Ceftriaxone-bhfz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE-BCPP (CEFTRIAXONE-BCPP)

Composition:

active substance: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 2 g.

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 J01DD04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, the biosynthesis of the cell wall (peptidoglycan) is halted, leading to bacterial cell lysis and death.

Resistance

Bacterial resistance to ceftriaxone may develop through one or more of the following 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 permeability of the outer membrane in Gram-negative bacteria.
• Bacterial efflux pumps.

Breakpoints for susceptibility testing

Breakpoints for minimum inhibitory concentration defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a. The conclusion on susceptibility is based on susceptibility to cefoxitin.

b. The conclusion on susceptibility is based on susceptibility to penicillin.

c. Rare isolates have minimal inhibitory concentrations exceeding the susceptibility breakpoints. If observed, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory.

d. The breakpoints apply 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 that may develop 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 of at least 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 after a single intramuscular dose of 1 g is 81 mg/L, reached within 2–3 hours after administration. The area under the plasma concentration–time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations exceeding the minimal inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated administration; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence is expected in low concentrations 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 degree of binding decreases with increasing concentration (to 85% at a plasma concentration of 300 mg/L).

Biotransformation

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

Elimination.

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

Patients with renal or hepatic impairment

In patients with impaired renal or liver function, the pharmacokinetics of ceftriaxone are only slightly altered: a minor increase in elimination half-life (less than two-fold) is observed, even in patients with severe renal impairment.

The moderate increase in elimination 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 extrarenal clearance.

In patients with impaired liver function, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance with an increased volume of distribution.

Geriatric patients

In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times higher 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 children, the elimination half-life is shorter than in neonates or adults.

Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.

Linearity/non-linearity

The pharmacokinetics of ceftriaxone are non-linear. All major pharmacokinetic parameters based on total drug concentration, except elimination half-life, are dose-dependent; they increase at a rate less than proportional to dose. Non-linearity results from saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone, but not for 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 minimal inhibitory concentration of ceftriaxone for specific target organisms (i.e., percentage of T > minimal inhibitory concentration).

Clinical characteristics.

Indications.

Ceftriaxone 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.

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)] in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of infections at the site of surgical intervention;
• 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 if the potential range of bacterial pathogens is not covered by the spectrum of ceftriaxone (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, 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, since bilirubin binding is likely impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions" and "Side effects").
  • In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thereby increasing the risk of bilirubin encephalopathy in such patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). See also the instructions for medical use of lidocaine, particularly the "Contraindications" section.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used 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-type infusion system. However, in all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adults and umbilical cord plasma from newborns have shown an increased risk of ceftriaxone-calcium salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Side effects", "Incompatibilities").

Concomitant use of ceftriaxone with oral anticoagulants may enhance the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonists should be adjusted accordingly, 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 guidelines for monitoring aminoglycoside levels (and renal function) is recommended.

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 tests for galactosemia.

Similarly, false-positive results may occur when urine glucose is tested using non-enzymatic methods. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

No renal function impairment has been observed following concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce the excretion of ceftriaxone.

Special precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Coombs syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other 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 reactions, including Stevens–Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), have been reported during ceftriaxone use, which may be fatal; however, the frequency of these events is unknown (see section "Side effects").

Jarisch–Herxheimer reaction.

In some patients with infections caused by spirochetes, a Jarisch–Herxheimer reaction may occur shortly after initiation of ceftriaxone therapy. The Jarisch–Herxheimer reaction is usually self-limiting or may require symptomatic treatment. If such a reaction occurs, antibiotic therapy should not be discontinued.

Interaction with calcium-containing medicinal products.

Cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys, with fatal outcomes, have been reported in premature and full-term infants up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitation in patients other than 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 ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or administered simultaneously with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through separate infusion systems into different body sites or the infusion line is replaced or thoroughly flushed with physiological saline between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous parenteral nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children.

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

Ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.

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

Prolonged treatment.

During prolonged treatment, a complete blood count should be performed regularly.

Colitis/overgrowth of non-susceptible 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 medicinal products should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible to the drug may occur.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of 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 testing (see section "Side effects").

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 blood glucose values obtained by various blood glucose monitoring systems. Refer to the instructions for each system and use alternative testing methods if necessary.

Sodium.

Each 1 gram of the medicinal product Ceftriaxone-BHFS contains 3.6 mmol (or 83 mg) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Antibacterial spectrum.

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

In the presence of shadows on ultrasound, the possibility of ceftriaxone calcium salt precipitation should be considered. Shadows, which were mistakenly interpreted as 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. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone calcium salt precipitation has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended. The physician should consider discontinuing the drug, weighing the benefit-risk ratio in each individual case (see section "Side effects").

Biliary stasis.

Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported during ceftriaxone therapy. Most of these patients had risk factors for cholestasis and biliary sludge, such as prior extensive therapy, severe illness, or total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone use cannot be ruled out 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 "Side effects"). Ultrasound examination should be performed if symptoms occur. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician, considering the benefit-risk ratio in each individual case.

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, myoclonia, seizures), discontinuation of ceftriaxone should be considered.

Disposal of the medicinal product.

Environmental release of the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Unused medicinal product or waste after completion of treatment or expiry should be disposed of in accordance with local requirements.

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- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the potential 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. The possibility of sensitization should be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility. Reproductive function studies have not revealed any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, side effects such as dizziness may occur, which could affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Method of administration and dosage.

Dosage

The dose of the medicinal product depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and liver and kidney function.

Recommended dosages for indications are listed below. In particularly severe cases, the highest dose within the recommended range should be used.

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

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

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

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

Acute otitis media

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

Some data suggest that in patients with severe disease or in whom prior therapy has failed, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g daily for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g prior to 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)]

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

Children

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

Children weighing 50 kg or more should receive the standard adult doses.

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

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

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or failure of prior therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prophylaxis of surgical site infections

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

Syphilis

In general, a dose of 75–100 mg/kg (maximum 4 g) once daily for 10–14 days is recommended for children. 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.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates up to 41 weeks postmenstrual age (gestational age + postnatal 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 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 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 ceftriaxone therapy depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or confirmation of eradication of bacterial infection.

Geriatric patients

In the presence of normal renal and hepatic function, dose adjustment is not required in elderly patients.

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 from studies in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

For patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in patients with preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.

If the patient is undergoing dialysis, there is no need for additional administration 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 dysfunction

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

Route of administration

Intramuscular administration

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

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

Intravenous administration

Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (the preferred route) or by slow intravenous injection over 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). Intramuscular administration should be considered when intravenous access is not feasible or less acceptable to the patient. Doses exceeding 2 g should be administered intravenously.

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

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

Preparation of infusion solutions

Concentration for intravenous injection: 100 mg/mL.

Concentration for intravenous infusion: 50 mg/mL.

Freshly prepared solutions are recommended.

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

The intravenous line should be flushed after each administration.

Intravenous injection.

For intravenous injections, the contents of a 2 g vial should be dissolved in 20 mL of water for injections. Administer slowly over at least 5 minutes directly into a vein, preferably a large vein, or via an intravenous infusion line.

Intravenous infusion.

To prepare the solution for intravenous infusion, 2 g of ceftriaxone should be dissolved in 40 mL of one of the following infusion solutions not containing calcium ions:

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

The solution is prepared in two steps.

Step I: For primary reconstitution, add 20 mL of one of the above-mentioned calcium-free infusion solutions to the vial containing 2 g of ceftriaxone using a syringe. After adding the diluent, visually assess complete dissolution. Shake the vial until the powder is fully dissolved.

Step II: Transfer the resulting solution into a container containing 20 mL of the same infusion solution used for reconstitution.

Intravenous infusion should last no less than 30 minutes.

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

Due to possible incompatibility, solutions containing ceftriaxone must not be mixed with solutions containing other antibiotics, either during preparation or administration.

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of 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 administration set. Therefore, ceftriaxone must not be mixed or co-administered intravenously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications," "Special precautions," and "Incompatibility").

Children.

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

Overdose.

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis does not effectively reduce excessive plasma concentrations of the drug. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

The most commonly observed adverse reactions associated with ceftriaxone use are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

The frequency of adverse reactions to ceftriaxone was determined based on clinical trial data.

Events are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and frequency not known (cannot be estimated from available data).

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

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

Immune system disorders:
Frequency not known^a — anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch-Herxheimer reaction.

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

Ear and labyrinth disorders:
Frequency not known^a — vertigo.

Respiratory, thoracic and mediastinal disorders:
Rare — bronchospasm.

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

Hepatobiliary disorders:
Common — elevated liver enzymes;
Frequency not known^a — biliary precipitates^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,c.

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

Cardiovascular disorders:
Frequency not known — Kounis syndrome.

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

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

Investigations:
Uncommon — increased blood creatinine levels;
Frequency not known^a — false-positive Coombs test^b, false-positive galactosemia test^b, false-positive non-enzymatic glucose tests^b.

^a Based on post-marketing reports. Since these reactions are voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency, hence the classification as "frequency not known".
^b See section "Special precautions for use".
^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

Cases of diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions for use").

Ceftriaxone calcium salt precipitates.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing 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 precautions for use", and "Pharmacodynamics").

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 total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation is increased in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic, and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence of precipitate formation with intravenous administration—over 30% in some studies. The incidence is lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present 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 precautions for use").

Reporting suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

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

The reconstituted solution should be used within 6 hours when stored at a temperature not exceeding 25 °C, or within 24 hours when stored at 2–8 °C.

Depending on concentration and storage duration, the color of solutions may vary from pale yellow to yellow. This property of the active substance does not affect the efficacy or tolerability of the medicinal product.

Incompatibilities.

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

Ceftriaxone must not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". In particular, ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, due to the potential for precipitate formation. Ceftriaxone must not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions for use", and "Adverse reactions").

Pharmaceutically incompatible with other antimicrobial agents. If combination therapy with another antibiotic and ceftriaxone is intended, these agents must not be mixed in the same syringe or infusion solution.

Ceftriaxone must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Packaging. 2 g in a vial, 1 vial per pack.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.