Ceftriaxone yuria-pharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE YURIYA-PHARM

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Basic physico-chemical properties: crystalline powder from white to yellow-orange in color.

Pharmacotherapeutic group

Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone.

ATC code J01D D04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

Resistance

Bacterial resistance to ceftriaxone may develop 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 some 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.

Susceptibility testing Breakpoints Susceptibility testing Breakpoints

The minimum inhibitory concentration breakpoints 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 of the Viridans group	≤ 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. The conclusion on susceptibility is based on susceptibility to cefoxitin.

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

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

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

Clinical efficacy against specific pathogens

The prevalence of resistance among individual species may vary geographically and over time. Local information on microbial resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the benefit of using the drug at least questionable for certain types of infections.

Susceptible species

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.

Gram-negative aerobes

Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.

Species with potential for 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.

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

Following 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 1 g intramuscular dose is 81 mg/L, achieved 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 substantially 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 secretions. An 8–15% increase in mean peak plasma concentration (Cmax) is observed upon repeated administration; steady state is 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 peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningeal inflammation. Peak concentrations in cerebrospinal fluid are achieved 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").

Plasma 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

Total plasma clearance (bound and unbound) of ceftriaxone 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 minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderately increased elimination half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced plasma protein binding and a corresponding increase in total extrarenal clearance of ceftriaxone.

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, contributing to the observed paradoxical increase in total drug clearance, paralleled by an increase in 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. From birth to 14 days of age, free ceftriaxone levels may continue to rise due to factors such as decreased glomerular filtration and impaired plasma 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 elimination half-life, are dose-dependent based on total drug concentration, decreasing to a lesser extent than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding, thus occurring 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 species (i.e., % T > minimum inhibitory concentration).

Clinical characteristics

Indications

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 site infection prophylaxis;
• 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 any of the above-mentioned infections are suspected.

CEFTRIAXONE YURIA-PHARM should be administered 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 ≤ 41 weeks of postmenstrual age (gestational age + postnatal age)*;
• in full-term newborns (≤ 28 days of age):
  • with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely to be impaired under these conditions*;
  • who require (or are expected to require) intravenous administration of calcium-containing drugs or calcium-containing infusions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions for use", "Side effects", and "Incompatibilities").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thereby increasing the risk of bilirubin-induced encephalopathy in these 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"). See the instructions for medical use of lidocaine, particularly contraindications.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute the drug in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown an increased risk of ceftriaxone-calcium salt precipitate formation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Side effects", "Incompatibilities").

Concomitant use of the medicinal product with oral anticoagulants may enhance the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be appropriately adjusted 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 practice recommendations for monitoring 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 cases of interaction between ceftriaxone and orally administered calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration) have been reported.

Patients receiving ceftriaxone may have false-positive Coombs test results.

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

Similarly, when urine glucose is tested by non-enzymatic methods, results may be falsely positive. For this reason, enzymatic methods should be used to determine urine glucose levels during ceftriaxone therapy.

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"). Hypersensitivity reactions may also progress to Coombs syndrome, a severe allergic reaction that can lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, administration of ceftriaxone 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. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

Cases of severe skin adverse reactions [Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)] have been reported during treatment with ceftriaxone, which may be life-threatening; however, the frequency of these events is unknown (see section "Adverse reactions").

Interaction with calcium-containing medicinal products

In preterm and term neonates under 1 month of age, cases of precipitation of calcium ceftriaxone salt in the lungs and kidneys with fatal outcomes have been described. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. There are 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 newborns are at increased risk of calcium ceftriaxone 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 different infusion systems or different infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered via different infusion systems at different body sites or the infusion system is replaced or thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone administration is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", "Pharmacokinetics", and "Incompatibilities").

Children

The safety and efficacy of the drug 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 preterm and term newborns at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated haemolytic anaemia

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

If anaemia develops during ceftriaxone treatment, a diagnosis of cephalosporin-associated anaemia should be considered, and ceftriaxone should be discontinued until the aetiology is established.

Prolonged treatment

During prolonged treatment, a full 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 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 diarrhoea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis 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

The Coombs test may yield false-positive results during treatment with ceftriaxone. The drug may also cause false-positive results in galactosaemia testing (see section "Adverse reactions").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During treatment with the drug, urine glucose levels should be determined using enzymatic methods (see section "Adverse reactions").

Ceftriaxone use may cause falsely low blood glucose readings with certain glucose monitoring systems. Refer to the instructions for use of each specific system. Alternative testing methods should be used if necessary.

Sodium

Each gram of the drug contains 3.6 mmol of sodium. This should be taken into account if the patient is on a sodium-controlled diet.

Antibacterial spectrum

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

Gallstone disease

In case of shadows on ultrasound, precipitation of calcium ceftriaxone salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency when ceftriaxone is administered at doses of 1 g/day or higher. Particular caution is required when using the drug in children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of calcium ceftriaxone salt has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on the necessity of discontinuing the drug based on a benefit-risk assessment in the individual case (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, or total parenteral nutrition. Precipitation in the biliary tract due to drug administration may be 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"). In case of symptoms, 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 a benefit-risk assessment in the individual case.

Jarisch-Herxheimer reaction

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

Encephalopathy

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

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding

Ceftriaxone passes into breast milk in low concentrations, and no effects on infants who are breastfed are expected when the drug is used at therapeutic doses. However, the risk of developing diarrhoea 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/forego ceftriaxone therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Dosage

The dosage 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 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)

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 patients with neutropenia who develop fever and are suspected of bacterial infection Bacterial endocarditis Bacterial meningitis

* 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 the medicinal product may be administered.

Some data suggest that in cases of severe clinical condition or previous ineffective therapy, the drug may be effective when administered intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g administered preoperatively.

Gonorrhea

A single intramuscular dose of 500 mg.

Syphilis

The recommended dose is 0.5 g–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)]

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 with a body weight of 50 kg or more 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 newborns, infants, and children aged 15 days to 12 years (< 50 kg) requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of CEFTRIAXONE Yuria-Pharm at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or previous ineffective therapy, the drug may be effective when administered intramuscularly at a dose of 50 mg/kg 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. National or local guidelines should also be taken into account.

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

50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Newborns aged 0–14 days

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 febrile neutropenic patients suspected of 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 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

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.

Treatment duration

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.

Elderly patients

No dose adjustment is required for elderly patients if renal and hepatic functions are adequate.

Patients with hepatic impairment

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

There are no data from studies in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

In patients with impaired renal function, dose reduction of ceftriaxone is not required if hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.

For patients undergoing dialysis, there is no need for additional drug administration after dialysis. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the drug's safety and efficacy is recommended.

Patients with severe hepatic and renal impairment

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

Administration method

Intramuscular administration

The medicinal product can be administered by deep intramuscular injection. The injection should be given into the bulk of a relatively large muscle. 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"). It is recommended to consult the lidocaine product information leaflet.

Intravenous administration

The medicinal product can be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes 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 only when intravenous access 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 infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium-ceftriaxone 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 calcium-ceftriaxone 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 precautions", and "Incompatibilities").

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

Preparation method

Concentration for intravenous injection: 100 mg/mL.

Concentration for intravenous infusion: 50 mg/mL.

For information on storage conditions of the reconstituted solution, see section "Storage conditions".

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

The intravenous line should be flushed after each administration of the drug.

For intravenous injection, 1 g of ceftriaxone should be dissolved in 10 mL of water for injection. The injection should be administered directly into a vein or into an intravenous infusion system over more than 5 minutes.

For intramuscular injection, 1 g of ceftriaxone should be dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The medicinal product should be administered by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at more than one site.

Children

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

Overdose

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis does not 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 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.

Adverse reactions are classified by frequency as follows:

very common (≥ 1/10);
common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000);
frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon — genital fungal infections; rare — pseudomembranous colitis^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^b.

Nervous system disorders: uncommon — headache, dizziness; rare — encephalopathy; frequency not known^a — seizures.

Aural and vestibular system disorders: frequency not known^a — vertigo.

Cardiac disorders: not known — Kounis syndrome.

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 (bilirubin encephalopathy), 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 syndrome)^b.

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 — edema, chills.

Investigations: uncommon — increased blood creatinine levels; frequency not known^a — false-positive Coombs test^b, false-positive galactosemia test^b, false-positive results in non-enzymatic glucose testing methods^b.

^a Based on post-marketing reports. Since these reports are voluntary, the frequency cannot be reliably estimated.
^b See section "Special precautions".
^c Usually reversible after 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").

Precipitates of ceftriaxone calcium salt

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 precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").

Cases of renal precipitate formation have been reported, primarily in children receiving high daily doses (e.g., ≥ 80 mg/kg/day or total doses exceeding 10 g), especially when additional risk factors were present (e.g., dehydration or immobilization). Precipitates may be symptomatic or asymptomatic, may lead to ureteral obstruction and post-renal acute kidney injury, and typically resolve after discontinuation of ceftriaxone (see section "Special precautions").

Cases of ceftriaxone calcium salt precipitate formation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence rates of precipitate formation with intravenous administration—over 30% in some studies. The incidence appears to be lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions").

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years (from the date of manufacture of the bulk form).

Storage conditions

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

Keep out of reach of children.

From a microbiological standpoint, the reconstituted solution should be used immediately. If not used immediately, storage conditions and duration are the responsibility of the user.

The reconstituted solution should be stored for no more than 6 hours at 25 °C and no more than 24 hours at 2–8 °C.

Incompatibilities

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

Solutions containing ceftriaxone should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". Solvents containing calcium, such as Ringer's solution or Hartmann's solution, should not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitates may form.

Ceftriaxone should not be mixed or co-administered with solutions containing calcium, including total parenteral nutrition solutions (see sections "Dosage and administration", "Contraindications", "Special precautions", and "Adverse reactions"). When combination therapy with another antibacterial agent is required, the agents should not be administered via the same infusion line or mixed in the same infusion solution.

Packaging

Vial with powder. Pack of 1 or 10 vials per carton.

Prescription status: Prescription only.

Manufacturer

LLC "Yuria-Pharm" (packaging of bulk form manufactured by NSPC Hebei Huamin Pharmaceutical Co., Ltd., China).

Manufacturer's address and location of business activity

18030, Cherkasy, Cherkasy region, Kobzarska St., 108, Ukraine. Tel.: (044) 281-01-01.