Ceftriaxone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 1.0 g.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: crystalline powder, from almost white to light yellow in color.

Pharmacotherapeutic group. Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, biosynthesis of the cell wall (peptidoglycan) is halted, leading to lysis and death of the bacterial cell.

Resistance

Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms:

• Hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably expressed in certain aerobic gram-negative bacteria.
• Reduced affinity of penicillin-binding proteins for ceftriaxone.
• Impermeability of the outer membrane in gram-negative bacteria.
• Bacterial efflux pump.

Breakpoints for susceptibility testing

Minimum inhibitory concentration (MIC) breakpoints have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Pathogen	Dilution method (minimum inhibitory concentration, mg/l)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	> 2
Staphylococcus spp.	a	a
Streptococcus spp. (groups A, B, C and G)	b	b
Streptococcus pneumoniae	≤ 0.5c	> 2
Streptococci group Viridans	≤ 0.5	> 0.5
Haemophilus influenzae	≤ 0.12c	> 0.12
Moraxella catarrhalis	≤ 1	> 2
Neisseria gonorrhoeae	≤ 0.12	> 0.12
Neisseria meningitidis	≤ 0.12 c	> 0.12
Non-species related	≤ 1d	> 2

a Susceptibility conclusion is based on susceptibility to cefoxitin.

b Susceptibility conclusion is based on susceptibility to penicillin.

c Rare isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints may occur; if observed, repeat testing should be performed and, if confirmed, isolates should be sent to a reference laboratory.

d Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose, at least 2 g × 1.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance in certain pathogen species may vary geographically and over time; therefore, local resistance data are desirable, especially when treating severe infections. If local resistance prevalence renders the use of the medicinal product questionable against at least some infection types, consultation with specialists is recommended.

Generally susceptible species

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.

Gram-negative aerobes

Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.

Species for which acquired resistance may be problematic

Gram-positive aerobes

Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.

Gram-negative aerobes

Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.

Anaerobes

Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.

Initially resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

• Resistance frequency >50% in at least one region.

% Strains producing extended-spectrum beta-lactamases are always resistant.

Pharmacokinetics.

Absorption

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration (Cmax) after a single 1 g intramuscular dose is 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration–time curve (AUC) after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of 1 g ceftriaxone, the mean peak plasma concentration is approximately 200 mg/L. After intravenous infusion of 1 g ceftriaxone, the plasma concentration is approximately 150 mg/L.

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear and nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean Cmax was observed upon repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration increases during meningeal inflammation. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningeal inflammation. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous administration. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (see section "Use during pregnancy or breastfeeding").

Protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the extent of binding decreases as concentration increases (to 85% at a plasma concentration of 300 mg/L).

Metabolism

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

Elimination

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

Patients with renal or hepatic impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderately prolonged half-life in renal impairment is explained by compensatory increase in extrarenal clearance due to reduced protein binding and the consequent increase in total ceftriaxone extrarenal clearance.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increase in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, leading to an apparent paradoxical increase in total drug clearance with an increase in volume of distribution parallel to total clearance.

Elderly patients

In patients aged 75 years and older, the mean elimination half-life is generally 2–3 times longer than in younger adults.

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as decreased glomerular filtration and impaired protein binding. In children, the elimination half-life is shorter than in neonates or adults.

Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.

Linearity/non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it occurs for total ceftriaxone in plasma but not for the free (unbound) fraction.

Pharmacokinetic/pharmacodynamic relationship

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index that best correlates with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for specific target species (i.e., % T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

Ceftriaxone 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;
• gonorrhoea;
• syphilis;
• bacterial endocarditis.

The medicinal product may be used for:

• treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme disease (early (stage II) and late (stage III)) in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of site infections during surgical procedures;
• management of patients with neutropenia who have developed fever suggestive of bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections are suspected.

The medicinal product should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special warnings and precautions for use").

Official recommendations on 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 ≤ 41 weeks of gestational age (gestational age + postnatal age)*.

In full-term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired in these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing solutions or infusions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special warnings and precautions for use" and "Undesirable effects").

