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.

Main physico-chemical properties: crystalline powder, almost white or yellowish in color.

Pharmacotherapeutic group. Antibacterial agents 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) ceases, leading to bacterial cell lysis and death.

Resistance. Bacterial resistance to ceftriaxone may develop through one or more of the following mechanisms:

• hydrolysis by β-lactamases, including extended-spectrum β-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• reduced outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Breakpoints for susceptibility testing. Breakpoints for minimum inhibitory concentration 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 of the Viridans group	≤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
Enterobacteriaceae	≤1	>2

a. The susceptibility conclusion was based on susceptibility to cefoxitin.

b. The susceptibility conclusion was based on susceptibility to penicillin.

c. Isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely observed. If such isolates are detected, repeat testing should be performed, and if confirmed, they should be sent to a reference laboratory.

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

Clinical efficacy against specific pathogens

The prevalence of acquired resistance among isolated species may vary depending on geographical location and time; therefore, local resistance data are needed, especially in cases of severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the drug questionable for treating at least some types of infections.

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.

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 β-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 after a single 1 g intramuscular dose is 81 mg/L, achieved within 2–3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration. After intravenous bolus injection of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma concentrations are approximately 120 mg/L and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.

Distribution. The volume of distribution of ceftriaxone is 7–12 L. Concentrations exceeding the minimum inhibitory concentrations for most clinically relevant 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 peak plasma concentration (Cmax) was observed upon repeated administration; 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 is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also detected in low concentrations in breast milk (see section "Use during pregnancy or breastfeeding").

Plasma 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 degree of binding decreases with increasing concentration (down to 85% at a plasma concentration of 300 mg/L).

Biotransformation. 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 (t½) 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 t½ (less than two-fold), even in patients with severe renal impairment.

The moderately prolonged t½ in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced plasma protein binding, resulting in increased total extrarenal clearance of ceftriaxone.

In patients with hepatic impairment, the t½ of ceftriaxone does not increase due to compensatory increases in renal clearance. This is also a result of increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance, with volume of distribution increasing in parallel to total clearance.

Elderly patients. In patients aged 75 years and older, the mean t½ is generally 2–3 times higher than in younger adults.

Children. The t½ of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired plasma protein binding. In children, t½ is shorter than in neonates or adults.

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

Linearity/non-linearity. The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except t½, are dose-dependent and decrease to a lesser extent than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding, and thus occurs for total ceftriaxone in plasma, but not for free (unbound) ceftriaxone.

Pharmacokinetic/pharmacodynamic relationship. As with other β-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 organisms (i.e., %T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

The medicinal product 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.

The medicinal product may be used for:

• treatment of acute exacerbation 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 aged from 15 days;
• preoperative prophylaxis of infections during surgical procedures;
• management of patients with neutropenia who develop fever suspected to be of bacterial origin;
• treatment of patients with bacteremia arising from any of the listed infections or when there is suspicion of any of the above-mentioned infections.

The drug should be prescribed in combination with other antibacterial agents if the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions for use").

Official recommendations on the 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 β-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, as bilirubin binding is likely impaired under 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 for use" and "Adverse reactions").

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

Before intramuscular injection of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). 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 ceftriaxone 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 solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type administration 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 precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Adverse reactions").

Concomitant use of the drug with oral anticoagulants may enhance the effect of vitamin K antagonists 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 appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxic effect 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.

False-positive results of the Coombs test may occur in patients receiving ceftriaxone.

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

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

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

Concomitant administration of probenecid does not reduce the elimination of ceftriaxone.

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 Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In the event of severe hypersensitivity reactions, administration of ceftriaxone should be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine 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 adverse reactions (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]), which may be life-threatening, have been reported in association with ceftriaxone therapy; however, the frequency of these events is unknown (see section "Adverse reactions").

Jarisch-Herxheimer reaction. Some patients with spirochetal infections may experience a Jarisch-Herxheimer reaction shortly after initiation of ceftriaxone therapy. Typically, the Jarisch-Herxheimer reaction is self-limiting or may be managed symptomatically. Antibiotic therapy should not be discontinued if this reaction occurs.

