Rotacef

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROTACEF (ROTACEF)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 0.5 g or 1 g;

1 ampoule of solvent contains 1% lidocaine hydrochloride solution (lidocaine hydrochloride, sodium hydroxide, water for injections),

or

1 ampoule of solvent contains water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder, partially hygroscopic, nearly white or yellowish in color.

Solvent (1% lidocaine hydrochloride solution): colorless, clear, odorless solution.

Solvent (water for injections): colorless, clear solution.

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) 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;
• reduced permeability of the outer membrane in gram-negative bacteria;
• bacterial efflux pumps.

Breakpoints for susceptibility testing.

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

Pathogen	Dilution method (minimum inhibitory concentration, mg/l)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	˃ 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups A, B, C and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	˃ 2
Streptococci group Viridans	≤ 0.5	˃ 0.5
Haemophilus influenzae	≤ 0.12c.	˃ 0.12
Moraxella catarrhalis	≤ 1	˃ 2
Neisseria gonorrhoeae	≤ 0.12	˃ 0.12
Neisseria meningitidis	≤ 0.12c.	˃ 0.12
Non-species related	≤ 1d.	˃ 2
a. Susceptibility conclusion based on susceptibility to cefoxitin. b. Susceptibility conclusion based on susceptibility to penicillin. c. Isolates with MICs exceeding the susceptibility breakpoints are rare. If observed, repeat testing should be performed; if confirmed, isolate should be sent to a reference laboratory. d. Breakpoints apply to an intravenous daily dose of 1 g x 1 and high dose of at least 2 g x 1

Clinical effectiveness against specific microorganisms.

The prevalence of resistance among individual species may vary depending on the region and time. When treating serious infections, it is advisable to consider local information on resistance. Consultation with specialists should be sought if local resistance prevalence has reached a level at which the benefit of use is questionable.

Usually 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% 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 one or more regions. % Strains producing extended-spectrum beta-lactamases (ESBLs) are always resistant.

Pharmacokinetics.

Absorption.

Intramuscular administration.

After intramuscular injection, the mean maximum plasma concentration (C_max) of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The C_max after a single 1 g intramuscular dose of ceftriaxone is 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration–time curve after intramuscular administration is equivalent to that observed 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 C_max of ceftriaxone is approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma levels of ceftriaxone are approximately 80, 150, and 250 mg/L, respectively.

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the MIC for most clinically relevant pathogens are observed in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean C_max 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 the meninges. Penetration is enhanced during meningitis. The mean C_max 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 meningitis. The C_max of ceftriaxone in CSF is reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations is expected in breast milk (see section "Use during pregnancy or breastfeeding").

Protein binding.

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

Metabolism.

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

Elimination.

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 (T_1/2) of ceftriaxone in adults is approximately 8 hours.

Special patient populations.

Patients with renal or hepatic impairment.

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered: a minor increase in T_1/2 (less than two-fold) is observed, even in patients with severe renal impairment.

The moderate increase in T_1/2 in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in total extrarenal clearance of ceftriaxone.

In patients with impaired liver function, T_1/2 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 clearance of ceftriaxone with an expanded volume of distribution.

Elderly patients.

In patients aged 75 years and older, the mean T_1/2 is typically 2–3 times higher than in younger adults.

Children.

The T_1/2 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, T_1/2 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 ceftriaxone concentrations, except T_1/2, are dose-dependent. Non-linearity results from saturation of plasma protein binding; thus, it is observed for total ceftriaxone in plasma 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 MIC of ceftriaxone for specific target organisms (i.e., the percentage of time T > MIC).

Clinical characteristics.

Indications.

The medicinal product 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.

The medicinal product 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 surgical site infections;
• management of patients with neutropenia who develop fever suspected to be of bacterial origin;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections is suspected.

The medicinal product should be used in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special precautions for use").

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

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin.

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

Ceftriaxone is contraindicated:

• in preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

• in full-term newborns (aged ≤ 28 days):

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

*In vitro studies have shown that ceftriaxone may displace bilirubin from plasma albumin binding, 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 for use"). Refer to the lidocaine product information, particularly contraindications.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Solvents containing calcium.