* In vitro studies have shown that ceftriaxone may displace bilirubin from albumin binding, 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 warnings and precautions for use"). Refer to the lidocaine product 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 ceftriaxone in vials or for further dilution of reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts 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-site connector. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and neonatal umbilical plasma have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Contraindications", "Special warnings and precautions for use", "Dosage and administration", and "Undesirable effects").

Concomitant use of ceftriaxone 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 "Undesirable effects").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful monitoring of aminoglycoside levels (and renal function) according to clinical practice guidelines 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 interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).

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

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

Similarly, false-positive results may occur when urine glucose is tested by non-enzymatic methods. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

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 beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Cowden syndrome, a severe allergic reaction that can lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, administration of 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 beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis and drug reactions with eosinophilia and systemic symptoms (DRESS syndrome)) associated with ceftriaxone therapy have been reported. These reactions may be life-threatening or fatal, although the frequency of such events is unknown (see section "Side effects").

Interaction with calcium-containing medicinal products

Fatal cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitation except in neonates who received ceftriaxone and calcium-containing solutions or any 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 co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using separate infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided that different infusion systems are used at different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", 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 premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia

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

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

Prolonged treatment

Complete blood counts should be performed regularly during prolonged treatment.

Colitis/overgrowth of non-susceptible microorganisms

Cases of colitis and pseudomembranous colitis associated with antibiotic use have been reported during treatment with 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 diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfections caused by non-susceptible microorganisms 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 ceftriaxone, the Coombs test may yield false-positive results. Ceftriaxone may also cause false-positive results in galactosemia testing (see section "Side effects").

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 "Side effects").

Sodium

One gram of the medicinal product contains 3.6 mmol (83 mg) of sodium. This should be taken into account in patients on a sodium-restricted diet.

Antibacterial spectrum

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

Use of lidocaine

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

Cholelithiasis

On ultrasound imaging, shadows should raise suspicion of ceftriaxone-calcium salt precipitation. Ultrasound findings mimicking gallstones have been observed in the gallbladder, with increased frequency at ceftriaxone doses of 1 g per day or higher. Particular caution is advised when administering ceftriaxone to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone-calcium precipitates were associated with symptoms. If symptoms occur, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Side effects").

Biliary stasis

Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving ceftriaxone (see section "Side effects"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone use cannot be ruled out as an initiating or contributing factor in this disorder.

Nephrolithiasis

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). In case of symptoms, ultrasound examination should be performed. The decision to use ceftriaxone 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.

Jarisch-Herxheimer reaction (JHR)

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur shortly after initiation of ceftriaxone therapy. This reaction is typically self-limiting or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if a Jarisch-Herxheimer reaction occurs.

Encephalopathy

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), 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.

Use during pregnancy or breastfeeding

Pregnancy

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

Lactation

Ceftriaxone is excreted into 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 diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

During ceftriaxone therapy, side effects such as dizziness may occur, which can affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating 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 febrile neutropenic patients 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, consideration should be given to administering the drug twice daily (at 12-hour intervals).

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 used.

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

Prophylaxis of surgical site infections

A single dose of 2 g prior to surgery.

Gonorrhea

Single dose of 500 mg administered intramuscularly.

Syphilis

The recommended dose is 0.5–1 g once daily, increased to 2 g once daily in cases of neurosyphilis, for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be considered.

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

Children aged 15 days to 12 years (<50 kg)

Children with a body weight ≥ 50 kg should receive standard adult doses.

Ceftriaxone dose*	Frequency of administration**	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 with suspected bacterial infection
80–100 mg/kg (maximum – 4 g)	Once daily	Bacterial meningitis
100 mg/kg (maximum – 4 g)	Once daily	Bacterial endocarditis

*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 (at 12-hour intervals) should be considered.

Indications in children aged 15 days to 12 years (< 50 kg) 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. Some data suggest that in cases where the child's condition is severe or prior therapy has been ineffective, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day 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. Recommended treatment duration varies; national or local guidelines should also be considered.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates under 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 neutropenic patients with fever 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.

Geriatric patients

In patients with normal renal and hepatic function, dose adjustment is not required for elderly patients.

