Ceftriaxone

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE (CEFTRIAXONE)

Composition:

Active substance: ceftriaxone;

One vial contains sterile sodium ceftriaxone salt equivalent to ceftriaxone 0.5 g or 1.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder, almost white or yellowish in color, slightly hygroscopic.

Pharmacotherapeutic group. Antibacterials 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. As a result, biosynthesis of the cell wall (peptidoglycan) ceases, leading to bacterial cell lysis and death.

Resistance

Bacterial resistance to ceftriaxone may develop via 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.
• Impermeability of the outer membrane in Gram-negative bacteria.
• Bacterial efflux pumps.

Susceptibility testing breakpoints

The minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

a – susceptibility conclusion was based on susceptibility to cefoxitin;

b – susceptibility conclusion was based on susceptibility to penicillin;

c – rare isolates with MICs exceeding susceptibility breakpoints may occur; if observed, repeat testing should be performed, and if confirmed, isolates should be sent to a reference laboratory;

d – breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose of at least 2 g × 1.

Clinical efficacy against specific microorganisms

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local resistance data are desirable, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the utility of ceftriaxone, at least for certain types of infections, questionable.

£ 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 peak plasma concentration following a single 1 g intramuscular dose is approximately 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration-time curve (AUC) 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 ceftriaxone, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusion of ceftriaxone 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 significantly exceeding the MIC for most relevant pathogenic microorganisms are found in tissues, including lungs, heart, biliary tract/liver, tonsils, middle ear, and nasal mucosa, bones, as well as in cerebrospinal, pleural, synovial fluids, and prostatic secretions. An 8–15% increase in mean peak plasma concentration (Cmax) is observed upon repeated dosing; steady state is generally achieved within 48–72 hours depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates across the meninges. The degree of penetration is greater during meningeal inflammation. The mean Cmax of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of the plasma level, compared to 2% of the plasma level in patients without meningeal inflammation. The Cmax of ceftriaxone in cerebrospinal fluid is reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in breast milk in low concentrations (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 becomes saturated, and the extent of binding decreases with increasing concentration (to 85% at a plasma concentration of 300 mg/L).

Biotransformation

Ceftriaxone is not systemically metabolized but is converted to inactive metabolites by intestinal flora.

Elimination

The plasma clearance of total ceftriaxone (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 impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

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

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increase in renal clearance. This is also associated with an increased free fraction of ceftriaxone in plasma, contributing to a 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 mean elimination half-life is typically 2–3 times higher than in younger patients.

Pediatric population

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

The 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. All major pharmacokinetic parameters based on total drug concentrations (free and protein-bound ceftriaxone), except elimination half-life, are dose-dependent and increase less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding, thus inherent to total plasma ceftriaxone, but not to 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 MIC of ceftriaxone for specific target organisms (i.e., %T > MIC).

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 borreliosis (early (Stage II) and late (Stage III)) in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of infection at the surgical site;
• management of neutropenic patients who develop fever suspected to be due to bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when there is suspicion of any of the above-mentioned infections.

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

Official recommendations regarding the 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 infants ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

in term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or calcium-containing infusions, due to the risk of precipitation of ceftriaxone calcium salt (see sections "Special precautions" and "Adverse reactions").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially 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 lidocaine prescribing information, particularly contraindications.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other types of interactions.

Diluents 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. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. 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 plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone calcium salt precipitate formation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

Concomitant use of ceftriaxone with oral anticoagulants may potentiate the vitamin K antagonist 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 during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical guidelines for monitoring aminoglycoside levels (and renal function) is advised.

An in vitro study of ceftriaxone 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.

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

Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia testing.

Additionally, false-positive results may occur when glucose in urine is tested by 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 ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In the event 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 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 skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported. These reactions may be life-threatening or fatal; however, the frequency of such events is unknown (see section "Side effects").

Jarisch-Herxheimer reaction

In some patients with spirochetal infections, Jarisch-Herxheimer reactions may occur shortly after initiating ceftriaxone therapy. Jarisch-Herxheimer reactions are typically transient and can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if such a reaction occurs.

Interaction with calcium-containing medicinal products

In preterm and full-term neonates under 1 month of age, cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys with fatal outcomes have been 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, no confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies of sodium ceftriaxone have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's 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 another, provided the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusions of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents that do not carry a similar risk of precipitate formation. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusions may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", and "Incompatibilities").

Children

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

Ceftriaxone is contraindicated in 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 cephalosporins, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported in both adults and children during ceftriaxone therapy.

If anemia develops during ceftriaxone therapy, ceftriaxone-associated hemolytic anemia should be considered, and ceftriaxone should be discontinued until the etiology is determined.

Prolonged therapy

During prolonged therapy, a complete blood count should be monitored regularly.

Colitis/overgrowth of resistant microorganisms

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported during treatment with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant 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.

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

The presence of ceftriaxone may falsely lower calculated blood glucose levels obtained by some blood glucose monitoring systems. Refer to the instructions for use for each system. Alternative testing methods should be used if necessary.

Antibacterial spectrum of activity

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate as monotherapy for certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In 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.

Gallstone disease

When shadows are observed on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their frequency increases with ceftriaxone doses of 1 g/day or higher. Particular caution is advised when administering ceftriaxone to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone calcium salt has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue ceftriaxone based on a benefit-risk assessment for the individual case (see section "Side effects").

Biliary stasis

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

Nephrolithiasis

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). In symptomatic cases, ultrasound examination should be performed. The decision to use ceftriaxone in patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment for the individual case.

Disposal of medicinal product

Environmental contamination by the medicinal product should be minimized. The product must not be disposed of via wastewater systems or household waste. Any unused medicinal product after completion of treatment or after expiry should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal.

Encephalopathy

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), 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

Each gram of ceftriaxone contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

Pregnancy

Ceftriaxone crosses the placental barrier. Data on the use of ceftriaxone in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding

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

Fertility

Reproductive function studies have not shown evidence of adverse effects of ceftriaxone on male or female fertility.

Ability to affect reaction speed when driving or operating machinery

Due to the possibility of side effects such as dizziness, ceftriaxone may affect the ability to drive vehicles or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery during ceftriaxone therapy.

Method of Administration and Dosage.

Dosage

The dosage of the drug depends on the severity of the infection, pathogen sensitivity, site and type of infection, as well as the patient's age and hepatic and renal function.

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

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

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

** When doses exceeding 2 g per day are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).

Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens:

Acute otitis media

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

Some data suggest that in cases of severe illness or when prior therapy has been ineffective, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative prophylaxis of surgical site infections

2 g as a single dose prior to surgery.

Gonorrhoea

A single 500 mg intramuscular dose.

Syphilis

The generally recommended doses are 0.5–1 g once daily, increasing to 2 g once daily in cases of neurosyphilis, for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.

Disseminated Lyme borreliosis (early (Stage II) and late (Stage III))

2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Pediatric population

Children with body weight of 50 kg or more should receive the standard adult doses.

Neonates, infants, and children from 15 days to 12 years of age (<50 kg)

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

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

Indications in 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 ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has failed, ceftriaxone may be effective when administered intramuscularly at 50 mg/kg once daily for 3 days.

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

Recommended doses: 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

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

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

The maximum daily dose of 50 mg/kg 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 ceftriaxone 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 treatment should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Elderly patients

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

Patients with hepatic impairment

Available data indicate that dose adjustment is not necessary in patients with mild or moderate hepatic impairment if renal function is normal.

There are no study data available for 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 hepatic function is normal. Only in patients with preterminal 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 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 impairment

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.

Administration method

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. Intramuscular injections should be given into a relatively large muscle mass, and no more than 1 g should be injected at a single site.

Since lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, refer to the lidocaine medical instructions.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes. Intermittent intravenous injections should be administered over 5 minutes, preferably into larger veins.

Intravenous doses of 50 mg/kg or higher in infants and children under 12 years of age should be given by 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 the intravenous route 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) intravenous calcium-containing solutions, including continuous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications").

Infusion solutions containing calcium (e.g., Ringer's solution or Hartmann's solution) must not be used as a solvent for ceftriaxone or for further dilution of reconstituted ceftriaxone 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 and calcium-containing solutions must not be mixed or administered simultaneously (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").

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

Preparation of solutions

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

Solutions should be prepared immediately before use.

Freshly prepared solutions maintain their physical and chemical stability for 6 hours at room temperature (or for 24 hours at 2–8 °C). Depending on concentration and storage duration, the color of solutions may vary from pale yellow to amber. This property of the active substance does not affect the efficacy or tolerability of the drug.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user and must not exceed the time specified above for chemical and physical stability during use.

Ceftriaxone must not be mixed in the same syringe with other medicinal products except 1% lidocaine hydrochloride solution (for intramuscular injections only).

Infusion lines should be flushed after each administration.

Ceftriaxone, powder for injection solution 1 g

Intravenous administration (injection or infusion)

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

The contents of the vial containing 1 g of ceftriaxone should be dissolved in 10 mL of water for injections.

The vial should be gently rolled between the palms and visually inspected to ensure complete dissolution and absence of particles.

The injection should be administered over 5 minutes directly into a vein or via an intravenous infusion line.

Alternatively, for intravenous infusion, the reconstituted solution should be transferred into 10 mL of one of the following infusion fluids that do not contain calcium: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, water for injections. The infusion should be administered over at least 30 minutes.

Use in pediatric population

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

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

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

To prepare a final solution concentration of 100 mg/mL, dissolve 1 g of ceftriaxone in 9.4 mL of water for injections.

Intramuscular injection

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

The contents of the vial containing 1 g of ceftriaxone should be dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The vial should be gently rolled between the palms and visually inspected to ensure complete dissolution and absence of particles. The solution should be administered by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at multiple sites.

Use in pediatric population

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

The displacement volume of 1 g of ceftriaxone is 0.71 mL in 1% lidocaine hydrochloride solution. This requires compensation of the solvent volume to facilitate dosing according to body weight (primarily in children under 12 years of age) when only a portion of the total solution is measured and administered. To obtain a final solution concentration of 285 mg/mL, dissolve 1 g of ceftriaxone in 2.9 mL of 1% lidocaine hydrochloride solution.

Children.

The drug should be administered to children according to the dosing specified in the section "Administration and dosage".

Overdose.

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

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone administration are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

Adverse reactions associated with ceftriaxone use are classified by frequency as follows:

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

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

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

Cardiac disorders: Frequency not known: Kounis syndrome.

Immune system disorders: Frequency not known: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions including Quincke's edema, dyspnea, Jarisch-Herxheimer reaction.

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

Ear and labyrinth disorders: Frequency not known: vertigo.

Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm.

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

Hepatobiliary disorders: Common: elevated liver enzymes; Frequency not known: gallbladder precipitates, kernicterus, hepatitis1, cholestatic hepatitis1,2.

1 Usually reversible upon discontinuation of ceftriaxone.
2 See section "Special warnings and precautions for use".

Skin and subcutaneous tissue disorders: Common: rash; Uncommon: pruritus; Rare: urticaria; Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

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

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

Investigations: Uncommon: increased blood creatinine levels; Frequency not known: false-positive Coombs test, false-positive galactosemia test, false-positive results with non-enzymatic glucose tests.

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 warnings and precautions for use").

Ceftriaxone calcium salt precipitates.

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

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

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation—over 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 clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach and sight of children.

Incompatibilities.
Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution due to the risk of precipitate formation.

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

It should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". Ceftriaxone must not be mixed or co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Special warnings and precautions for use", "Dosage and administration", and "Adverse reactions").

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

Packaging.
0.5 g or 1.0 g in vials; 10 vials per carton.

Prescription status. Prescription only.

Manufacturer.
JSC "Kievmedpreparat"

Manufacturer's address and place of business.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine