Ceftriaxone

INSTRUCTIONS for medical use of the medicinal product ceftriaxone (Ceftriaxone)

Composition:

Active substance: ceftriaxone;

1 vial contains: ceftriaxone (as ceftriaxone sodium) – 1.0 g;

1 ampoule of solvent contains lidocaine hydrochloride solution (lidocaine hydrochloride monohydrate – 35 mg, sodium chloride, sodium hydroxide 1 M solution, water for injections)

or

1 ampoule of solvent contains water for injections – 10 ml.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder of nearly white or yellowish 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) ceases, leading to lysis of the bacterial cell and its death.

Resistance. Bacterial resistance to ceftriaxone may develop due to 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.
• Impermeability of the outer membrane in Gram-negative bacteria.
• Bacterial efflux pumps.

Breakpoints for susceptibility testing. Breakpoints for minimum inhibitory concentration, as 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
Viridans group Streptococci	≤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
Not species-related	≤1d.	>2

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

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

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

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

Clinical efficacy against specific pathogens

The prevalence of acquired resistance among specific species may vary geographically and over time; therefore, local information on resistance patterns is needed, especially in cases of severe infections. Expert advice should be sought if local resistance rates are such that the efficacy of the drug for treating at least some types of infections is questionable.

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, Providenspp., 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 intramuscular dose of 1 g is 81 mg/L, reached 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 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 substantially exceeding the minimum inhibitory concentrations for most clinically significant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, 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 with 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 is enhanced in the presence of meningeal inflammation. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of the plasma concentration, compared to 2% in patients without meningeal inflammation. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also detected in breast milk in low concentrations (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 degree of binding decreases as concentration increases (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. The 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 minimally altered, with only a slight increase in t½ (less than twofold), even in patients with severe renal impairment.

The moderate increase in t½ observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in extrarenal clearance of total ceftriaxone.

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

Elderly patients. In patients aged 75 years and older, the mean t½ is typically 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 protein binding. In children, t½ is shorter than in neonates or adults.

The 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 the free (unbound) fraction.

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 species (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 product should be administered 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 products or calcium-containing infusions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions for use" and "Undesirable effects").

* In vitro studies have shown that ceftriaxone may displace bilirubin from binding to serum albumin, which may lead to the development 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 for use"). Refer to the lidocaine product information, particularly contraindications.

Solutions of ceftriaxone 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 for reconstitution of the medicinal product 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 adult plasma and umbilical cord plasma from newborns have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Undesirable effects").

Concomitant use of the product with oral anticoagulants may potentiate 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 adjusted appropriately both 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 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 Coombs' test results 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 glucose in urine is tested by non-enzymatic methods. Therefore, during ceftriaxone therapy, glucose in urine 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 ceftriaxone elimination.

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 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 determine whether the patient has a history of severe hypersensitivity to ceftriaxone, other cephalosporins, or other types of β-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other β-lactam agents.

Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]) associated with ceftriaxone therapy have been reported, which may be life-threatening; 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. Symptomatic treatment may be required if such a reaction occurs. Antibiotic therapy should not be discontinued if this reaction develops.

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 disorders of the central nervous system. If encephalopathy is suspected to be related to ceftriaxone use (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, with fatal outcomes, have been reported. In at least one of these cases, 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 precipitates 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, regardless of patient age, even when using separate 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 given through separate infusion systems at different body sites or the infusion system is thoroughly flushed with saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider alternative antibacterial agents not associated with this precipitation risk. If ceftriaxone use is deemed necessary in patients on continuous TPN, 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 lines 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 newborns 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 during ceftriaxone therapy in both adults and children.

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

Prolonged therapy. 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 nearly all antibacterials, 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 "Adverse reactions"). 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 microorganisms resistant to ceftriaxone may occur.

Acute renal and hepatic impairment. In cases of acute renal or 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. Administration of the medicinal product may result in false-positive direct Coombs' test results. Ceftriaxone may also cause false-positive galactosemia test results (see section "Adverse reactions").

False-positive glucose in urine results may occur when non-enzymatic methods are used. During ceftriaxone therapy, glucose in urine should be measured 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. See the instructions for use of each system. Alternative methods of analysis should be used if necessary.

Spectrum of antibacterial activity. Ceftriaxone has a limited spectrum of antibacterial activity and may be inappropriate for use as monotherapy in the treatment of certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In cases of 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, shadows should raise suspicion of ceftriaxone-calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in the gallbladder on ultrasound, and their incidence increases with 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 precipitation has 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 an individual benefit-risk assessment (see section "Adverse reactions").

