Brescek
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRESAC (BRESEC®)
Composition:
Active substance: ceftriaxone;
1 vial contains: ceftriaxone sodium equivalent to ceftriaxone 1 g or 2 g.
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: almost white or yellowish crystalline powder.
Pharmacotherapeutic group.
Antibacterials 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. This leads to interruption of cell wall (peptidoglycan) biosynthesis, resulting in bacterial cell lysis and death. Resistance.
Bacterial resistance to ceftriaxone may develop via one or more of the following mechanisms:
- Hydrolysis by beta-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 outer membrane permeability in Gram-negative bacteria.
- Bacterial efflux pumps.
Breakpoint values for susceptibility testing
Breakpoints for minimum inhibitory concentration (MIC) have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):
| Pathogen |
Dilution method (minimum inhibitory concentration, mg/l) |
|
| Susceptible |
Resistant |
|
| Enterobacteriaceae |
≤ 1 |
> 2 |
| Staphylococcus spp. |
a |
a |
| Streptococcus spp. (groups A, B, C and G) |
b |
b |
| Streptococcus pneumoniae |
≤ 0.5c |
> 2 |
| Viridans group streptococci |
≤ 0.5 |
> 0.5 |
| Haemophilus influenzae |
≤ 0.12c |
> 0.12 |
| Moraxella catarrhalis |
≤ 1 |
> 2 |
| Neisseria gonorrhoeae |
≤ 0.12 |
> 0.12 |
| Neisseria meningitidis |
≤ 0.12 c |
> 0.12 |
| Non-species related |
≤ 1d |
> 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; if observed, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory;
d the breakpoints refer to a daily intravenous dose of 1 g × 1 and a high dose of at least 2 g × 1.
Clinical efficacy against specific pathogens
The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local information on resistance is desirable, especially when treating severe infections. Expert consultation should be sought if local resistance prevalence renders the benefit of ceftriaxone at least questionable for certain types of infections.
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, Streptococci of the Viridans group.
Gram-negative aerobes.
Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.
Species for which acquired resistance may be problematic.
Gram-positive aerobes.
Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+. Gram-negative aerobes.
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens. Anaerobes.
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens. 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 β-lactamases are always resistant.
Pharmacokinetics.
Absorption.
Intramuscular administration.
After intramuscular injection, the average 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 and is 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 500 mg and 1 g of ceftriaxone, the average peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of 500 mg, 1 g, and 2 g of ceftriaxone, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.
Distribution.
The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically significant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in average peak plasma concentration (Cmax) was observed with repeated administration; steady state was generally achieved within 48–72 hours, depending on the route of administration.
Penetration into specific tissues.
Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The average peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence is expected in low concentrations in breast milk (see section "Use during pregnancy or breastfeeding").
Plasma protein binding.
Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the degree of binding decreases as concentration increases (to 85% at a plasma concentration of 300 mg/L).
Metabolism.
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 twofold), even in patients with severe renal impairment. The relatively modest increase in half-life with renal impairment is explained by compensatory increases in extrarenal clearance due to reduced plasma protein binding and a corresponding increase in total extrarenal clearance of ceftriaxone.
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, contributing to the observed paradoxical increase in total drug clearance with an increase in volume of distribution parallel to total clearance.
Elderly patients.
In patients aged 75 years and older, the average 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 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 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 based on total drug concentration, decreasing less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it occurs for total ceftriaxone in plasma, but not for free (unbound) ceftriaxone.
Pharmacokinetic/pharmacodynamic relationship.
As with other β-lactams, the pharmacokinetic/pharmacodynamic index that best correlates with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for specific target species (i.e., %T > minimum inhibitory concentration).
Clinical characteristics.
Indications.
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.
Brescek 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;
- preoperative prophylaxis of surgical 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 there is suspicion of any of the above-mentioned infections.
Brescek 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").
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 neonates aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;
− in full-term newborns (aged ≤ 28 days):
- with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired under these conditions*;
- who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions" and "Adverse reactions").
*In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thereby increasing the risk 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"). Refer to the instructions for medical use of lidocaine, particularly contraindications.
Solutions of ceftriaxone containing lidocaine must never be administered intravenously.
Under no circumstances should ceftriaxone be used with calcium-containing solutions (Ringer's solution)! Calcium-containing solutions must not be administered within 48 hours after the last dose of ceftriaxone.
Interaction with other medicinal products and other types of interactions.
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of Brescek 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 administration system. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and neonatal umbilical plasma have shown an increased risk of ceftriaxone-calcium salt precipitation in neonates (see sections "Contraindications", "Special precautions", "Method of administration and dosage", "Adverse reactions", "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 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 "Adverse reactions").
There are conflicting data regarding the potential for increased nephrotoxic effect of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.
An in vitro study showed antagonistic effects 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 in 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 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 the excretion of ceftriaxone.
Special precautions for use.
Hypersensitivity reactions.
As with all β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Coombs syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, 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.
Serious adverse skin reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and reactions with eosinophilia and systemic symptoms (DRESS) have been reported during ceftriaxone use; these may be life-threatening or fatal; however, the frequency of such events is unknown (see section "Adverse reactions").
Jarisch-Herxheimer reaction (JHR).
In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone therapy. JHR is usually self-limiting, or symptomatic treatment may be administered. Antibiotic therapy should not be discontinued if such a reaction occurs.
Interaction with calcium-containing medicinal products.
Fatal cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. Confirmed cases of intravascular precipitates have not 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 have an 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 different infusion systems or different infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through different infusion systems into 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), healthcare providers may consider alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different 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 "Pharmacokinetics", "Contraindications", "Adverse reactions", "Incompatibilities").
Children.
The safety and efficacy of ceftriaxone (Bressek) in neonates, infants, and 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. Bressek 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 Bressek (see section "Adverse reactions"). Severe cases of hemolytic anemia, including fatal cases, have been reported during Bressek treatment in both adults and children.
If a patient develops anemia during ceftriaxone therapy, cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is determined.
Prolonged therapy.
During prolonged treatment, a complete blood count should be performed regularly.
After ceftriaxone administration, particularly at doses exceeding standard recommended doses, shadows may be observed on ultrasound examination of the gallbladder, which may be misinterpreted as gallstones. These are precipitates of ceftriaxone calcium salt that disappear after completion or discontinuation of ceftriaxone therapy. Such changes are rarely associated with any symptoms. Conservative treatment is recommended even in such cases. However, if clinical symptoms occur, the decision to discontinue the drug should be made by the physician.
Pancreatitis, possibly due to biliary tract obstruction, has been reported in patients receiving ceftriaxone. Most of these patients had risk factors for biliary stasis, such as prior treatment, severe illness, and total parenteral nutrition. The role of ceftriaxone-induced precipitates in the biliary tract in the development of pancreatitis cannot be excluded.
Ceftriaxone may displace bilirubin from its binding to serum albumin, which may increase the risk of encephalopathy. Therefore, the use of ceftriaxone in neonates with hyperbilirubinemia is contraindicated (see section "Contraindications"). Caution should be exercised when using ceftriaxone in patients with renal impairment who are concurrently receiving aminoglycosides and diuretics.
Ceftriaxone must not be mixed or co-administered with calcium-containing solutions, even when administered through different infusion systems. Fatal cases of precipitates in the lungs and kidneys have been reported in neonates and premature infants after simultaneous administration of ceftriaxone and calcium-containing drugs. Cases of intravascular precipitates after concomitant use of ceftriaxone with intravenous calcium-containing solutions have also been reported in patients of other age groups. Therefore, calcium-containing solutions for intravenous administration must not be used in neonates and patients of other age groups for at least 48 hours after the last dose of ceftriaxone (see section "Contraindications").
Colitis / overgrowth of non-susceptible microorganisms.
Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported during the use of 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 administration of appropriate agents against Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.
As with other antibacterial agents, superinfections caused by microorganisms not susceptible to the drug may occur.
Severe renal and hepatic impairment.
In cases of severe renal and hepatic impairment, careful clinical monitoring of drug safety and efficacy is recommended (see section "Dosage and administration").
Effect on serological test results.
The use of Bressek may result in false-positive Coombs test results. Bressek may also cause false-positive galactosemia test results (see section "Adverse reactions").
False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Bressek therapy, urine glucose levels should be determined using enzymatic test methods (see section "Adverse reactions").
Ceftriaxone use may cause falsely low blood glucose readings when measured with certain glucose monitoring systems. Refer to the instructions for use of each specific system. Alternative testing methods should be used if necessary.
Sodium.
Each gram of Bressek 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 use as monotherapy in treating certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In cases of polymicrobial infections where resistant microorganisms are suspected, additional antibiotics should be considered.
Use of lidocaine.
When lidocaine solution is used as a solvent, ceftriaxone may be administered only intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Cholelithiasis.
In case of shadows on sonography, the possibility of ceftriaxone calcium salt precipitate formation should be considered. Shadows, misinterpreted as gallstones, have been observed on gallbladder sonography; their frequency increases with ceftriaxone doses of 1 g per day or higher. Particular caution should be exercised when using the drug in children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone calcium salt precipitate formation has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on a benefit-risk assessment for the individual case (see section "Adverse reactions").
Biliary stasis.
Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving Bressek (see section "Adverse reactions"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to Bressek use cannot be excluded as an initiating or contributing factor in the development of this disorder.
Nephrolithiasis.
Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). In case of symptoms, ultrasound examination should be performed. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment for the individual case.
Encephalopathy.
Encephalopathy has been reported during ceftriaxone use (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. In suspected ceftriaxone-associated encephalopathy (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.
Disposal of unused or 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 using a dedicated "waste collection system" if available.
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, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.
Breastfeeding period.
Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed 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/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 shown evidence of adverse effects on male or female fertility.
Ability to affect reaction speed when driving vehicles or operating machinery.
During ceftriaxone therapy, adverse reactions such as dizziness may occur, which may affect the ability to drive vehicles or operate machinery (see section "Adverse reactions"). Patients should exercise caution when driving vehicles or operating machinery.
Method of administration and dosage.
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 following dosages are generally recommended for these indications. In particularly severe cases, the highest dose within the recommended range should be used.
Table 1
Adults and children aged 12 years and older (≥ 50 kg).
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 1–2 g |
Once daily |
Community-acquired pneumonia. Acute exacerbation of chronic obstructive pulmonary disease. Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis) |
| 2 g |
Once daily |
Hospital-acquired pneumonia. Complicated skin and soft tissue infections. Bone and joint infections |
| 2–4 g |
Once daily |
Management of febrile neutropenic patients suspected of bacterial infection. Bacterial endocarditis. Bacterial meningitis |
* In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.
** When doses exceeding 2 g per day are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).
Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens:
Acute otitis media.
A single intramuscular dose of 1–2 g of Brescek may be administered.
Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Brescek may be effective when administered intramuscularly at a dose of 1–2 g once daily for 3 days.
Preoperative prevention of surgical site infections.
A single dose of 2 g prior to surgery.
Gonorrhea.
A single intramuscular dose of 500 mg.
Syphilis.
The generally recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dose recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III)).
2 g once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be considered.
Children.
Neonates, infants, and children from 15 days to 12 years of age (<50 kg).
Children with a body weight of 50 kg or more should receive the standard adult doses.
Table 2
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 50–80 mg/kg |
Once daily |
Intra-abdominal infections. |
| 50–100 mg/kg (maximum – 4 g) |
Once daily |
Complicated skin and soft tissue infections. |
| 80–100 mg/kg (maximum 4 g) |
Once daily |
Bacterial meningitis |
| 100 mg/kg |
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, consideration should be given to administering the drug twice daily (with a 12-hour interval).
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 Brescek at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or previous ineffective therapy, Brescek may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.
Preoperative prophylaxis of surgical site infections.
50–80 mg/kg as a single dose before surgery.
Syphilis.
The generally recommended doses are 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III)).
50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.
Newborns aged 0–14 days.
Brescek is contraindicated in preterm newborns with a postmenstrual age of less than 41 weeks (gestational age + chronological age).
Table 3
| 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 neonates aged 0–14 days requiring special dosing regimens: Acute otitis media.
For initial treatment of acute otitis media, a single intramuscular injection of Bresak at a dose of 50 mg/kg may be administered.
Preoperative prophylaxis of surgical site infections.
20–50 mg/kg as a single dose before surgery.
Syphilis.
The generally 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 fever subsides or after confirmation of eradication of bacterial infection.
Geriatric patients.
In patients with normal renal and hepatic function, dose adjustment is not required for elderly patients.
Patients with hepatic impairment.
Available data indicate no need for dose adjustment in patients with mild or moderate hepatic impairment, provided renal function is normal. There are no data from studies in patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment.
In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.
Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not removed 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.
Bresak can be administered by deep intramuscular injection. The 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"). For detailed information, refer to the lidocaine instructions for medical use.
Intravenous administration.
Bresak can 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 infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). Intramuscular administration should be considered when intravenous access is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.
Ceftriaxone is contraindicated in neonates (≤ 28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications"). Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications," "Special precautions," and "Incompatibilities").
For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes before surgery.
Reconstitution instructions
Freshly prepared solutions are recommended. The prepared solution is stable for 6 hours at 15–25 °C or 24 hours at 2–8 °C.
The ceftriaxone solution should not be mixed in the same syringe with any other drugs except 1% lidocaine hydrochloride solution (for intramuscular injections only).
The infusion system should be flushed after each administration.
For intramuscular injection, 1 g of Bresak should be dissolved in 3.5 mL of 1% lidocaine solution.
For intravenous injection, 1 g of Bresak should be dissolved in 10 mL of water for injections.
For intravenous infusion, 2 g of Bresak should be dissolved in 40 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, 6–10% hydroxyethyl starch, water for injections. Due to possible incompatibility, solutions containing ceftriaxone must not be mixed with solutions containing other antibiotics, either during preparation or administration.
The displacement volume of 1 g of ceftriaxone is 0.71 mL in water for injections and in 1% lidocaine hydrochloride solution. After adding 10 mL of water for injections, the final concentration of the reconstituted solution is 93.37 mg/mL. After adding 3.5 mL of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 237.53 mg/mL.
Children.
The drug 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
Adverse reactions most commonly observed during ceftriaxone use include: eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes. The frequency of adverse reactions to ceftriaxone was determined based on data from clinical trials.
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 colitisb;
Frequency not knowna – superinfectionsb.
Blood and lymphatic system disorders:
Common – eosinophilia, leukopenia, thrombocytopenia;
Uncommon – granulocytopenia, anemia, coagulation disorders;
Frequency not knowna – hemolytic anemiab, agranulocytosis.
Immune system disorders:
Frequency not knowna – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactionsb, Jarisch-Herxheimer reactionb (see section "Special precautions for use").
Nervous system disorders:
Uncommon – headache, dizziness;
Rare – encephalopathy;
Frequency not knowna – seizures.
Ear and labyrinth disorders:
Frequency not knowna – vertigo.
Respiratory, thoracic and mediastinal disorders:
Rare – bronchospasm.
Gastrointestinal disorders:
Common – diarrheab, loose stools;
Uncommon – nausea, vomiting;
Frequency not knowna – pancreatitisb, stomatitis, glossitis.
Hepatobiliary disorders:
Common – elevated liver enzymes;
Frequency not knowna – biliary precipitatesb, kernicterus, hepatitis1, cholestatic hepatitis1,b.
Skin and subcutaneous tissue disorders:
Common – rash;
Uncommon – pruritus;
Rare – urticaria;
Frequency not knowna – Stevens-Johnson syndromeb, toxic epidermal necrolysisb, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS)b (see section "Special precautions for use").
Renal and urinary disorders:
Rare – hematuria, glucosuria;
Frequency not knowna – oliguria, renal precipitates (reversible).
General disorders and administration site conditions:
Uncommon – phlebitis, injection site pain, fever;
Rare – swelling, chills.
Cardiac disorders:
Frequency not known – Kounis syndrome.
Investigations:
Uncommon – increased blood creatinine levels;
Frequency not knowna – false-positive Coombs testb, false-positive galactosemia testb, false-positive results in non-enzymatic glucose testsb.
a Based on post-marketing reports. Since information on these reactions is voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency; therefore, the frequency is described as not known.
b See section "Special precautions for use"
1 Usually reversible upon discontinuation of ceftriaxone
Infections and infestations.
Cases of 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 term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing products. 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 "Pharmacodynamics", "Contraindications", "Special precautions for use").
Cases of renal precipitates 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 g, and who also had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those with dehydration. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and typically resolve after discontinuation of ceftriaxone (see section "Special 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 shown variable rates of precipitate formation with intravenous administration—over 30% in some studies. The incidence of precipitate formation 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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any 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 at a temperature not exceeding 25 °C, protected from light. Keep out of reach of children.
Incompatibilities.
Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.
Solutions containing ceftriaxone should not be mixed with or added to other medicinal products 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 potential for precipitate formation. Ceftriaxone should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Contraindications", "Special precautions for use", "Dosage and administration", and "Adverse reactions").
For combination with other antibiotics, separate syringes or infusion solutions should be used.
Packaging.
Powder for solution for injection: 1 g; 2 g; 1 or 10 vials per cardboard box; 1 or 20 vials per cardboard box.
Prescription status.
Prescription only.
Manufacturer(s).
ANFARM HELLAS S.A., Greece / ANFARM HELLAS S.A., Greece
BROS LTD, Greece / BROS LTD, Greece
Manufacturer's address.
Schimatari Viotias, 32009, 61st km Nat. Rd. Athens-Lamia, Greece
Augis & Galinis 15, Nea Kifisia (Attiki) 14564, Greece
Marketing Authorization Holder.
Pharmaceutical company «VOCATE S.A.», Greece /
Pharmaceutical company «VOCATE S.A.», Greece
Address of Marketing Authorization Holder.
Greece, Athens, 166 74 Ano Glyfada, Gounari str., 150 /
Greece, Athens, 166 74 Ano Glyfada, Gounari str., 150