Trimec

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIMEK (TRYMEK)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder ranging from white to yellow-orange in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. 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, biosynthesis of the cell wall (peptidoglycan) ceases, leading to lysis of the bacterial cell and its death.

Resistance

Bacterial resistance to ceftriaxone may develop due to 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 some aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• decreased outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Breakpoints for susceptibility testing

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

Pathogen	Dilution method (minimum inhibitory concentration, mg/l)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	> 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups A, B, C and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	> 2
Streptococci group Viridans	≤ 0.5	> 0.5
Haemophilus influenzae	≤ 0.12c.	> 0.12
Moraxella catarrhalis	≤ 1	> 2
Neisseria gonorrhoeae	≤ 0.12	> 0.12
Neisseria meningitidis	≤ 0.12 c.	> 0.12
Not species-related	≤ 1d.	> 2

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

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

c. Isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely encountered. If such isolates are observed, repeat testing should be performed, and if confirmed, they should be referred 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 capable of developing 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.

Inherently resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia

Anaerobes

Clostridium difficile

Others:

Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

• Resistance frequency > 50% in at least one region.

% Strains producing extended-spectrum beta-lactamases are always resistant.

Pharmacokinetics.

Absorption

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration following a single 1 g intramuscular dose is 81 mg/L, achieved 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 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 minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated dosing; 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 (CSF) in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningeal inflammation. Peak CSF concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (see section "Use in 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 transformed into inactive metabolites by intestinal flora.

Elimination

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

Patients with renal or hepatic impairment

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

The moderate increase in half-life observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a consequent increase in total ceftriaxone extraren0072enal clearance.

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

Elderly patients

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

Children

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

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

Linearity/Non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters (except half-life) are dose-dependent and decrease to a lesser extent than proportionally with dose. Non-linearity arises due to saturation of plasma protein binding, thus observed for total ceftriaxone in plasma, but not for the free (unbound) fraction.

Pharmacokinetic/Pharmacodynamic relationship

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

Clinical characteristics.

Indications.

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)] 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 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 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 ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

in term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired in these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, 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, which may lead to development of bilirubin encephalopathy in such patients.

Before intramuscular injection of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions" and the lidocaine package leaflet, particularly contraindications).

Solutions of ceftriaxone 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 to reconstitute Trimex 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-site system. However, in all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical plasma have shown an increased risk of ceftriaxone-calcium salt precipitate formation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions", "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 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 monitoring recommendations for aminoglycoside levels (and renal function) is advised.

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).

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

Like other antibiotics, ceftriaxone may cause false-positive results in tests for galactosemia.

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam medicinal products. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Severe adverse skin reactions have been reported during treatment with ceftriaxone: rapidly developing rash with blisters, possibly affecting the mouth, or skin peeling (Stevens–Johnson syndrome or Lyell’s syndrome / toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening. However, the frequency of these events is unknown (see section "Adverse reactions").

If symptoms such as rash, redness of the skin, blistering of the lips, eyes or mouth, skin peeling, high body temperature, flu-like symptoms, elevated liver enzymes in blood, increase in a type of white blood cells (eosinophilia), or enlarged lymph nodes (signs of severe skin reactions) occur, the physician must be informed immediately (see "Adverse reactions").

The combination of several of these symptoms—widespread rash, high body temperature, elevated liver enzymes, blood abnormalities (eosinophilia), enlarged lymph nodes, and organ involvement (drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)) or drug hypersensitivity syndrome—should raise suspicion.

Jarisch–Herxheimer reaction.

In some patients with infections caused by spirochetes, such as Lyme disease, the Jarisch–Herxheimer reaction (fever, chills, headache, muscle pain, and skin rash) may develop shortly after initiation of ceftriaxone therapy. This reaction usually resolves spontaneously but may occasionally require symptomatic treatment. If a Jarisch–Herxheimer reaction occurs, antibiotic therapy should not be discontinued.