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute the medicinal product 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-site connector. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical plasma have shown that newborns are at increased risk of ceftriaxone calcium salt precipitation (see sections "Contraindications", "Special precautions for use", "Dosage and administration", "Adverse reactions", and "Incompatibilities").

Oral anticoagulants.

Concomitant use of ceftriaxone with oral anticoagulants may potentiate their effect and increase the risk of bleeding. When these agents are used together, frequent monitoring of the international normalized ratio (INR) is recommended, and anticoagulant dosage should be appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").

Aminoglycosides.

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. When these agents are used together, clinical practice recommendations for monitoring aminoglycoside levels (and renal function) should be strictly followed.

Chloramphenicol.

In an in vitro study, antagonistic effects were observed when chloramphenicol was used in combination with ceftriaxone. The clinical significance of these findings is unknown.

Calcium-containing medicinal products.

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

Diuretics.

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

Probenecid.

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Effect on laboratory test results.

False-positive results in the Coombs test may occur in patients receiving ceftriaxone.

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

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

Special precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported during administration of ceftriaxone (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, the drug should 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 types of beta-lactam agents. The drug should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Skin reactions.

Severe cutaneous adverse reactions have been reported during ceftriaxone use, including Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal; however, the frequency of these reactions is unknown (see section "Adverse reactions").

Jarisch–Herxheimer reaction.

In some patients infected with spirochetes, a Jarisch–Herxheimer reaction may occur immediately after initiation of ceftriaxone therapy. This reaction is usually self-limiting or may be managed with symptomatic treatment. The drug need not be discontinued if this reaction occurs.

Interaction with calcium-containing drugs.

Fatal precipitations of ceftriaxone calcium salt in the lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitation have only been reported in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medications. In vitro studies have shown that neonates are at higher risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

The drug solution must not be mixed or co-administered simultaneously with any intravenous solutions containing calcium, even when using separate infusion systems or administering through different infusion sites, in patients of any age. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are given through separate infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), alternative antibacterial agents not associated with such precipitation risk may be considered. If ceftriaxone use is deemed necessary in patients requiring continuous TPN, TPN solutions and ceftriaxone may be administered simultaneously through separate infusion systems into 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", and "Incompatibilities").

Use in 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 plasma albumin.

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

Risk of immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibiotics, including ceftriaxone (see section "Adverse reactions"). Severe cases of hemolytic anemia, including fatal cases, have been reported in both adults and children during ceftriaxone therapy.

If anemia develops, cephalosporin-associated hemolytic anemia should be considered, and the drug should be discontinued until the etiology is determined.

Prolonged treatment.

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

Risk of colitis/overgrowth of resistant microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibiotic use have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of the drug and initiation of appropriate therapy against 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.

Use in patients with severe renal or hepatic impairment.

Careful clinical monitoring of safety and efficacy is recommended when administering the drug to patients with severe renal or hepatic impairment (see section "Dosage and administration").

Effect on serological test results.

Coombs' test may yield false-positive results during ceftriaxone therapy. Ceftriaxone may also cause false-positive results in galactosemia screening tests (see section "Adverse reactions").

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 "Adverse reactions").

Ceftriaxone may lead to falsely low blood glucose readings when measured with certain monitoring systems. Refer to the instructions for each such system. Alternative testing methods should be used if necessary.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for monotherapy in certain types of infections unless 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 only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information in the lidocaine product instructions must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Risk of biliary lithiasis.

Shadows observed on ultrasound may indicate precipitation of ceftriaxone calcium salt. Such precipitates, often mistaken for gallstones, have been observed in the gallbladder on ultrasound, with increased frequency during ceftriaxone therapy at doses of 1 g/day or higher. The drug should be used with particular caution in children. These 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, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Adverse reactions").

Risk of biliary stasis.

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

Risk of nephrolithiasis.

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

Risk of encephalopathy.

Encephalopathy has been reported during ceftriaxone therapy (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of the drug should be considered.

Warnings regarding excipients.

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

Disposal of the medicinal product.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on 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. The drug 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 breastfed infants are expected when used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization should also be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from the drug, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

Adverse reactions such as dizziness may occur during ceftriaxone therapy, which may affect the ability to drive or operate machinery (see section "Adverse reactions"). Caution should be exercised when driving or operating machinery.

Administration and dosage.

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.

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

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

Ceftriaxone dose*	Frequency of administration**	Indications
1–2 g	Once daily	Community-acquired pneumonia Acute exacerbation of chronic obstructive pulmonary disease Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis)
2 g	Once daily	Hospital-acquired pneumonia Complicated skin and soft tissue infections Bone and joint infections
2–4 g	Once daily	Management of febrile neutropenic patients suspected of 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, 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) who require special dosing regimens.

Acute otitis media.

The medicinal product may be administered intramuscularly as a single dose of 1–2 g.

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.

The medicinal product should be administered at a dose of 2 g as a single dose before surgery.

Gonorrhea.

The medicinal product should be administered intramuscularly as a single dose of 500 mg.

Syphilis.

The recommended dose of the medicinal product is 0.5–1 g once daily, increased 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)].

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

Children.

Children aged 15 days to 12 years (<50 kg).

Children with a body weight ≥ 50 kg should receive the standard adult doses.

Ceftriaxone dose*	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 children aged 15 days to 12 years (< 50 kg) requiring special dosing regimens.

Acute otitis media.

For initial treatment of acute otitis media, intramuscular administration of the drug at a dose of 50 mg/kg as a single dose may be considered. Some data suggest that in cases where the child's condition is severe or prior therapy has been ineffective, 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.

The drug should be administered at a dose of 50–80 mg/kg as a single dose before surgery.

Syphilis.

The recommended dose of the drug is 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

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

The drug should be administered at a dose of 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 under 41 weeks of postmenstrual age (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 febrile neutropenic patients with suspected bacterial infection
50 mg/kg	Once daily	Bacterial meningitis Bacterial endocarditis

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

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

Indications in neonates aged 0–14 days who require special dosing regimens.

Acute otitis media.

For initial treatment of acute otitis media, intramuscular administration of the medicinal product at a dose of 50 mg/kg as a single dose may be used.

Preoperative prophylaxis of surgical site infections.

The medicinal product should be administered at a dose of 20–50 mg/kg as a single dose before surgery.

Syphilis.

The recommended dose of the medicinal product is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Duration of treatment.

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

Special patient populations.

Elderly patients.

In elderly patients with normal renal and hepatic function, there is no need for dose adjustment.

Patients with hepatic impairment.

Available data indicate that dose adjustment is not required in patients with mild or moderate hepatic impairment provided 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, dose adjustment is not required provided hepatic function is normal. Only in cases of preterminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

If the patient is undergoing dialysis, there is no need for additional ceftriaxone 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 medicinal product 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 medicinal product is recommended.

Route of administration.

Intramuscular injection.

Ceftriaxone may be administered by deep intramuscular injection. The intramuscular injection should be given in the center of the gluteal muscle. It is recommended not to administer more than 1 g at one injection site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to consult the lidocaine medicinal product information leaflet.

Intravenous administration.

Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children up to 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 warnings and precautions for use"). Intramuscular administration should be considered only when intravenous administration is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.

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

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

For intramuscular injection, the following should be used:

• 0.5 g in 2 mL of 1% lidocaine solution;
• 1 g in 3.5 mL of 1% lidocaine solution.

For intravenous injection, the following should be used:

• 0.5 g in 5 mL of water for injections;
• 1 g in 10 mL of water for injections.

Freshly prepared injection solutions are recommended. The prepared solution (with 1% lidocaine hydrochloride as solvent) is stable for 24 hours when stored at 2–8 °C or for 6 hours when stored at 15–25 °C.

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

The infusion line must be flushed after each administration.

Children.

The medicinal product should be administered to children according to the dosing instructions specified in the section "Method of administration and dosage."

Overdose.

In case of ceftriaxone overdose, nausea, vomiting, and diarrhea may occur.

In case of overdose, symptomatic therapy should be administered. Hemodialysis or peritoneal dialysis does not reduce excessive plasma concentrations of ceftriaxone. There is no specific antidote.

Adverse Reactions.

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

The frequency of adverse reactions to ceftriaxone was determined based on data from clinical trials. Adverse reactions are classified by frequency as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), and not known (frequency cannot be estimated from available data).

Infections and infestations:

Uncommon – fungal genital infections; rare – pseudomembranous colitis (see section "Special precautions for use"); not known – superinfections (see section "Special precautions for use").

Blood and lymphatic system disorders:

Common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; not known – hemolytic anemia (see section "Special precautions for use"), agranulocytosis.

Immune system disorders:

Not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity (see section "Special precautions for use"), Jarisch–Herxheimer reaction (see section "Special precautions for use").

Nervous system disorders:

Uncommon – headache, dizziness; rare – encephalopathy; not known – seizures.

Ear and labyrinth disorders:

Not known – vertigo.

Cardiac disorders:

Not known – Kounis syndrome.

Respiratory, thoracic and mediastinal disorders:

Rare – bronchospasm.

Gastrointestinal disorders:

Common – loose stools, diarrhea (see section "Special precautions for use"); uncommon – nausea, vomiting; not known – pancreatitis (see section "Special precautions for use"), stomatitis, glossitis.

Hepatobiliary disorders:

Common – increased liver enzymes; not known – biliary precipitates (see section "Special precautions for use"), kernicterus, hepatitis¹, cholestatic hepatitis^1,2.

Skin and subcutaneous tissue disorders:

Common – rash; uncommon – pruritus; rare – urticaria; not known – Stevens-Johnson syndrome (see section "Special precautions for use"), toxic epidermal necrolysis (see section "Special precautions for use"), erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use").

Renal and urinary disorders:

Rare – hematuria, glucosuria; not known – oliguria, renal precipitates (reversible).

General disorders and administration site conditions:

Uncommon – phlebitis, injection site pain, fever; rare – edema, chills.

Investigations:

Uncommon – increased plasma creatinine levels; not known – false-positive Coombs test (see section "Interaction with other medicinal products and other forms of interaction"), false-positive galactosemia test (see section "Interaction with other medicinal products and other forms of interaction"), false-positive non-enzymatic glucose tests (see section "Interaction with other medicinal products and other forms of interaction").

¹ Usually reversible upon discontinuation of ceftriaxone.

² See section "Special precautions for use".

Description of selected adverse reactions.

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 elimination half-life of ceftriaxone compared to adults (see sections "Pharmacological properties", "Contraindications", and "Special precautions for use").

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of ceftriaxone (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 increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they usually 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 ceftriaxone doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence rates of precipitate formation with intravenous ceftriaxone administration, reaching over 30% in some studies. The incidence appears to be lower when ceftriaxone 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 suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life.

Rotacef – 3 years.

Storage conditions.

Store at 15–25 °C in a light-protected and child-resistant place.

The reconstituted solution is stable for 24 hours at 2–8 °C or for 6 hours at 15–25 °C.

Incompatibilities.

According to literature data, ceftriaxone solution is incompatible with solutions of amsacrine, vancomycin, fluconazole, and aminoglycosides.

Ceftriaxone solution must not be mixed with certain calcium-containing diluents, such as Ringer's solution or Hartmann's solution, due to the potential formation of precipitates.

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

Ceftriaxone solution must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications", "Special precautions for use", "Dosage and administration", and "Adverse reactions").

When ceftriaxone is used in combination with another antibiotic, the solutions should be administered via separate syringes or in separate infusion solutions.

Packaging.

For 0.5 g dosage:

0.5 g powder for solution for injection in a glass vial; 10 vials per cardboard box, or 1 vial with 1 ampoule of diluent (Water for Injections – 5 ml) in a cardboard box, or 1 vial with 1 ampoule of diluent (1% lidocaine hydrochloride solution – 2 ml) in a cardboard box.

For 1 g dosage:

1 g powder for solution for injection in a glass vial; 10 vials per cardboard box, or 1 vial with 1 ampoule of diluent (Water for Injections – 10 ml) in a cardboard box, or 1 vial with 1 ampoule of diluent (1% lidocaine hydrochloride solution – 3.5 ml) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

PharmaVision San. ve Tic. A.S.

Manufacturer's address and place of business.

Davutpasa Cad. No:145 Zeytinburnu Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.