Biliary stasis. Cases of pancreatitis possibly caused by biliary tract 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, and total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone administration cannot be excluded as an initiating or contributing factor in the development of this condition.

Nephrolithiasis. Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (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 an individual benefit-risk assessment.

Sodium. One gram of ceftriaxone contains 3.6 mmol of sodium. This should be taken into account for 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, peri- 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 when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy should be made, 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 evidence of adverse effects on male or female fertility.

Ability to affect reaction speed 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 complex machinery.

Dosage and Administration.

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.

The 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, 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 illness or when prior therapy has been ineffective, Ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative surgical site infection prophylaxis. 2 g as a single dose before surgery.

Gonorrhea. Single intramuscular dose of 500 mg.

Syphilis. Recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily in 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

Children aged 15 days to 12 years (<50 kg). For children weighing 50 kg or more, the usual adult doses should be used.

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 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 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 been ineffective, 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 neonates under 41 weeks of gestational 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 with suspected 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.

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. According to 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. In the presence of normal renal and hepatic function, dose adjustment in elderly patients is not required.

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 in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment. In patients with impaired renal function, dose reduction of ceftriaxone is not required if hepatic function is normal. 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 a 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 dysfunction. 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 by deep intramuscular injection. The intramuscular injection should be given into the center 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 lidocaine package insert for medical 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 neonates 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) who require or are expected to require treatment with intravenous calcium-containing 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 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 "Incompatibilities").

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

Children.

The medicinal product is administered to children according to the dosing regimen specified in the section "Dosage and administration".

Overdose.

In case of overdose, hemodialysis or peritoneal dialysis do 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 associated with the use of ceftriaxone are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes. The frequency of adverse reactions to ceftriaxone was determined based on data from clinical studies.

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 gallbladderb Nuclear jaundice Hepatitisc Cholestatic hepatitib,c
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 kidneys (reversible)
General disorders and administration site reactions		Phlebitis Injection site reactions Hyperthermia	Edema Chills
Investigations		Increased blood creatinine levels		False-positive Coombs test resultsb False-positive galactosemia test resultsb 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 and therefore they are categorized as "frequency unknown".

b See section "Special precautions".

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 administered (see section "Special precautions").

Precipitation of ceftriaxone calcium salt. Rare, serious, and in some cases fatal adverse reactions have been reported in premature and full-term neonates (aged <28 days) who received intravenous ceftriaxone and calcium-containing solutions. Precipitates of ceftriaxone calcium salt were observed in the lungs and kidneys at autopsy. The high risk of precipitate formation in neonates is due to their small blood volume and longer t½ of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").

Cases of precipitation in the urinary tract have been reported, primarily in children treated with high doses (e.g., ≥80 mg/kg/day or total doses exceeding 10 g) and who have other risk factors (e.g., dehydration, bed rest). These cases may be symptomatic or asymptomatic and may lead to ureteral obstruction or post-renal acute kidney injury; however, they are usually reversible after discontinuation of ceftriaxone (see section "Special precautions").

Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitate formation with intravenous administration—over 30% in some studies. The incidence is lower with slow infusion (20–30 minutes). This effect is usually asymptomatic, but occasionally associated with clinical symptoms such as pain, nausea, and vomiting in isolated cases. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

Shelf life.

Ceftriaxone, powder for solution for injection, 1.0 g – 3 years.

Lidocaine, solution for injection, 10 mg/ml, 3.5 ml in ampoule – 3 years.

Water for injections, solvent for parenteral use, 10 ml in ampoule – 4 years.

The shelf life of the final preparation is determined by the component (powder or solvent) with the shorter expiration date.

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

Incompatibility.

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 should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". Ceftriaxone must not be mixed or co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions", and "Adverse reactions").

If ceftriaxone therapy is to be combined with another antibiotic, these products 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; or 1 or 5 vials in a blister, 1 blister per pack. One vial and one ampoule of solvent (Lidocaine, solution for injection, 10 mg/ml, 3.5 ml in ampoule) in a blister, 1 blister per pack. One vial and one ampoule of solvent (Water for injections, 10 ml in ampoule) in a blister, 1 blister per cardboard pack.

Prescription status. Prescription only.

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

Bulk production and packaging by the manufacturer Qilu Pharmaceutical Co., Ltd., China.

Manufacturer's address and place of business.

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

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