Ceftriaxone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (as sterile ceftriaxone sodium salt) 1000 mg.

Pharmaceutical form. Powder for solution for injection.

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

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 (PBPs). This disrupts cell wall (peptidoglycan) biosynthesis, leading to lysis and death of the bacterial cell.

Resistance

Bacterial resistance to ceftriaxone may result from one or more of the following mechanisms:

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases, and Amp C enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacterial species;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• reduced permeability of the outer membrane in Gram-negative organisms;
• presence of bacterial efflux pumps.

Breakpoints for susceptibility testing

The table below shows the minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Table 1

a Susceptibility determined based on susceptibility to cefoxitin.

b Susceptibility determined based on susceptibility to penicillin.

c Isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints are rare. If detected, repeat testing should be performed, and if confirmed, isolates should be referred to a reference laboratory.

d Susceptibility 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 in certain bacterial species may vary geographically and over time. It is therefore advisable to obtain local resistance data, especially when treating severe infections. If local resistance prevalence renders the benefit of ceftriaxone for treating at least some types of infections questionable, expert advice should be sought.

Commonly 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 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 rate > 50% in at least one region.

% Strains producing ESBLs are always resistant.

Pharmacokinetics.

Absorption

The mean peak plasma concentration of ceftriaxone after intramuscular injection is approximately half of that observed after intravenous administration of an equivalent dose. The peak plasma concentration after a single intramuscular dose of 1 g is approximately 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.

The mean peak plasma concentrations of ceftriaxone after intravenous bolus injection of 500 mg and 1 g ceftriaxone are approximately 120 and 200 mg/L, respectively. Plasma concentrations of ceftriaxone after intravenous infusion of 500 mg, 1 g, and 2 g are approximately 80, 150, and 250 mg/L, respectively.

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Tissue concentrations in the lungs, heart, bile ducts/liver, tonsils, nasal mucosa, middle ear, bones, cerebrospinal fluid, pleural fluid, prostatic secretion, and synovial fluid exceed the minimum inhibitory concentrations for most clinically relevant pathogens. After repeated administration, mean peak plasma concentrations (Cmax) increase by 8–15%; in most cases, steady-state concentrations are achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates the meninges. Penetration is greatest during inflammation. In patients with bacterial meningitis, the mean peak concentration of ceftriaxone in cerebrospinal fluid is up to 25% of the plasma concentration, whereas in patients without meningeal inflammation, this concentration is only 2% of the plasma level. Peak cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous administration. Ceftriaxone crosses the placenta and is excreted in low concentrations into breast milk (see section "Special precautions").

Protein binding

Ceftriaxone reversibly binds to serum albumin. Plasma protein binding is approximately 95% at plasma ceftriaxone concentrations below 100 mg/L. Binding is saturable, and the fraction of bound ceftriaxone decreases as concentration increases (down to 85% at a plasma concentration of 300 mg/L).

Biotransformation

Ceftriaxone does not undergo systemic metabolism but is converted to inactive metabolites by intestinal flora.

Elimination

The plasma clearance of total ceftriaxone (both bound and unbound) is 10–22 mL/min. Renal clearance is 5–12 mL/min. 50–60% of ceftriaxone is excreted unchanged in urine, primarily by glomerular filtration, while 40–50% is excreted unchanged in bile. The elimination half-life of total ceftriaxone in adults is approximately 8 hours.

Patients with renal or hepatic impairment

In patients with renal or hepatic dysfunction, the pharmacokinetic parameters of ceftriaxone are only minimally altered, with a slight increase in half-life (less than two-fold), even in patients with severe renal impairment.

The moderate prolongation of half-life in patients with 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 half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This increase is also associated with an increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total ceftriaxone clearance. The volume of distribution increases in parallel with the increased total clearance.

