Medaxon
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product MEDAXONE (MEDAXONE)
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 physico-chemical properties: crystalline powder, almost white or slightly yellowish, slightly hygroscopic.
Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action. Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins, thereby interrupting the biosynthesis of the cell wall (peptidoglycan), which in turn leads to bacterial cell lysis and death.
Resistance. Bacterial resistance to ceftriaxone may develop through one or more 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; decreased outer membrane permeability in gram-negative bacteria; and 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 |
| Streptococci group Viridans |
≤ 0.5 |
> 0.5 |
| Haemophilus influenzae |
≤ 0.12c |
> 0.12 |
| Moraxella catarrhalis |
≤ 1 |
> 2 |
| Neisseria gonorrhoeae |
≤ 0.12 |
> 0.12 |
| Neisseria meningitidis |
≤ 0.12 c |
> 0.12 |
| Non-species related |
≤ 1d |
> 2 |
a The conclusion on susceptibility was based on susceptibility to cefoxitin.
b The conclusion on susceptibility was based on susceptibility to penicillin.
c Rare isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints have been observed. In such cases, 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.
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 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.
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 of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration (Cmax) after a single 1 g intramuscular dose 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 Cmax was observed upon 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 mean Cmax of ceftriaxone in cerebrospinal fluid (CSF) in patients with bacterial meningitis is up to 25% of the plasma concentration, compared to 2% in patients without meningitis. The Cmax of ceftriaxone in CSF is reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (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 (down 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 minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment. The relatively moderate increase in half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in total ceftriaxone clearance.
In patients with hepatic impairment, 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 volume of distribution increasing in parallel to 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 protein binding. In older children, the 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 and decrease to a lesser extent than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding and thus affects total plasma ceftriaxone, but not 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).
Clinical characteristics.
Indications.
Medaxon 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.
Medaxon may also be used for the treatment of: acute exacerbation of chronic obstructive pulmonary disease in adults; 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 neutropenic patients who develop fever and are suspected of having a bacterial infection; treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.
Medaxon should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions"). Official guidelines 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 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 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", "Side effects").
* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin encephalopathy in these 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 medical instructions for lidocaine, particularly contraindications. Ceftriaxone solutions containing lidocaine must never be administered intravenously.
Interaction with other medicinal products and other forms of interactions.
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstituting the drug 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-site connector. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn cord plasma have shown that newborns are at increased risk of forming ceftriaxone-calcium salt precipitates (see sections "Contraindications", "Special precautions", "Method of administration and dosage", "Side effects", and "Incompatibilities").
Concomitant use of the drug with oral anticoagulants may potentiate the anti-vitamin K effect 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 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 monitoring recommendations for aminoglycoside levels (and renal function) is advised.
In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.
No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).
Patients receiving ceftriaxone may exhibit false-positive results in the Coombs test. Like other antibiotics, ceftriaxone may cause false-positive results in galactosemia testing. Similarly, false-positive glucose results in urine may occur when non-enzymatic methods are used. 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 ceftriaxone excretion.
Special precautions for use.
Hypersensitivity reactions. As with all beta-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 beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.
Cases of severe adverse reactions involving the skin (Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with ceftriaxone-containing medicinal products, which may be life-threatening or fatal; however, the frequency of these events is unknown (see section "Adverse reactions").
Jarisch-Herxheimer reaction (JHR). In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur immediately after initiation of ceftriaxone therapy. JHR is usually self-limiting or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if this reaction occurs.
Interaction with calcium-containing medicinal products. In preterm and full-term neonates up to 1 month of age, cases of precipitation of calcium-ceftriaxone salt in the lungs and kidneys with fatal outcome have been reported. 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, there have been no confirmed cases of intravascular precipitates except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of calcium-ceftriaxone 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 that the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing 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 into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").
Children. The safety and efficacy of Medaxon 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 binding to serum albumin. Medaxon 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 "Adverse reactions"). Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children. If anemia develops during ceftriaxone therapy, ceftriaxone-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is determined.
Long-term therapy. During prolonged treatment, complete blood counts should be performed regularly.
Colitis/overgrowth of non-susceptible microorganisms. Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and administration of appropriate agents against Clostridium difficile should be considered. Antiperistaltic drugs should not be used.
As with other antibacterial agents, superinfections caused by non-susceptible microorganisms may occur during therapy.
Severe renal and hepatic impairment. In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended (see section "Dosage and administration").
Effect on serological test results. During Medaxon therapy, the Coombs test may yield false-positive results. The drug may also cause false-positive results in galactosemia testing (see section "Adverse reactions"). False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Medaxon therapy, urine glucose levels should be determined using enzymatic methods (see section "Adverse reactions"). Ceftriaxone may falsely lower blood glucose values measured by certain blood glucose monitoring systems (see instructions for use for each system). Alternative testing methods should be used if necessary.
Encephalopathy. Encephalopathy has been reported during ceftriaxone therapy (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.
Sodium. One gram of Medaxon contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-restricted 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 been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant microorganisms are suspected, additional antibiotics should be considered.
Use of lidocaine. If lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Cholelithiasis. In case of shadows on ultrasound, precipitation of calcium-ceftriaxone salt should be considered. Shadows, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency during ceftriaxone therapy at doses of 1 g/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, precipitation of calcium-ceftriaxone salt 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 caused by biliary tract obstruction, have been reported in patients receiving ceftriaxone (see section "Adverse reactions"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, and total parenteral nutrition. Precipitation in the biliary tract due to Medaxon use cannot be excluded as a triggering or contributing factor in the development of this disorder.
Nephrolithiasis. Cases of kidney stone formation, resolving after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). In symptomatic cases, 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.
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 embryo/fetal, peri- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the risk.
Breastfeeding period. 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. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility. Reproductive function studies have not shown any adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery
During ceftriaxone therapy, adverse reactions such as dizziness may occur, which could affect the ability to drive or operate machinery (see section "Adverse reactions"). Patients should exercise caution when driving vehicles or operating machinery.
Dosage and method of administration.
The dosage of the drug 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 listed below are general guidelines. In particularly severe cases, the highest recommended dose should be used.
Adults and children aged 12 years and older (≥ 50 kg).
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 1–2 g |
Once daily |
Community-acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, intra-abdominal infections, complicated urinary tract infections (including pyelonephritis) |
| 2 g |
Once daily |
Hospital-acquired pneumonia, complicated skin and soft tissue infections, bone and joint infections |
| 2–4 g |
Once daily |
Management of febrile neutropenic patients 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, 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 severe clinical conditions or after failure of prior therapy, ceftriaxone may be effective when given 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.
Gonorrhoea. 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 for 10–14 days in neurosyphilis. 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 may vary; national or local guidelines should also be considered.
Neonates, infants, and children from 15 days to 12 years of age (<50 kg)
Children with body weight of 50 kg or more should receive the standard adult doses.
| Dose of ceftriaxone* |
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 neutropenic patients with fever suspected of bacterial infection |
| 80–100 mg/kg (maximum – 4 g) |
Once daily |
Bacterial meningitis |
| 100 mg/kg (maximum – 4 g) |
Once daily |
Bacterial endocarditis |
* In documented cases of bacteremia, consideration should be given to using the highest recommended dose.
** 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 under 12 years of age (<50 kg) requiring special dosing regimens
Preoperative prophylaxis of surgical site infections: 50–80 mg/kg as a single dose before surgery.
Syphilis: The generally recommended pediatric dose is 75–100 mg/kg/day (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.
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 failure of prior therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg/day for 3 days.
Newborns aged 0–14 days
Ceftriaxone is contraindicated in premature infants up to 41 weeks of gestational age (gestational age + postnatal age).
| Dose of ceftriaxone* |
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 of the recommended doses.
The maximum daily dose of 50 mg/kg should not be exceeded.
Indications in newborns aged 0–14 days requiring special dosing regimens
Acute otitis media: for initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used.
Preoperative prophylaxis of surgical site infections: 20–50 mg/kg as a single dose before surgery.
Syphilis: the 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.
Administration method
Intramuscular administration: ceftriaxone may 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, it is recommended to consult the lidocaine product information.
The use of lidocaine requires prior sensitivity testing to determine individual hypersensitivity to this medicinal product.
Intravenous administration: ceftriaxone may be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in 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. Intramuscular administration should be considered when intravenous access is not feasible or less acceptable 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 dissolve 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 prior to surgery.
Elderly patients: dose adjustment in elderly patients is not required 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 data in patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment: there is no need to reduce the dose of ceftriaxone if renal function is normal. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g. Patients undergoing dialysis do not require additional doses after dialysis. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.
Patients with severe hepatic and renal dysfunction: in cases of concomitant severe impairment of both renal and hepatic function, careful clinical monitoring of the safety and efficacy of the drug is recommended.
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 does not reduce the excessive plasma concentration 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. Adverse reactions are classified by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); frequency not known (cannot be estimated from available data).
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.
Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not knowna – seizures.
Ear and labyrinth disorders: frequency not knowna – vertigo.
Cardiac disorders: frequency not known – Kounis syndrome.
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 – increased liver enzymes; frequency not knowna – biliary precipitatesb, kernicterus, hepatitisc, cholestatic hepatitisb,c.
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 syndrome)b.
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, sweating; rare – swelling, chills.
Investigations: uncommon – increased blood creatinine; frequency not knowna – false-positive Coombs testb, false-positive galactosemia testb, false-positive results in non-enzymatic methods of glucose determinationb.
a Based on post-marketing reports. Since these reactions are voluntarily reported from an undefined population size, it is not possible to reliably estimate their frequency; hence, the frequency is categorized as not known.
b See section "Special precautions".
c Usually reversible upon discontinuation of ceftriaxone.
Infections and infestations: Diarrhea occurring after ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions").
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 precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Pharmacodynamics", "Contraindications", and "Special precautions"). Cases of ceftriaxone calcium precipitates in the gallbladder have also been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation, exceeding 30% in some studies. The incidence appears to be 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 typically resolve after discontinuation of ceftriaxone (see section "Special precautions").
Reporting of suspected adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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 at temperatures not exceeding 30 °C in the original packaging, in a place inaccessible to children. Prepared solutions are stable for 24 hours at 2–8 °C and for 6 hours at room temperature.
Incompatibilities. Medoxon must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution. Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides. It should not be mixed with other solvents except those specified in the section "Administration and dosage".
Packaging. 1 g or 2 g of powder in a vial, pack of 10 in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Medochemie Limited.
Manufacturer's address and location of operations.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.