Ceftriaxone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE

Composition:

Active substance: ceftriaxone;

1 vial contains: sodium ceftriaxone equivalent to ceftriaxone 1000 mg.

Dosage form. Powder for solution for injection.

Main physicochemical properties: crystalline powder ranging from white to yellow-orange in color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Third-generation cephalosporins.

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 beta-lactamases, including extended-spectrum beta-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 permeability of the outer membrane in Gram-negative bacteria.
• Bacterial efflux pumps.

Breakpoints for susceptibility testing

Breakpoints for minimum inhibitory concentration have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

1. Information on the use of breakpoints in parentheses can be found at: https://www.eucast.org/eucastguidancedocuments/.
2. Isolates susceptible to benzylpenicillin may be considered susceptible to all beta-lactam antibacterial agents for which breakpoints have been established (including those with footnotes), without additional testing. Isolates resistant to benzylpenicillin should be tested for susceptibility to individual agents.
3. Susceptibility of staphylococci to cephalosporins is inferred from susceptibility to cefoxitin, except for cefixime, ceftazidime, ceftazidime-avibactam, cefditoren, and ceftolozane-tazobactam, for which breakpoints are not defined and which should not be used for treatment of staphylococcal infections. For orally administered agents, adequate exposure at the site of infection must be ensured. If susceptibility to cefotaxime and ceftriaxone is reported for methicillin-susceptible staphylococci, it should be reported as "Susceptible with increased exposure" (I). Some methicillin-resistant S. aureus isolates are susceptible to ceftaroline and ceftobiprole (see footnotes 6/D and 8/F).
4. Susceptibility of Streptococcus groups A, B, C, and G to cephalosporins is inferred from susceptibility to benzylpenicillin.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local resistance data are desirable, especially when treating severe infections. When necessary, if local resistance prevalence renders the benefit of ceftriaxone use, at least for treatment of certain infections, questionable, expert advice should be sought.

Generally susceptible species

Gram-positive aerobes

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

Gram-negative aerobes

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

Species with potential for acquired 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.

Initially resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others:

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

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

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

Pharmacokinetics.

Absorption

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g of ceftriaxone 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 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 secretions. An 8–15% increase in mean peak plasma concentration (Cmax) is observed with repeated dosing; steady state is generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates 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 that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (see section "Use during pregnancy or breastfeeding").

Protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the extent of binding decreases 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

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 of ceftriaxone in adults is approximately 8 hours.

Patients with renal or hepatic impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than 2-fold), even in patients with severe renal impairment.

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

In patients with impaired hepatic function, the elimination half-life 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 an increased volume of distribution.

Elderly patients

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

Children

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

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

Linearity/non-linearity

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

Pharmacokinetic/pharmacodynamic relationship

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

Preclinical safety data

Available animal study data indicate that high doses of the calcium salt of ceftriaxone led to the formation of precipitates and concretions in the gallbladder of dogs and monkeys, which were found to be reversible. Animal studies did not reveal toxic effects on the reproductive system or genotoxicity. Carcinogenicity studies with ceftriaxone have not been conducted.

Clinical characteristics.

Indications.

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

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

Ceftriaxone 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 15 days and older;
• surgical prophylaxis of infections at the site of intervention;
• management of neutropenic patients 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 these infections is suspected.

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

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

Contraindications.

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

Ceftriaxone is contraindicated:

In preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*.

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

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely to be 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" and "Side effects").

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

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of 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 connector. 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 plasma from adult and newborn umbilical cord blood have shown an increased risk of ceftriaxone-calcium salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Side effects", "Incompatibilities").

Concomitant use of ceftriaxone 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 adjusted appropriately both during and after ceftriaxone therapy (see section "Side effects").

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 guidelines 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 use) have been reported.

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

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

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions.

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

Serious skin adverse reactions (severe rash rapidly progressing with blistering or skin peeling and possibly oral lesions — Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported during ceftriaxone treatment; these reactions may be life-threatening or fatal. However, the frequency of these events is unknown (see section "Side effects").

Jarisch-Herxheimer reaction.

In some patients with infections caused by spirochetes, such as Lyme disease, Jarisch-Herxheimer reactions (fever, chills, headache, muscle pain, and skin rash) may occur shortly after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is usually self-limiting, but may occasionally require symptomatic treatment. Antibiotic therapy should not be discontinued if such a reaction occurs.

Interaction with calcium-containing medicinal products.

In preterm and full-term neonates under 1 month of age, cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys with fatal outcomes have been observed. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitation have not been reported except in newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that newborns 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 the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents that do not carry a similar risk of precipitation. If ceftriaxone administration is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, although through separate infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and the infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children.