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

Interaction with calcium-containing medicinal products. Cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys of premature and full-term neonates under 1 month of age, some with fatal outcomes, have been reported. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased 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, even when using separate infusion systems or administering through different infusion sites, in patients of any age. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are administered through different infusion systems at different body sites or the infusion system is thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous TPN is deemed necessary, 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", "Adverse reactions", and "Incompatibilities").

Children. The safety and efficacy of ceftriaxone in 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 "Adverse reactions"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported in both adults and children during ceftriaxone therapy.

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

Prolonged therapy. During prolonged treatment, a complete blood count should be monitored regularly.

Colitis/Overgrowth of non-susceptible microorganisms.

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

As with other antibacterial agents, superinfections caused by non-susceptible microorganisms may occur.

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

Effect on serological test results. During ceftriaxone therapy, the Coombs test may yield false-positive results. Ceftriaxone may also cause false-positive results in galactosemia testing (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 methods (see section "Adverse reactions").

The presence of ceftriaxone may lead to falsely low glucose levels when certain blood glucose monitoring systems are used. Refer to the instructions for use of each system. Alternative methods of analysis should be used if necessary.

Antibacterial spectrum. Ceftriaxone has a limited antibacterial spectrum and may be inappropriate as monotherapy for certain types of infections unless the causative pathogen has 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 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. Precipitates, mistaken for gallstones, have been observed in gallbladder ultrasound scans, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering ceftriaxone to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone-calcium precipitates have been associated with symptoms. In symptomatic cases, conservative non-surgical management is recommended, and the physician should decide on discontinuation of ceftriaxone based on individual benefit-risk assessment (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 intensive therapy, severe illness, or 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.

Nephrolithiasis. Cases of kidney stone formation, resolving after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). Ultrasound examination should be performed if symptoms occur. The decision to use ceftriaxone in patients with a history of kidney stones or hypercalciuria should be made by the physician based on individual benefit-risk assessment.

Sodium. 1 gram of ceftriaxone contains 3.6 mmol of sodium. This should be taken into account in patients on a sodium-controlled diet.

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, perinatal, or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding. Ceftriaxone is excreted in breast milk in low concentrations, and no effects on infants are expected with 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/abandon ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility. Reproductive function studies have not shown evidence of adverse effects on male or female fertility.

Ability to affect reaction rate when driving or operating machinery.

Ceftriaxone may affect the ability to drive or operate machinery due to possible adverse reactions such as dizziness. Patients should exercise caution when driving or operating machinery.

Method of administration and dosage.

Dosage. The dose 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 doses 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 with suspected bacterial infection Bacterial endocarditis Bacterial meningitis

* 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, consideration should be given to administering the drug twice daily (with a 12-hour interval).

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 per day for 3 days.

Prophylaxis of surgical site infections. A single dose of 2 g prior to surgery.

Gonorrhea. Single intramuscular dose of 500 mg.

Syphilis. The recommended dose is 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing 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*	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 neutropenic patients with fever suspected to be of bacterial origin
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 (with a 12-hour interval) 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 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.

Surgical prophylaxis of surgical site infections.
A single dose of 50–80 mg/kg administered preoperatively.

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 neonates 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 must 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.

Perioperative 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. No dose adjustment is required in elderly patients if renal and hepatic functions are adequate.

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. Dose reduction of ceftriaxone is not required in patients with impaired renal function if renal function is not compromised. Only in patients with 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. Close clinical monitoring of the drug's safety and efficacy is recommended.

Patients with severe hepatic and renal dysfunction. In cases of concomitant severe impairment of both renal and hepatic function, close clinical monitoring of the drug's safety and efficacy is recommended.

Administration method

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 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"). The package leaflet for lidocaine should be consulted before use.

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 suitable for the patient. Doses exceeding 2 g should be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusion solutions 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 dissolve 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 "Incompatibilities").

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

Children.

The medicinal product should be used in children according to the dosing instructions specified in the section "Dosage and administration".

Overdose.

In case of overdose, hemodialysis or peritoneal dialysis will not effectively 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 use are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes. The frequency of adverse reactions to ceftriaxone was determined based on data from clinical trials.

Reactions are classified by frequency as follows:

Very common (≥1/10);

Common (≥1/100 to <1/10);

Uncommon (≥1/1000 to <1/100);

Rare (≥1/10000 to <1/1000);

Frequency not known (cannot be estimated from available data).

System Organ Class	Common	Uncommon	Rare	Frequency not known a
Infections and infestations		Genital fungal infections	Pseudomembranous colitisb	Superinfectionb
Blood and lymphatic system disorders	Eosinophilia Leukopenia Thrombocytopenia	Granulocytopenia Anemia Coagulopathy		Hemolytic anemiab Agranulocytosis
Immune system disorders				Anaphylactic shock Anaphylactic reaction Anaphylactoid reaction Hypersensitivityb Jarisch-Herxheimer reactionb
Cardiac disorders				Kounis syndrome
Nervous system disorders		Headache Dizziness	Encephalopathy	Convulsions
Ear and labyrinth disorders				Vertigo
Respiratory, thoracic and mediastinal disorders			Bronchospasm
Gastrointestinal disorders	Diarrheab Loose stools	Nausea Vomiting		Pancreatitisb Stomatitis Glossitis
Hepatobiliary disorders	Increased levels of liver enzymes			Precipitates in the gallbladderb Nuclear jaundice Hepatitisc Cholestatic hepatitisc,b
Skin and subcutaneous tissue disorders	Rash	Pruritus	Urticaria	Stevens-Johnson syndromeb Toxic epidermal necrolysisb Multiform erythema Acute generalized exanthematous pustulosis Drug reaction with eosinophilia and systemic symptoms (DRESS)b
Renal and urinary disorders			Hematuria Glucosuria	Oliguria Precipitates in the kidneys (reversible)
General disorders and administration site conditions		Phlebitis Administration site reactions Hyperthermia	Edema Chills
Investigations		Increased blood creatinine levels		False-positive Coombs testb False-positive galactosemia testb False-positive results in non-enzymatic glucose testsb

a Based on post-marketing reports. Since reports of these reactions were spontaneous and derived from a population of unknown size, it is not possible to reliably estimate their frequency; therefore, they are categorized as "frequency unknown".

b See section "Special precautions for use".

c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations. Cases of diarrhoea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be provided (see section "Special precautions for use").

Precipitation of ceftriaxone calcium salt. Rare cases of severe adverse reactions, sometimes fatal, have been reported in premature and full-term neonates (age <28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed ceftriaxone calcium precipitates in the lungs and kidneys. The high risk of precipitation in neonates is due to their small blood volume and longer ceftriaxone half-life (t½) compared to adults (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Cases of renal precipitation have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥80 mg/kg/day) or total doses exceeding 10 grams, and who also had additional risk factors (e.g., limited fluid intake or immobilization). Precipitates may be symptomatic or asymptomatic and can lead to ureteral obstruction and post-renal kidney injury, which are usually reversible after discontinuation of therapy (see section "Special precautions for use").

Cases of ceftriaxone calcium salt precipitation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. According to prospective studies in children, the incidence of precipitation following intravenous administration varied—exceeding 30% in some studies. The incidence of precipitation is lower when the drug is administered slowly (over 20–30 minutes). Precipitation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. After discontinuation of ceftriaxone, precipitates usually resolve (see section "Special precautions for use").

Reporting of adverse reactions following marketing authorization of the medicinal product is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children. No special storage conditions required.

Incompatibilities.

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

Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Ceftriaxone must not be mixed or combined with other medicinal products except those specified in the section "Method of administration and dosage". Ceftriaxone must not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Method of administration and dosage", "Special precautions for use", and "Adverse reactions").

If combination therapy with ceftriaxone and another antibiotic is planned, these drugs must not be mixed in the same syringe or in the same infusion solution.

Packaging. 1 g of powder in a vial; 1 or 5 or 50 vials per cardboard pack; 1 or 5 vials in a blister, 1 blister per pack.

Prescription status. Prescription only.

Manufacturer. Private Joint Stock Company "Lekhym-Kharkiv". LLC "Lekhym-Obukhiv".

Manufacturer's address and place of business.

Ukraine, 61115, Kharkiv region, Kharkiv, Severina Pototskogo St., 36.

Ukraine, 08700, Kyiv region, Obukhiv, Kyivska St., 126 A.

Date of last review.