.
50 mg/kg	Once daily	Bacterial meningitis. Bacterial endocarditis.

* In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.

The maximum daily dose of 50 mg/kg should not be exceeded.

Indications in newborns aged 0–14 days requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose before surgery.

Syphilis

The recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Duration of treatment

The duration of treatment depends on the course of the disease. In accordance with general principles of antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Elderly patients

Dose adjustment is not required in elderly patients provided renal and hepatic functions are normal.

Patients with hepatic impairment

Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment if renal function is normal.

There are no study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

For patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.

If the patient is undergoing dialysis, there is no need for additional administration of the drug after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

In cases of concomitant severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Route of administration

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. The injection should be given into the central portion of the gluteal muscle. It is recommended not to inject more than 1 g at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to consult the medical instructions for lidocaine.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children up to 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special warnings and precautions for use"). Intramuscular administration should be considered when intravenous access is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤ 28 days) who require or are expected to require treatment with intravenous calcium-containing solutions, including infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone-calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").

For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes before surgery.

Instructions for reconstituting the medicinal product prior to administration are provided in the section "Special precautions for handling".

Children.

The medicinal product should be administered to children according to the dosing instructions specified in the section "Posology and method of administration".

Overdose.

In case of overdose, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone administration are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

The frequency of adverse reactions to ceftriaxone was determined based on clinical trial data.

Events are classified by frequency as follows:

Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Frequency not known (cannot be estimated from available data; based on post-marketing reports. Since reports of these reactions were voluntary and the population size is unknown, reliable frequency estimation is not possible; therefore, these are categorized as reactions with unknown frequency).

Infections and infestations: Uncommon: fungal genital infections; rare: pseudomembranous colitis; frequency not known: superinfections.

Blood and lymphatic system disorders: Common: eosinophilia, leukopenia, thrombocytopenia; uncommon: granulocytopenia, anemia, coagulation disorders; frequency not known: hemolytic anemia, agranulocytosis.

Immune system disorders: Frequency not known: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity, Jarisch–Herxheimer reaction.

Nervous system disorders: Uncommon: headache, dizziness; rare: encephalopathy; frequency not known: seizures.

Cardiac disorders: Frequency not known: Coombs' syndrome.

Aural and vestibular disorders: Frequency not known: vertigo.

Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm.

Gastrointestinal disorders: Common: loose stools, diarrhea; uncommon: nausea, vomiting; frequency not known: pancreatitis, stomatitis, glossitis.

Hepatobiliary disorders: Common: elevated liver enzymes; frequency not known: biliary precipitates, kernicterus, hepatitis\textsuperscript{1}, cholestatic hepatitis\textsuperscript{1,2}.

Skin and subcutaneous tissue disorders: Common: rash; uncommon: pruritus; rare: urticaria; frequency not known: Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders: Rare: hematuria, glucosuria; frequency not known: oliguria, renal precipitates (reversible).

General disorders and administration site conditions: Uncommon: phlebitis, injection site pain, malaise; rare: edema, chills.

Investigations: Uncommon: increased blood creatinine levels; frequency not known: false-positive Coombs' test, false-positive galactosemia test, false-positive results with non-enzymatic glucose tests.

Infections and infestations

Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions").

\textsuperscript{1} Usually reversible upon discontinuation of ceftriaxone.
\textsuperscript{1,2} See section "Special precautions".

Ceftriaxone calcium salt precipitates

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing products. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Contraindications", "Special precautions").

Cases of renal precipitates have been reported, primarily in children aged ≥ 3 years receiving high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, especially when additional risk factors were present (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special precautions").

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have reported varying incidence rates of precipitate formation after intravenous administration—over 30% in some studies. The incidence appears lower with slow infusion (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions").

Shelf life.

2 years.

Storage conditions.
Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

The prepared solution should be used within 6 hours at room temperature or within 24 hours if stored at 2–8 °C.

Incompatibilities.

Auroxon must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution.

The drug is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Should not be used with solvents other than those specified in the section "Dosage and administration".

Packaging.

The product is placed in a type 1 vial sealed with a stopper. One vial per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Ltd, India.

Manufacturer's address.

Unit–VI, Sy. No. 329/39 & 329/47, Chitkul Village, Patancheru Mandal, Medak District, Andhra Pradesh, India.

Marketing authorization holder.

Aurobindo Pharma Ltd, India.

Address of marketing authorization holder.

Plot No. 2, Maitrivihar, Ameerpet, Hyderabad – 500 038, A.P., India.