Ceftriaxone 500: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE 500 CEFTRIAXONE 1000 (Ceftriaxone 500) (Ceftriaxone 1000)

Composition:

Active substance: ceftriaxone;

ceftriaxone (as ceftriaxone sodium) 0.5 g or 1 g.

1 set for preparation of solution for intramuscular injections contains:

1 vial: ceftriaxone (as ceftriaxone sodium) — 1 g.

1 ampoule of 3.5 ml solvent: lidocaine, injection solution, 10 mg/mL.

1 set for preparation of solution for intravenous injections contains:

1 vial: ceftriaxone (as ceftriaxone sodium) — 0.5 g or 1 g.

1 ampoule of 5 mL or 10 mL solvent: water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder of nearly white or yellowish color.

Solvent: lidocaine, injection solution, 10 mg/mL, 3.5 mL in ampoule;

main physicochemical properties: clear colorless or slightly colored liquid.

Solvent: water for injections, solvent for parenteral use, 5 mL or 10 mL in ampoule;

main physicochemical properties: colorless transparent liquid, tasteless and odorless.

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 bacterial cell lysis and 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 induced or stably derepressed in certain aerobic gram-negative bacteria;
reduced affinity of penicillin-binding proteins for ceftriaxone;
reduced permeability 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)
Pathogen	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	≤0.12c.	>0.12
Not species-related	≤1d.	>2
Enterobacteriaceae	≤1	>2

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

b. The conclusion on susceptibility was 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 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 information on resistance patterns is required, especially in cases of severe infections. Expert advice should be sought when 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 that may develop resistance

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.

Organisms with intrinsic resistance

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 following a single intramuscular dose of 1 g 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 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 relevant 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 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 is enhanced during meningeal inflammation. 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 meningeal inflammation. Peak concentrations in cerebrospinal fluid are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also present 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 extent of binding decreases with increasing concentration (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 moderate increase in t½ observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding, resulting in increased extrarenal clearance of total ceftriaxone.

In patients with hepatic impairment, 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 clearance of the drug, paralleled by an increase in volume of distribution.

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 older 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 due to saturation of plasma protein binding and is therefore observed 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 organisms (i.e., %T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

Used for the treatment of the following infections in adults and children, including 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 from 15 days of age;
preoperative prophylaxis of infections during surgical procedures;
management of patients with neutropenia who develop fever suspected to be due to 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 if the possible range of bacterial pathogens is not covered by its spectrum of activity (see section "Special precautions for use").

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

Contraindications.

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

Ceftriaxone is contraindicated:

in preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;
in term newborns (aged ≤ 28 days):
with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis — since bilirubin binding is likely impaired under these conditions*;
who require (or are expected to require) intravenous administration of calcium-containing drugs or calcium-containing infusions — due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions for use" and "Side effects").

* 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 administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). See the instructions for medical use of lidocaine, particularly contraindications.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

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. 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 solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in all patients except 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 newborn umbilical plasma have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and method of administration", "Contraindications", "Special precautions for use", "Side effects", "Incompatibilities").

Concomitant use of the drug 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 during and after ceftriaxone therapy (see section "Side 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 monitoring recommendations for 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 galactosemia testing.

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 disturbances have been observed in patients receiving high doses of ceftriaxone concomitantly with 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, there have been reports of serious hypersensitivity reactions, sometimes fatal (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Couney's syndrome — a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In cases 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 reactions 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 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 syndrome), 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. In some patients with infections caused by spirochetes, a Jarisch-Herxheimer reaction may develop shortly after initiation of ceftriaxone therapy. This reaction is usually self-limiting, but symptomatic treatment may occasionally be required. If a Jarisch-Herxheimer reaction occurs, antibiotic therapy should not be discontinued.

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 is suspected to be associated with ceftriaxone use (e.g., decreased level of consciousness, altered mental status, myoclonia, 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 have been reported in premature and full-term neonates under 1 month of age, some of which were fatal. In at least one of these cases, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. No confirmed cases of intravascular precipitate formation have been reported 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 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 different infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are given through separate infusion systems at different body sites or the infusion system is replaced or 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 prescribing alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous parenteral 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", "Adverse reactions", and "Incompatibilities").

Children. The safety and efficacy of ceftriaxone in children have been established when using 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 antibiotics, 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 monitored regularly.

Colitis / overgrowth of non-susceptible microorganisms. Cases of colitis and pseudomembranous colitis associated with antibiotic use have been reported 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 "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 not susceptible 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. The Coombs test may yield false-positive results during ceftriaxone therapy. 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, glucose in urine should be determined using enzymatic methods (see section "Adverse reactions").

Ceftriaxone may lead to falsely low results when using certain blood glucose monitoring systems. Refer to the respective instructions for use of the system. Alternative methods of analysis should be used if necessary.

Sodium. One gram of the medicinal product Ceftriaxone contains 3.6 mmol of sodium. This should be taken into account if the patient is on a sodium-restricted diet.

Spectrum of antibacterial activity. Ceftriaxone has a limited spectrum of antibacterial activity and may be inappropriate for use as monotherapy in 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 organisms are suspected, additional antibiotics should be considered.

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

Gallstone disease. In the presence of shadows on ultrasound, the possibility of ceftriaxone-calcium salt precipitate formation should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases with ceftriaxone doses of 1 g/day or higher. Particular caution is advised when administering the drug 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 treatment is recommended, and the physician should decide whether to discontinue the drug based on an individual benefit-risk assessment (see section "Adverse reactions").

Biliary stasis. Cases of pancreatitis, possibly due to 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, or total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone administration cannot be ruled out as a triggering or contributing factor.

Nephrolithiasis. Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). If symptoms occur, an 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 an individual benefit-risk assessment.

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 benefit outweighs the potential risk.

Breastfeeding. Ceftriaxone passes into breast milk in low concentrations, and no effects on infants are expected when the drug is used at therapeutic doses. However, the risk of developing diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should also be considered. 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 mother.

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.

Appropriate studies have not been conducted. 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.

Method of administration and dosage.

Dosage. The dose of the medicinal product depends on the severity, sensitivity, location, 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 patients with neutropenia who develop fever and are suspected of bacterial infection Bacterial endocarditis Bacterial meningitis

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

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

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

Acute otitis media. A single intramuscular dose of 1–2 g may be administered.

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. 500 mg as a single intramuscular dose.

Syphilis. The recommended dose is 500 mg – 1 g once daily, increasing 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 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 may vary; 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 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 (with a 12-hour interval) should be considered.

Indications in neonates, infants, and 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 previous ineffective therapy, 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 considered.

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.

Neonates aged 0–14 days. Ceftriaxone is contraindicated in preterm neonates under 41 weeks of postmenstrual age (gestational age + chronological age).

Ceftriaxone dose*

Frequency of administration

Indications

20–50 mg/kg

Once daily

Intra-abdominal infections

Complicated skin and soft tissue infections

Complicated urinary tract infections (including pyelonephritis)

Community-acquired pneumonia

Hospital-acquired pneumonia

Bone and joint infections

Management of febrile neutropenic patients suspected of having a bacterial infection

50 mg/kg

Once daily

Bacterial meningitis

Bacterial endocarditis

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

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

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

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

Preoperative prophylaxis of surgical site infections. 20–50 mg/kg as a single dose before surgery.

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

Duration of treatment. Duration of treatment depends on the course of the disease. In accordance with general principles of antibiotic therapy, ceftriaxone treatment should be continued for 48–72 hours after fever subsides or after confirmation of eradication of bacterial infection.

Geriatric patients. No dose adjustment is required for 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 or 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 compromised. 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 dosing after dialysis. Ceftriaxone is not eliminated from the body 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.

Route of administration

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

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

Intravenous administration. Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children 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 administration 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 calcium salts of ceftriaxone (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 calcium salts of ceftriaxone 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 should be administered to children according to the dosing regimen specified in the section "Dosage and administration".

Overdose.

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

Adverse Reactions

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

The frequency of adverse reactions to ceftriaxone was determined based on 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).

Body systems	Common	Uncommon	Rare	Frequency unknowna
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 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 liver enzymes			Precipitates in gallbladderb Nuclear jaundice Hepatitisc Cholestatic hepatitisb,c
Skin and subcutaneous tissue disorders	Rash	Itching	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 Renal precipitates (reversible)
General disorders and administration site reactions		Phlebitis Injection site reactions Hyperthermia	Edema Chills
Effects on laboratory test results		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 these reactions were reported spontaneously and derived from a population of unknown size, it is not possible to reliably estimate their frequency; therefore, they are categorized as "frequency not known".

b See section "Special precautions for use".

c Usually reversible after discontinuation of ceftriaxone.

Infections and infestations. Diarrhea occurring after administration of ceftriaxone 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 (aged <28 days) who received intravenous ceftriaxone and calcium-containing medications. Post-mortem examinations revealed ceftriaxone calcium salt 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 bed rest). The risk of precipitation increases in immobilized patients or those who are dehydrated. Precipitates may be symptomatic or asymptomatic and may lead to ureteral obstruction and post-renal kidney injury, which are, however, usually reversible after discontinuation of therapy (see section "Special precautions for use").

Cases of biliary precipitation of ceftriaxone calcium salt have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitation following intravenous administration—over 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. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

Ceftriaxone 500, powder for solution for injection, 0.5 g – 3 years;

Ceftriaxone 1000, powder for solution for injection, 1 g – 3 years;

Lidocaine, solution for injection, 10 mg/mL, 3.5 mL in ampoule – 3 years;

Water for injections, solvent for parenteral use, 5 mL or 10 mL in ampoule – 4 years.

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

Storage conditions.

Keep out of reach and sight of 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 formation of precipitates.

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

Ceftriaxone must not be mixed or combined with other medicinal products except those specified in 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 for use", and "Adverse reactions").

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

Packaging. 0.5 g of powder in a vial; 1, 10, or 50 vials per carton; or 1 vial per blister, 1 blister per carton; or 5 vials per blister, 2 blisters per carton;

1 vial of powder and 1 ampoule of solvent (water for injections, solvent for parenteral use, 5 mL in ampoule) in a blister; 1 blister per carton.

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

1 vial of powder and 1 ampoule of solvent (lidocaine, solution for injection, 10 mg/mL, 3.5 mL in ampoule) in a blister; 1 blister per carton;

1 vial of powder and 1 ampoule of solvent (water for injections, solvent for parenteral use, 10 mL in ampoule) in a blister; 1 blister per carton.

Prescription status. Prescription only.

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

Manufacturer's address and location of its business operations.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

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