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

The medicinal product is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

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

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

Prolonged treatment.

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

Colitis/overgrowth of non-susceptible microorganisms.

Cases of colitis and pseudomembranous colitis associated with the use of antibacterial agents have been reported during therapy 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 possible diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and administration of appropriate agents against Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.

Superinfections caused by microorganisms not susceptible to the drug may occur during antibacterial therapy.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the medicinal product is recommended (see section "Administration and dosage").

Effect on serological test results.

Ceftriaxone may cause false-positive results in the Coombs test. The drug may also cause false-positive results in galactosemia screening tests (see section "Side effects").

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

The presence of ceftriaxone may cause falsely low glucose readings in some blood glucose monitoring systems. Refer to the instructions for use of each test system. Alternative monitoring methods should be used if necessary.

Sodium.

1 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-controlled diet.

Antibacterial spectrum.

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

Use of lidocaine.

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

Cholelithiasis.

On ultrasound imaging, shadows should prompt consideration of ceftriaxone calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in gallbladder ultrasound scans, and their incidence increases with ceftriaxone doses of 1 g/day or higher. Particular caution should be exercised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone calcium salt has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether discontinuation of the drug is necessary based on an individual benefit-risk assessment (see section "Side effects").

Biliary stasis.

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

Nephrolithiasis.

Cases of kidney stone formation that resolved after discontinuation of ceftriaxone have been reported (see section "Side effects"). If symptoms occur, an ultrasound examination should be performed. The decision to administer the medicinal product to patients with a history of kidney stones or hypercalciuria should be made by the physician based on an individual benefit-risk assessment.

Encephalopathy.

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Administration and dosage") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonia, seizures), discontinuation of ceftriaxone should be considered.

Disposal of unused and expired medicinal product:
Environmental contamination by the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out via a designated waste collection system, if available.

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 passes into breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision on whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, side effects such as dizziness may occur, which may affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Dosage and Administration

Dosage

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

The doses listed below are generally recommended doses for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

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

* 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 the drug may be administered.

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 1–2 g per day for 3 days.

Preoperative prophylaxis of surgical site infections.

A single dose of 2 g prior to surgery.

Gonorrhea.

A single intramuscular dose of 500 mg.

Syphilis.

The recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily in cases of neurosyphilis, for 10–14 days. 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)

For children weighing 50 kg or more, the usual adult doses should be used.

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

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

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

Acute otitis media.

For initial treatment of acute otitis media, a single intramuscular injection of the drug at a dose of 50 mg/kg may be used. Some data suggest that in cases where the child's condition is severe or previous 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.

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 varies; national or local guidelines should also be considered.

Newborns aged 0–14 days

The medicinal product is contraindicated in preterm newborns with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

* 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 the drug at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections.

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

Syphilis.

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

Duration of treatment

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

Geriatric patients

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

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

For patients with impaired renal function, dose reduction of ceftriaxone is not required if renal function is not impaired. Only in patients with pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.

For patients undergoing dialysis, there is no need for additional administration of the drug after dialysis. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the drug's safety and efficacy is recommended.

Patients with severe hepatic and renal dysfunction

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

Administration method

Intramuscular administration

The drug may be administered by deep intramuscular injection. Intramuscular injection should be given into the center of a relatively large 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 refer to the lidocaine package insert.

Intravenous administration

The drug may be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children 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 warnings and precautions for use"). 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 calcium-containing intravenous solutions, including infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications").

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

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

The medicinal product is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation of injection and infusion solutions

Freshly prepared solutions are recommended. Storage conditions of the reconstituted medicinal product are described in the section "Storage conditions".

Ceftriaxone dissolves completely in the appropriate solvent within 150 seconds.

Ceftriaxone must not be mixed in the same syringe with any other medicinal product except 1% lidocaine hydrochloride solution (for intramuscular use only). The infusion line should be flushed after each administration.

Intravenous administration (injection or infusion)

Use in adults and children aged 12 years and older (≥ 50 kg)

Dissolve 1 g of ceftriaxone in 10 mL of water for injections. The vial should be gently rolled between the palms until the medicinal product is completely dissolved and foreign particles disappear.

For intravenous injection, the medicinal product should be administered directly into a vein or via an intravenous infusion system over 5 minutes (see section "Incompatibilities").

Alternatively, for intravenous infusion, the reconstituted solution should be transferred into 10 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride solution, 0.45% sodium chloride solution + 2.5% dextrose solution, 5% dextrose solution, 10% dextrose solution, 6% dextran in 5% dextrose solution, water for injections. The infusion should last at least 30 minutes (see section "Incompatibilities").

Use in pediatric practice

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

In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy.

The displacement volume for 1 g of ceftriaxone is 0.71 mL in water for injections and in 1% lidocaine hydrochloride solution. This requires adjustment of the solvent volume to ensure accurate dosing according to body weight (especially in children under 12 years of age) when only a portion of the total solution is measured and administered. To prepare a final solution concentration of 100 mg/mL, dissolve 1 g of ceftriaxone in 9.4 mL of water for injections.

Intramuscular injection

Use in adults and children aged 12 years and older (≥ 50 kg)

1 g of ceftriaxone should be dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The vial should be gently rolled between the palms until the drug is completely dissolved and foreign particles disappear. The solution should be administered by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at multiple different sites.

Use in pediatric practice

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

The displacement volume for 1 g of ceftriaxone is 0.71 mL in 1% lidocaine hydrochloride solution. This requires adjustment of the solvent volume to ensure accurate dosing according to body weight (especially in children under 12 years of age) when only a portion of the total solution is measured and administered.

To prepare a final solution concentration of 285 mg/mL, dissolve 1 g of ceftriaxone in 2.9 mL of 1% lidocaine hydrochloride solution.

Children.

The medicinal product should be administered to children at the doses specified in the section "Dosage and administration".

Overdose.

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

Adverse Reactions

The most commonly observed adverse reactions associated with ceftriaxone use are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

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

Events are classified by frequency as follows:

• Very common (≥ 1/10);
• Common (≥ 1/100 to < 1/10);
• Uncommon (≥ 1/1,000 to < 1/100);
• Rare (≥ 1/10,000 to < 1/1,000);
• Frequency not known (cannot be estimated from available data).

Infections and infestations: Uncommon – genital fungal infections; Rare – pseudomembranous colitis^b; Frequency not known^a – superinfections^b.

Blood and lymphatic system disorders: Common – eosinophilia, leukopenia, thrombocytopenia; Uncommon – granulocytopenia, anemia, coagulation disorders; Frequency not known^a – hemolytic anemia^b, agranulocytosis.

Cardiac disorders: Frequency not known^a – Kounis syndrome.

Immune system disorders: Frequency not known^a – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch-Herxheimer reaction (see "Special warnings and precautions for use").

Nervous system disorders: Uncommon – headache, dizziness; Rare – encephalopathy; Frequency not known^a – seizures.

Ear and labyrinth disorders: Frequency not known^a – vertigo.

Respiratory, thoracic and mediastinal disorders: Rare – bronchospasm.

Gastrointestinal disorders: Common – diarrhea^b, loose stools; Uncommon – nausea, vomiting; Frequency not known^a – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: Common – increased liver enzymes; Frequency not known^a – gallbladder precipitates^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,^c.

Skin and subcutaneous tissue disorders: Common – rash; Uncommon – pruritus; Rare – urticaria; Frequency not known^a – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see "Special warnings and precautions for use"), acute generalized exanthematous pustulosis.

Renal and urinary disorders: Rare – hematuria, glucosuria; Frequency not known^a – oliguria, renal precipitates (reversible).

General disorders and administration site conditions: Uncommon – phlebitis, injection site pain, chills; Rare – swelling, rigors.

Investigations: Uncommon – increased blood creatinine; Frequency not known^a – false-positive Coombs test^b, false-positive galactosemia test^b, false-positive results in non-enzymatic glucose tests^b.

^a Based on post-marketing reports. Since these reactions are voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency, hence the classification as "frequency not known".

^b See section "Special warnings and precautions for use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

Cases of diarrhea following ceftriaxone use may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see "Special warnings and precautions for use").

Ceftriaxone calcium salt precipitates.

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

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone (see "Special warnings and precautions for use").

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing 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 via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C. The reconstituted solution should be used within 6 hours if stored at room temperature and within 24 hours if stored at 2–8 °C.

Incompatibilities.

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

It should not be mixed or combined with other drugs except those specified in the section "Dosage and administration". Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, due to the risk of precipitate formation. Ceftriaxone must not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special warnings and precautions for use", and "Adverse reactions").

For combinations with other antibiotics, separate syringes or solutions should be used.

Packaging.

Powder in glass vials; 1, 5, or 10 vials per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

NSPC Hebei Huamin Pharmaceutical Company Limited.

Manufacturer's address.

No. 98 Huan Road, Economic and Technological Development Zone, Shijiazhuang, Hebei 052165, China.