Patients with hepatic impairment

Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment, provided 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, dose reduction of ceftriaxone is not required if renal function is not impaired. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

If the patient is undergoing dialysis, there is no need for additional drug administration 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 impairment

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

Administration method

Intramuscular administration

Ceftriaxone may be administered via deep intramuscular injection. The injection should be given into the central portion of the gluteal muscle. It is recommended not to administer more than 1 g at a single injection 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 (the 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 infants and children under 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 precautions"). Intramuscular administration should be considered when intravenous access is not feasible or less appropriate 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 precautions", and "Incompatibility").

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

Recommended solution concentrations:

• Concentration for intravenous injection: 100 mg/mL
• Concentration for intravenous infusion: 50 mg/mL

Preparation of injection and infusion solutions:

Freshly prepared solutions are recommended. For storage conditions of the reconstituted solution, see section "Storage conditions".

Ceftriaxone must not be mixed in the same syringe with any other agent except 1% lidocaine hydrochloride solution (for intramuscular injections only).

The infusion line should be flushed after each administration.

Preparation of solutions for administration:

Ceftriaxone, powder for solution for injection or infusion, 1 g.

For intravenous injection: Reconstitute 1 g of Ceftriaxone with 10 mL of water for injection. The injection should be administered over 5 minutes directly into a vein or via an intravenous infusion line.

For intramuscular administration: Reconstitute 1 g of Ceftriaxone with 3.5 mL of 1% lidocaine hydrochloride solution. The solution should be administered via deep intramuscular injection. Doses exceeding 1 g should be divided and administered at more than one site.

The displacement volume of 1 g of ceftriaxone is 0.71 mL in water for injection and in 1% lidocaine hydrochloride solution. After adding 10 mL of water for injection, the final concentration of the reconstituted solution is 93.37 mg/mL. After adding 3.5 mL of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 237.53 mg/mL.

Children.

The drug should be administered to children according to the dosing instructions specified in the section "Administration and dosage".

Overdose.

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis do not effectively reduce excessive plasma concentrations of the drug. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone use 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, < 1/10)
uncommon (≥ 1/1,000, < 1/100)
rare (≥ 1/10,000, < 1/1,000)
frequency not known (cannot be estimated from available data; based on post-marketing reports; since these reports are voluntary and the size of the population is unknown, reliable estimation of frequency is not possible, thus these events are categorized as reactions with unknown frequency).

Infections and infestations: uncommon – genital fungal 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; unknown – Coombs' syndrome.

Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity, Jarisch-Herxheimer reaction (see section "Special precautions").

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

Ear and labyrinth 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 – increased liver enzymes; frequency not known – gallbladder precipitates\textsuperscript{2}, 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 syndrome) (see section "Special precautions").

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, fever; rare – swelling, chills.

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

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

Description of selected adverse reactions

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").

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 elimination half-life compared to adults (see sections "Contraindications" and "Special precautions").

Cases of renal precipitate formation have been reported, primarily in children receiving high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, as well as those with additional risk factors (e.g., limited fluid intake or bed rest). 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 shown variable rates of precipitate formation: in some studies, over 30%. The incidence is lower when the drug is administered slowly (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").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution is chemically and physically stable for 6 hours when stored at a temperature not exceeding 25 °C or for 24 hours when stored at 2–8 °C. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user.

Incompatibilities.

According to literature data, ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Ceftriaxone must not be mixed with certain calcium-containing diluents, such as Ringer's solution or Hartmann's solution, due to the potential for precipitate formation.

Solutions containing ceftriaxone must not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration".

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications", "Dosage and administration", "Special precautions", and "Adverse reactions").

When prescribing ceftriaxone in combination with another antibiotic, the drugs should be administered using separate syringes or separate infusion solutions.

Packaging.

1 vial or 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Kilu Pharmaceutical Co., Ltd. (High-Tech Zone Site)
Qilu Pharmaceutical Co., Ltd. (High-Tech Zone Site)

Manufacturer's address.

No. 317, Xinluo Road, High-tech Zone, Jinan, Shandong Province, 250101, P.R. China

Marketing Authorisation Holder.

M.BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom