Ceftriaxone 0.5
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product ceftriaxone 0.5 (Ceftriaxone 0.5)
Composition:
Active substance: ceftriaxone;
ceftriaxone (as ceftriaxone sodium) – 0.5 g;
1 set for preparation of solution for intravenous injections contains:
1 vial: ceftriaxone (as ceftriaxone sodium) – 0.5 g,
1 ampoule of 5 ml solvent: water for injections.
Medicinal form. Powder for solution for injections.
Main physicochemical properties: crystalline powder of nearly white or yellowish color.
Solvent: water for injections, colorless clear liquid, solvent for parenteral administration, 5 ml per ampoule.
Pharmacotherapeutic group. Antibacterial agents for systemic use. Other β-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 several 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;
- decreased 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) |
|
| Susceptible |
Resistant |
|
| Enterobacteriaceae |
≤1 |
>2 |
| Staphylococcus spp. |
a. |
a. |
| Streptococcus spp. (groups A, B, C and G) |
b. |
b. |
| Streptococcus pneumoniae |
≤0.5c. |
>2 |
| Streptococcus group Viridans |
≤0.5 |
>0.5 |
| Haemophilus influenzae |
≤0.12c. |
>0.12 |
| Moraxella catarrhalis |
≤1 |
>2 |
| Neisseria gonorrhoeae |
≤0.12 |
>0.12 |
| Neisseria meningitidis |
≤0.12 c. |
>0.12 |
| Not species-related |
≤1d. |
>2 |
| Enterobacteriaceae |
≤1 |
>2 |
a. The conclusion on susceptibility is based on susceptibility to cefoxitin.
b. The conclusion on susceptibility is based on susceptibility to penicillin.
c. Rare isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints may occur. If observed, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory.
d. Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose of at least 2 g × 1.
Susceptible organisms
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.
Organisms with potential for developing 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.
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 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) is observed with repeated administration; steady state is generally achieved within 48–72 hours, depending on the route of administration.
Penetration into specific tissues. Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also excreted in low concentrations into breast milk (see section "Use during pregnancy or breastfeeding").
Plasma protein binding. Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the degree of binding decreases as concentration increases (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 two-fold), even in patients with severe renal impairment.
The moderately prolonged half-life in renal impairment is explained by compensatory increases in extra-renal clearance due to reduced plasma protein binding and a corresponding increase in total extra-renal clearance of ceftriaxone.
In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This occurs as a result of increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance, with a parallel increase in volume of distribution and total clearance.
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 reduced glomerular filtration and impaired plasma 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 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 to a lesser extent than proportionally with dose. Non-linearity results from saturation of plasma protein binding, and thus is observed for total ceftriaxone in plasma, but not for the unbound (free) 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.
To be used 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 drug 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 site infections;
- 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 is suspected.
The drug should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special precautions for use").
Official recommendations on appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).
Ceftriaxone is contraindicated:
- in preterm newborns ≤41 weeks postmenstrual age (gestational age + postnatal age)*;
- in full-term newborns (≤28 days of age):
- with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired in these conditions*;
- who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salt (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 development of bilirubin encephalopathy in such patients.
Before intramuscular injection of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). 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.
Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute the medicinal product in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitate may form. 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-site system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitate formation (see sections "Dosage and method of administration", "Contraindications", "Special precautions for use", "Side effects", "Incompatibilities").
Concomitant use of the drug with oral anticoagulants may enhance the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be appropriately adjusted both during and after ceftriaxone therapy (see section "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 practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.
In an in vitro study, antagonistic effects were observed when chloramphenicol was used in combination with ceftriaxone. The clinical significance of these findings is unknown.
No cases of interaction between ceftriaxone and orally administered calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration) have been reported.
False-positive results of the Coombs test may occur in patients receiving ceftriaxone.
Like other antibiotics, ceftriaxone may cause false-positive results in tests for galactosemia.
Similarly, false-positive results may occur when glucose in urine is tested by non-enzymatic methods. For this reason, enzymatic methods should be used to determine glucose levels in urine 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 β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that can lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, administration of ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to 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 reactions such as Stevens-Johnson syndrome or Lyell’s syndrome (toxic epidermal necrolysis) and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported during ceftriaxone use, which 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, a Jarisch-Herxheimer reaction may occur shortly after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is usually self-limiting but may require symptomatic treatment. If such a reaction occurs, antibiotic therapy should not be discontinued.
Encephalopathy. Cases of encephalopathy have been reported with ceftriaxone use (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If encephalopathy associated with ceftriaxone use is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.
Interaction with calcium-containing medicinal products. Cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys of premature and full-term neonates under 1 month of age, some with fatal outcomes, have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitates have only been reported in neonates receiving 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 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 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 not associated with this precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, provided they are delivered through separate infusion systems 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", "Side effects", and "Incompatibilities").
Children. The safety and efficacy of ceftriaxone in children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.
Ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").
Immune-mediated hemolytic anemia. Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported in both adults and children during ceftriaxone treatment.
If anemia develops during ceftriaxone therapy, cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is determined.
Prolonged treatment. Complete blood counts should be monitored regularly during prolonged therapy.
Colitis/Overgrowth of resistant microorganisms. Cases of colitis and pseudomembranous colitis associated with antibacterial 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 "Side effects"). Discontinuation of ceftriaxone and initiation of appropriate therapy against Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.
As with other antibacterial agents, superinfections caused by microorganisms resistant to the drug may occur.
Severe renal and hepatic impairment. In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the medicinal product is recommended (see section "Dosage and administration").
Patients with severe renal dysfunction may develop disturbances of consciousness (loss of consciousness, decreased level of consciousness), seizures, or involuntary movements (choreoathetosis, myoclonus), etc. Such patients should be closely monitored, and appropriate measures, including discontinuation of the drug, should be taken if any disturbances occur.
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 "Side effects").
False-positive results may occur in non-enzymatic urine glucose tests. During ceftriaxone therapy, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").
Ceftriaxone use may falsely lower blood glucose readings obtained by certain blood glucose monitoring systems. Instructions for use for each system should be consulted. Alternative testing methods should be used if necessary.
Sodium. One gram of the medicinal product contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.
Antibacterial spectrum. Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant organisms 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 medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Gallstone disease. On ultrasound imaging, shadows should raise suspicion of ceftriaxone-calcium salt precipitates. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in gallbladder ultrasound scans, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering 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 on discontinuation of the drug 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 ceftriaxone (see section "Side effects"). 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 the medicinal product cannot be ruled out as a triggering or contributing factor.
Nephrolithiasis. Cases of kidney stone formation, resolving after discontinuation of ceftriaxone, have been reported (see section "Side effects"). In symptomatic cases, 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.
Disposal of the medicinal product. Environmental release of the medicinal product should be minimized. The medicinal product should not enter sewage systems or household waste. Any unused medicinal product after completion of treatment or expiry should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal.
Use during pregnancy or breastfeeding.
Pregnancy. Ceftriaxone crosses the placental barrier. Data on ceftriaxone use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.
Breastfeeding. Ceftriaxone passes into breast milk in low concentrations, and no effects on infants are expected with therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision on whether to discontinue breastfeeding or discontinue/abstain from ceftriaxone therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.
Fertility. Reproductive function studies have not shown adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery.
No specific studies have been conducted. Ceftriaxone may affect the ability to drive or operate machinery due to possible side effects such as dizziness.
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).
| Dose of ceftriaxone* |
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, consideration should be given to administering the drug twice daily (with a 12-hour interval).
Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens.
Acute otitis media. A single intramuscular dose of 1–2 g of ceftriaxone may be 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 daily for 3 days.
Preoperative prophylaxis of surgical site infections. Single dose of 2 g administered 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 cases of neurosyphilis, for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be considered.
Disseminated Lyme borreliosis [early (Stage II) and late (Stage III)]. 2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be taken into account.
Children
Neonates, infants, and children from 15 days to 12 years of age (<50 kg)
For children with body weight of 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 suspected of having a 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 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.
Neonates aged 0–14 days. Ceftriaxone is contraindicated in preterm neonates up to 41 weeks 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 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 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.
Prophylaxis of surgical site infections. 20–50 mg/kg as a single dose before surgery.
Syphilis. The recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.
Duration of treatment. The duration of treatment depends on the course of the disease. In accordance with general principles of antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of the bacterial infection is confirmed.
Elderly patients. No dose adjustment is required in elderly patients if renal and hepatic functions are adequate.
Patients with hepatic impairment. Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment, provided renal function is normal. There are no study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment. Dose reduction of ceftriaxone is not required in patients with impaired renal function if renal function is not severely 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 drug administration 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 hepatic and renal impairment, 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 lidocaine package insert for medical use.
Intravenous administration. Ceftriaxone may be administered by intravenous infusion over 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 up to 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 calcium-containing intravenous solutions, including intravenous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone-calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications," "Special precautions," and "Incompatibilities").
For surgical prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes prior to surgery.
Children.
The medicinal product should be administered to children according to the dosing instructions specified in the section "Dosage and administration."
Overdose.
In case of overdose, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse Reactions
The most commonly observed adverse reactions during ceftriaxone administration include eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.
The frequency of adverse reactions to ceftriaxone was determined based on clinical trial data.
Reactions are classified by frequency as follows:
- very common (≥1/10);
- common (≥1/100 to <1/10);
- uncommon (≥1/1000 to <1/100);
- rare (≥1/10,000 to <1/1000);
- frequency not known (cannot be estimated from available data).
Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous colitis; frequency not known – superinfections.
Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not known – hemolytic anemia, agranulocytosis.
Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions, Jarisch-Herxheimer reaction (see section "Special precautions for use").
Cardiac disorders: frequency not known – Kounis syndrome.
Nervous system disorders: uncommon – headache, dizziness; frequency not known – seizures; rare – encephalopathy.
Ear and labyrinth disorders: frequency not known – vertigo.
Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.
Gastrointestinal disorders: common – diarrhea, loose stools; uncommon – nausea, vomiting; frequency not known – pancreatitis, stomatitis, glossitis.
Hepatobiliary disorders: common – increased liver enzyme levels; frequency not known – biliary precipitates, kernicterus, hepatitis, cholestatic hepatitis (usually reversible upon discontinuation of ceftriaxone).
Skin and subcutaneous tissue disorders: common – rash; uncommon – pruritus; rare – urticaria; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), DR\ESS syndrome (drug reaction with eosinophilia and systemic symptoms) (see section "Special precautions for use"), erythema multiforme, acute generalized exanthematous pustulosis.
Renal and urinary disorders: rare – hematuria, glucosuria; frequency not known – oliguria, renal precipitates (reversible).
General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – swelling, chills.
Investigations: uncommon – increased blood creatinine levels; frequency not known – false-positive Coombs test results, false-positive galactosemia test results, false-positive results in non-enzymatic glucose tests.
Infections and infestations. Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions for use").
Ceftriaxone calcium salt precipitates. Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-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 precautions for use", and "Pharmacodynamics").
Cases of renal precipitate formation 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 had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation increases in immobilized patients or those with dehydration. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria. Precipitates resolve after discontinuation of ceftriaxone (see section "Special precautions for use").
Cases of ceftriaxone calcium salt precipitate formation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown 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 clinically with 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 of adverse reactions. Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua.
Shelf life.
Ceftriaxone 0.5, powder for solution for injection, 0.5 g – 3 years;
Water for injections, solvent for parenteral use, 5 ml in ampoule – 4 years.
The shelf life of the final preparation is determined by the component (powder or solvent) with the earlier expiration date.
Storage conditions.
Store in a place inaccessible to children.
Store in the original packaging at a temperature not exceeding 25 °C.
Incompatibilities.
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 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 administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions for use", and "Adverse reactions").
Packaging. 0.5 g of powder in a vial; 1, 10, or 50 vials per carton;
1 vial of powder and 1 ampoule of solvent (Water for injections, 5 ml in ampoule) in a blister, 1 blister per carton.
Prescription status. Prescription only.
Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".
Manufacturer's location and address of its place of business.
36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.