Elderly patients

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

Children

In neonates, the elimination half-life of ceftriaxone is prolonged. From birth to 14 days of age, free ceftriaxone concentrations may increase due to factors such as reduced glomerular filtration and abnormal protein binding. In older children, the half-life is lower 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

Ceftriaxone exhibits non-linear pharmacokinetics, and all major pharmacokinetic parameters, except half-life, are dose-dependent based on total drug concentration; these parameters increase less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding. Therefore, non-linearity is observed only for total plasma ceftriaxone, not for free (unbound) ceftriaxone.

Pharmacokinetic/pharmacodynamic relationships

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

Clinical characteristics.

Indications.

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

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

Ceftriaxone may be used for:

• treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme disease [early (Stage II) and late (Stage III) stages] in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of infections during surgical procedures;
• treatment 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.

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

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

Contraindications.

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

Ceftriaxone is contraindicated:

• In preterm newborns up to 41 weeks postmenstrual age (gestational age + postnatal age)*.
• In term newborns (up to 28 days of life):
  • with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis (in these conditions, bilirubin binding to plasma proteins is reduced)*;
  • who require (or are expected to require) intravenous administration 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 can displace bilirubin from its binding to serum albumin, thereby increasing the risk of bilirubin-induced encephalopathy in such patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be ruled out if lidocaine is used as a solvent (see section "Special precautions" and the lidocaine product information, particularly regarding contraindications).

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interactions.

Calcium-containing products. Due to the risk of precipitation of ceftriaxone-calcium salts, calcium-containing solutions such as Ringer's solution or Hartmann's solution must not be used to reconstitute the drug in vials or for further dilution of the reconstituted solution for intravenous administration.

Precipitates of ceftriaxone-calcium may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including calcium-containing parenteral nutrition solutions, via a Y-site connector. However, in all patients except newborns, 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 plasma and umbilical cord plasma from newborns have shown an increased risk of ceftriaxone-calcium precipitate formation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

Oral anticoagulants. Concomitant use of ceftriaxone with oral anticoagulants may potentiate the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonists should be adjusted accordingly during and after ceftriaxone treatment (see section "Adverse reactions").

Aminoglycosides. Available data on the potential enhancement of nephrotoxic effects of aminoglycosides when used concomitantly with cephalosporins are conflicting. In such cases, careful monitoring of aminoglycoside levels and renal function is recommended in clinical practice.

Bacteriostatic antibiotics (chloramphenicol). An antagonistic effect has been observed in vitro when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

There are no reports of interactions between ceftriaxone and oral calcium-containing products, or between ceftriaxone administered intramuscularly and calcium-containing products administered intravenously or orally.

Loop diuretics. No renal function disturbances have been observed when high doses of ceftriaxone are used concomitantly with potent diuretics (e.g., furosemide).

Probenecid. Concomitant administration of probenecid does not reduce ceftriaxone elimination.

Substances used in laboratory tests. In patients treated with ceftriaxone, Coombs test results may be falsely positive. Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia tests. Similarly, non-enzymatic methods for urine glucose testing may yield false-positive results. Therefore, enzymatic methods should be used for urine glucose testing during ceftriaxone therapy.

Special precautions for use.

Hypersensitivity reactions.

As with other cephalosporins and beta-lactam antibiotics, severe acute hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, administration of the drug should be discontinued immediately and appropriate emergency measures initiated.

Prior to initiating therapy, it should be determined whether the patient has previously experienced a severe hypersensitivity reaction to ceftriaxone, another cephalosporin, or another type of beta-lactam antibiotic. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

Severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), 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 reactions is unknown (see section "Adverse reactions").

Interaction with calcium-containing products.

Cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys with fatal outcome have been reported in premature and full-term neonates up to 1 month of age. At least one of these newborns received ceftriaxone and calcium at different times via separate intravenous infusion systems. Available scientific data do not indicate any confirmed cases of intravascular precipitation in patients other than neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies have demonstrated that the risk of ceftriaxone-calcium salt precipitation is higher in neonates compared to patients in other age groups.