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 observed. In at least one of these patients, ceftriaxone and calcium were administered at different times via different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitates except in newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates have a higher risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of patient age, even when 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, provided the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous parenteral nutrition, 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", "Adverse reactions", "Pharmacokinetics", and "Incompatibilities").

Children.

The safety and efficacy of the medicinal product 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.

The medicinal product is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

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

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

Prolonged treatment.

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

Colitis / overgrowth of resistant microorganisms.

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

Superinfections caused by microorganisms resistant to the drug may occur during antibacterial therapy.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the medicinal product is recommended (see section "Dosage and administration").

Effect on serological test results.

Administration of Trimex may result in false-positive direct Coombs test results. Trimex may also cause false-positive results in galactosemia testing (see section "Adverse reactions").

False-positive results for glucose in urine may occur when non-enzymatic methods are used. During Trimex therapy, urine glucose levels should be determined using enzymatic test methods (see section "Adverse reactions").

Sodium.

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

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inadequate for monotherapy of 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.

If lidocaine solution is used as a solvent, the medicinal product may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

On ultrasound, shadows should raise suspicion of ceftriaxone calcium salt precipitate formation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases 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 decision to discontinue the drug should be made by the physician based on an individual benefit-risk assessment (see section "Adverse reactions").

Biliary stasis.

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

Nephrolithiasis.

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

Encephalopathy.

Encephalopathy has been reported during ceftriaxone therapy (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or disorders of the central nervous system. 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 unused or expired medicinal product.

Environmental release of the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. "Waste collection systems" should be used for disposal, if available.

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, 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. The possibility of sensitization should be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from 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 shown no evidence of adverse effects on male or female fertility.

Ability to influence reaction speed when driving or operating machinery.

During ceftriaxone therapy, adverse reactions such as dizziness may occur, which can affect 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, sensitivity, location, and type of infection, as well as on the patient's age and liver and kidney function.

Recommended doses for various 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).

Dose of ceftriaxone*	Frequency of administration**	Indications
1–2 g	Once daily	Community-acquired pneumonia Acute exacerbation of chronic obstructive pulmonary disease Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis)
2 g	Once daily	Hospital-acquired pneumonia Complicated skin and soft tissue infections Bone and joint infections
2–4 g	Once daily	Management of febrile neutropenic patients suspected of having a bacterial infection Bacterial endocarditis Bacterial meningitis

* 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, administration of the drug twice daily (with a 12-hour interval) should be considered.

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

Acute otitis media

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

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

Prophylaxis of surgical site infections

2 g as a single dose before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

Recommended dose is 500 mg – 1 g once daily, increasing the dose 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. 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; local guidelines should also be considered.

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

For children weighing 50 kg or more, standard adult doses should be used.

Dose of ceftriaxone*	Frequency of administration**	Indications
50–80 mg/kg	Once daily	Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis) Community-acquired pneumonia Hospital-acquired pneumonia
50–100 mg/kg (maximum 4 g)	Once daily	Complicated skin and soft tissue infections Bone and joint infections Management of febrile neutropenic patients with suspected bacterial infection
80–100 mg/kg (maximum 4 g)	Once daily	Bacterial meningitis
100 mg/kg (maximum 4 g)	Once daily	Bacterial endocarditis

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

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

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of the drug at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or previous ineffective therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 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 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. Local guidelines should also be considered.

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; local guidelines should also be taken into account.

Newborns aged 0–14 days

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

Ceftriaxone dose*	Frequency of administration	Indications
20–50 mg/kg	Once daily	Intra-abdominal infections Complicated skin and soft tissue infections Complicated urinary tract infections (including pyelonephritis) Community-acquired pneumonia Hospital-acquired pneumonia Bone and joint infections Management of neutropenic patients with fever and suspected bacterial infection
50 mg/kg	Once daily	Bacterial meningitis Bacterial endocarditis

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

The maximum daily dose of 50 mg/kg should not be exceeded.

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of the drug 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 recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. Local guidelines should also be considered.

Duration of treatment

The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

If renal and hepatic functions are adequate, dosage adjustment in elderly patients is not required.

Patients with hepatic impairment

Available data indicate no need for dose adjustment in patients with mild or moderate hepatic impairment, provided renal function is not impaired.

There are no study data available for 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 cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

For patients undergoing dialysis, there is no need for additional drug administration 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 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.

Administration method

Intramuscular administration

The drug may be administered by deep intramuscular injection. Intramuscular injection should be given into the center of a relatively large muscle. No more than 1 g should be injected at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to review the instructions for medical use of lidocaine.

Intravenous administration

The drug may be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion to infants and children under 12 years of age. For newborns, 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 suitable for the patient. Doses exceeding 2 g should be administered intravenously.

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

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone-calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").

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

Children.

The drug should be administered to children at doses specified in the section "Dosage and administration".

Overdose.

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

Adverse reactions.

The most commonly observed adverse reactions during 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)
frequency not known (cannot be estimated from available data)

Infections and infestations: uncommon: genital fungal infections; rare: pseudomembranous colitisb; frequency not knowna: superinfectionsb.

Blood and lymphatic system disorders: common: eosinophilia, leukopenia, thrombocytopenia; uncommon: granulocytopenia, anemia, coagulation disorders; frequency not knowna: hemolytic anemiab, agranulocytosis.

Immune system disorders: frequency not knowna: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivityb, Jarisch–Herxheimer reaction (see "Special precautions").

Nervous system disorders: uncommon: headache, dizziness; rare: encephalopathy; frequency not knowna: seizures.

Auditory and vestibular disorders: frequency not knowna: vertigo.

Respiratory, thoracic and mediastinal disorders: rare: bronchospasm.

Gastrointestinal disorders: common: diarrheab, loose stools; uncommon: nausea, vomiting; frequency not knowna: pancreatitisb, stomatitis, glossitis.

Hepatobiliary disorders: common: elevated liver enzymes; frequency not knowna: biliary precipitatesb, kernicterus, hepatitisc, cholestatic hepatitisc,b.

Skin and subcutaneous tissue disorders: common: rash; uncommon: pruritus; rare: urticaria; frequency not knowna: Stevens–Johnson syndromeb, toxic epidermal necrolysisb, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see "Special precautions"), acute generalized exanthematous pustulosis.

Renal and urinary disorders: rare: hematuria, glucosuria; frequency not knowna: oliguria, renal precipitates (reversible).

General disorders and administration site conditions: uncommon: phlebitis, injection site pain, fever; rare: swelling, chills.

Investigations: uncommon: increased blood creatinine levels; frequency not knowna: false-positive Coombs testb, false-positive galactosemia testb, false-positive results with non-enzymatic glucose testing methodsb.

a Based on post-marketing reports. As these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency.
b See "Special precautions" section.
c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

Diarrhea occurring after ceftriaxone administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be provided (see "Special precautions" section).

Ceftriaxone calcium salt precipitates.

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

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). 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 "Special precautions" section).

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 reported variable rates of precipitate formation following intravenous administration—up to over 30% in some studies. The incidence appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but occasionally 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 "Special precautions" section).

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C. Prepared solution should be used within 6 hours at room temperature or within 24 hours if stored at 2–8 °C.

Incompatibilities.

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 "Dosage and administration" section. 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 should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see "Dosage and administration", "Special precautions", and "Adverse reactions" sections).

For combination with other antibiotics, separate syringes or solutions should be used.

Packaging. Powder in glass vials. Packaged as 1 vial, 25 vials, or 50 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "AVANT", Ukraine.

(packaging of bulk form from manufacturer NSPC Hebei Huamin Pharmaceutical
Company Limited, China)

Manufacturer's address and place of business.
14 Anton Tsydika Street, Kyiv, 03057, Ukraine
Tel./fax: 044 496 19 94, e-mail: [email protected]