Regardless of patient age, ceftriaxone must not be mixed or co-administered simultaneously with any intravenous calcium-containing solutions, even when using separate 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 another, provided that the drugs are administered through separate infusion systems into different body sites, or that the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitation.

For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider using an alternative antibacterial agent that does not carry a similar precipitation risk. If ceftriaxone administration in patients requiring TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate 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 ceftriaxone in neonates, infants, and children have been established when doses specified in the section "Dosage and administration" are used. 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 reported in patients receiving cephalosporins, including ceftriaxone (see section "Adverse reactions"). Severe cases of hemolytic anemia (including fatal cases) have been observed during ceftriaxone treatment in both adults and children. If anemia develops during treatment with the drug, ceftriaxone-associated anemia should be considered, and ceftriaxone administration should be discontinued until the etiology of anemia is determined.

Prolonged treatment.

During prolonged treatment with the drug, regular monitoring of complete blood count is recommended.

Colitis/overgrowth of non-susceptible microorganisms.

Cases of antibiotic-associated colitis/pseudomembranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of symptoms may range from mild to life-threatening; therefore, it is important to consider this diagnosis in all patients who develop diarrhea during or after ceftriaxone administration (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of specific treatment against Clostridium difficile should be considered. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfection caused by microorganisms not susceptible to ceftriaxone 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 drug is recommended (see section "Dosage and administration").

Effect on serological test results.

Ceftriaxone may cause false-positive results in the Coombs test. Ceftriaxone may also cause false-positive results in galactosemia screening tests and in non-enzymatic methods for glucose determination in urine. Therefore, during ceftriaxone therapy, glucose levels in urine should be determined using enzymatic methods (see section "Adverse reactions").

Instructions for use of each test kit should be consulted. Alternative monitoring methods should be used if necessary.

Sodium.

One gram of the medicinal product contains 3.6 mmol (83.03 mg) of sodium, equivalent to 4.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inadequate as monotherapy for certain types of infections, except when the causative pathogen has been documented (see section "Dosage and administration"). In polymicrobial infections where resistant organisms are suspected, the need for 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 provided in the lidocaine medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

When shadows are observed on ultrasound, precipitation of ceftriaxone-calcium salt should be considered. Such shadows, which may be mistaken for gallstones, have been observed on gallbladder ultrasound and occur more frequently with ceftriaxone doses of 1 g/day or higher. Particular caution should be exercised when administering the drug to children. These precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, precipitation of ceftriaxone-calcium salt has been associated with symptoms. In symptomatic cases, conservative, non-surgical treatment is recommended. The physician should consider discontinuing the drug based on an individual benefit-risk assessment (see section "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly due to obstruction of biliary tracts, have been reported during ceftriaxone use. Most patients had risk factors for cholestasis and biliary sludge, such as prior intensive treatment, severe illness, or total parenteral nutrition. Precipitation in the biliary tracts due to ceftriaxone use cannot be excluded as a trigger or cofactor for this complication.

Nephrolithiasis.

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Adverse reactions"). Ultrasound examination should be performed if symptoms occur. The decision to use the drug in patients with a history of nephrolithiasis or hypercalciuria should be made by the physician based on an individual benefit-risk assessment.

Jarisch-Herxheimer reaction.

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction may occur shortly after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is usually self-limiting or may require symptomatic treatment. Antibiotic therapy should not be discontinued if such a reaction occurs.

Encephalopathy.

Cases of encephalopathy have 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. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of the medicinal product.

Environmental release of the medicinal product should be minimized. Disposal into sewage systems or household waste should be avoided. Unused medicinal product after completion of treatment or expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

Use during pregnancy or breastfeeding.

Pregnancy. Ceftriaxone crosses the placental barrier. Data on use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonal/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 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/abandon 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 negative effects on male or female fertility.

Ability to drive and use machines.

During ceftriaxone therapy, adverse reactions (e.g., dizziness) may occur that could impair the ability to drive or operate machinery (see section "Adverse reactions"). Patients should exercise caution when driving or operating machinery.

Dosage and Administration

Dosage

The dose of the medicinal product depends on the severity of the infection, pathogen sensitivity, location and type of infection, as well as the patient's age and hepatic and renal function.

The recommended dosages for the specified indications are listed below. In particularly severe cases, the maximum recommended doses should be used.

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

*In cases of documented bacteremia, consideration should be given to using the maximum recommended doses.

**When doses exceeding 2 g per day are used, administration of the drug twice daily (every 12 hours) should be considered.

Indications for adults and children aged 12 years and older (≥ 50 kg) requiring special dosage regimens

Acute otitis media

A single intramuscular dose of 1–2 g of ceftriaxone may be used.

Some data suggest that ceftriaxone may be effective when administered intramuscularly at a dose of 1–2 g once daily for 3 days in cases of severe infection or when prior therapy has been ineffective.

Preoperative prophylaxis of surgical site infections

Single dose of 2 g administered before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

The usual recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.

Disseminated Lyme borreliosis [early (Stage II) and late (Stage III) stages]

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 aged 15 days to 12 years (˂ 50 kg)

For children with body weight ≥ 50 kg, the standard recommended adult doses should be used.

*In cases of documented bacteremia, consideration should be given to using the maximum recommended doses.

**When doses exceeding 2 g per day are used, administration of the drug twice daily (every 12 hours) should be considered.

Indications for neonates, infants, and children aged 15 days to 12 years (˂ 50 kg) requiring special dosage regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular dose of Ceftriaxone at 50 mg/kg may be administered. Limited data suggest that in cases of severe infection in a child or when prior therapy has been ineffective, Ceftriaxone may be effective when given 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 preoperative dose.

Syphilis

The usual 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; therefore, 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).

* In documented cases of bacteremia, consideration should be given to using the maximum recommended doses. The maximum daily dose of 50 mg/kg must not be exceeded.

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

Acute otitis media

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

Preoperative prophylaxis of surgical site infections

A single dose of 20–50 mg/kg administered prior to surgery.

Syphilis

The usual 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 pathogen is confirmed.

Geriatric patients

No dose adjustment is required in elderly patients with normal renal and hepatic function.

Patients with hepatic impairment

Available data do not indicate the need for dose adjustment in mild to 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

Dose reduction of ceftriaxone is not required in patients with renal impairment if hepatic function is normal. Only in patients with 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 removed 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 impairment

In cases of concomitant severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Route of administration and reconstitution instructions

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. The injection should be given into the middle of a relatively large muscle mass. It is recommended not to administer more than 1 g at a single injection site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is also recommended to consult the lidocaine package insert.

For intramuscular administration, 1 g of Ceftriaxone should be reconstituted with 3.5 mL of 1% lidocaine hydrochloride solution. After adding the diluent, the solution should be visually inspected to ensure complete dissolution.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (recommended route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into larger veins.

Concentration for intravenous injection: 100 mg/mL.

Concentration for intravenous infusion: 50 mg/mL.

After adding the diluent, the solution should be visually inspected to ensure complete dissolution. Freshly prepared solutions are recommended.

For intravenous injection, 1 g of Ceftriaxone should be reconstituted with 10 mL of water for injection. The solution should be administered directly into a vein or via an intravenous infusion line.

For intravenous infusion, the contents of a 1 g Ceftriaxone vial should be reconstituted with 10 mL of water for injection. The reconstituted solution should then be added to 10 mL of one of the following infusion fluids that do not contain calcium:

• 0.9% sodium chloride solution;
• 5% glucose solution;
• 0.45% sodium chloride + 2.5% glucose solution;
• 10% glucose solution;
• 6% dextran in 5% glucose solution;
• sterile water for injection.

The infusion line should be flushed after each administration.

In infants and children under 12 years of age, intravenous doses of 50 mg/kg or higher should be administered by intravenous infusion.

In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special warnings and precautions for use").

Intramuscular administration should be considered when intravenous administration is not feasible or less acceptable to the patient.

Doses exceeding 2 g must be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous infusions of calcium-containing solutions such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").

Solvents containing calcium (e.g., 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 solutions containing calcium (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").

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

Freshly prepared solutions retain their physical and chemical stability for at least 6 hours at 25°C and for 24 hours at 2–8°C.

From a microbiological standpoint, the reconstituted medicinal product should be used immediately. If not used immediately, the duration and conditions of storage during use must not exceed the above-mentioned periods of chemical and physical stability, and responsibility for this lies with the user.

Ceftriaxone must not be mixed in the same syringe with any other medicinal product except 1% lidocaine hydrochloride solution (for intramuscular injection only). Depending on concentration and storage duration, the color of solutions may vary from pale yellow to amber-yellow. This property of the active substance does not affect the efficacy or tolerability of the drug.

The displacement volume of 1 g of Ceftriaxone is 0.71 mL in water for injection and in 1% lidocaine hydrochloride solution. Adding 10 mL of water for injection results in a final concentration of the reconstituted solution of 93.37 mg/mL. Adding 3.5 mL of 1% lidocaine hydrochloride solution results in a final concentration of 237.53 mg/mL.

Unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children.

The medicinal product should be administered to children according to the dosing regimens specified in the section "Dosage and administration".

Overdose.

Symptoms: nausea, vomiting, diarrhea may occur.

Treatment: hemodialysis and peritoneal dialysis do not reduce excessive plasma concentrations of the drug. There is no specific antidote. In case of overdose, symptomatic treatment should be administered.

Adverse reactions.

The most commonly reported adverse reactions associated with the use of ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes. The frequency of ceftriaxone adverse reactions was established 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 the available data).

a Based on post-marketing reports. Since information about these reactions is voluntarily reported and refers to an undefined number of patients, it is not possible to reliably estimate the frequency of occurrence of these reactions; therefore, the frequency is characterized as unknown.

1Usually reversible upon discontinuation of ceftriaxone.

2See section "Special precautions for use".

Description of individual adverse reactions

Infections and infestations.

Cases of diarrhoea following ceftriaxone administration may be associated with overgrowth of Clostridium difficile.

Treatment strategy should include administration of adequate amounts of fluids and electrolytes (see section "Special precautions for use").

Ceftriaxone calcium salt precipitates.

Rare cases of severe adverse reactions, sometimes with fatal outcome, have been reported in premature and full-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 elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions for use").

Cases of urinary tract precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (≥ 80 mg/kg/day) or had cumulative doses exceeding 10 g, and who had additional risk factors (limited fluid intake, dehydration, immobility, bed rest). Precipitate formation may be symptomatic or asymptomatic and may lead to ureteral obstruction, post-renal acute kidney injury, and anuria. Precipitates usually 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 on ceftriaxone have shown variable incidence of precipitate formation following intravenous administration – in some studies exceeding 30%. The incidence of precipitate formation 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 clinical symptoms such as 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 of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 3 years.

Storage conditions.

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

According to scientific literature, ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Solutions containing ceftriaxone should not be mixed with other medicinal products or added to other medicinal products except those specified in the section "Dosage and administration". In particular, solutions containing calcium (e.g., Ringer's solution, Hartmann's solution) should not be used to reconstitute ceftriaxone in the vial or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Ceftriaxone should not be mixed or co-administered with calcium-containing solutions, including total parenteral nutrition solutions (see sections "Contraindications", "Special precautions for use", "Dosage and administration", and "Adverse reactions").

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

Packaging. 1 vial of powder; 1 vial per pack.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and place of business.

17 Miru Street, Kyiv, 03134, Ukraine