Ceftriaxone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE

Composition:

Active ingredient: ceftriaxone;

One vial contains sodium ceftriaxone equivalent to 1000 mg of ceftriaxone.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder from white to yellowish-orange in color.

Pharmacotherapeutic group. Antibacterial agents 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 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 constitutively expressed 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.

Susceptibility testing

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

Organisms	Minimum inhibitory concentration (MIC, mg/l)
	Susceptible (S ≤)	Resistant (R >)
Brucella melitensis (meningitis)	(2)1	(2)1
Cutibacterium acnes	0.062	0.062
Enterobacterales (other indications except meningitis)	1	2
Enterobacterales (meningitis)	1	1
Haemophilus influenzae (other indications except meningitis)	0.125	0.125
Haemophilus influenzae (meningitis)	0.125	0.125
Kingella kingae	0.06	0.06
Moraxella catarrhalis	1	2
Neisseria gonorrhoeae	0.125	0.125
Neisseria meningitidis (all indications, including prophylaxis)	0.125	0.125
Staphylococcus spp.	Note3	Note3
Streptococcus groups A, B, C and G	Note4	Note4
Streptococcus pneumoniae (other indications except meningitis)	0.5	2
Streptococcus pneumoniae (meningitis)	0.5	0.5
Viridans group streptococci	0.5	0.5

1. For information on the use of breakpoints in parentheses, see https://www.eucast.org/eucastguidancedocuments/.
2. Isolates susceptible to benzylpenicillin may be considered susceptible to all beta-lactam agents with breakpoints (including those marked with a footnote) without further testing. Isolates resistant to benzylpenicillin must be tested for susceptibility to individual agents.
3. Susceptibility of staphylococci to cephalosporins is determined based on susceptibility to cefoxitin, except for cefixime, ceftazidime, ceftazidime-avibactam, cefditoren, and ceftolozane-tazobactam, which have no breakpoints and should not be used for staphylococcal infections. For oral administration, adequate exposure at the site of infection should be ensured. If use of cefotaxime and ceftriaxone for treatment of methicillin-susceptible staphylococci is reported, the following should be stated: "Susceptible, increased exposure" (I). Some methicillin-resistant S. aureus strains are susceptible to ceftaroline and ceftobiprole.
4. Susceptibility of Group A, B, C, and G streptococci to cephalosporins is determined based on susceptibility to benzylpenicillin.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local resistance data are desirable, especially when treating severe infections. When necessary, if local resistance prevalence renders the benefit of ceftriaxone use questionable, at least for treatment of certain types of infections, consultation with experts should be sought.

Susceptible species

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)*, coagulase-negative staphylococci (methicillin-susceptible)*, Streptococcus pyogenes (Group A), Streptococcus agalactiae (Group B), Streptococcus pneumoniae, Streptococcus viridans group.

Gram-negative aerobes

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

Species that may develop resistance

Gram-positive aerobes

Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.

Gram-negative aerobes

Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli**, Klebsiella pneumoniae**, Klebsiella oxytoca**, Morganella morganii, Proteus vulgaris, Serratia marcescens.

Anaerobes

Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.

Resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others:

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

* All methicillin-resistant staphylococci are resistant to ceftriaxone.

• Resistance frequency >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 that observed after intravenous administration of an equivalent dose. The maximum plasma concentration (Cmax) after a single intramuscular dose of 1 g is 81 mg/L, reached within 2–3 hours after administration. The area under the plasma concentration–time curve (AUC) after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of 500 mg and 1 g ceftriaxone, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions 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 (MICs) 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 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 reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak CSF concentrations are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also found in low concentrations 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 (down to 85% at a plasma concentration of 300 mg/L).

Biotransformation

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

Elimination

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

Patients with renal or hepatic impairment

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

The moderate increase in 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 body clearance of ceftriaxone.

In patients with hepatic impairment, the 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 clearance of the drug, with a parallel 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 up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired plasma protein binding. In children, the half-life is shorter than in neonates or adults.

The plasma clearance and volume of distribution of total ceftriaxone are higher in 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 is due to saturation of plasma protein binding; thus, it is 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 MIC of ceftriaxone for specific target organisms (i.e., %T > MIC).

Preclinical safety data

Available animal study data indicate that high doses of the calcium salt of ceftriaxone caused formation of precipitates and stones in the gallbladder of dogs and monkeys, which were reversible. Animal studies revealed no toxic effects on the reproductive system or genotoxicity. Carcinogenicity studies with ceftriaxone have not been conducted.

Clinical characteristics.

Indications.

Used 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 drug 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 from 15 days of age;
• surgical prophylaxis of surgical site infections;
• patients with neutropenia who develop fever suspected to be due to bacterial infection;
• patients with bacteremia arising from any of the above-mentioned infections or when there is suspicion of any of the above-mentioned infections.

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

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

Contraindications.

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

Ceftriaxone is contraindicated:

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

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

Solutions of ceftriaxone 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 dissolve ceftriaxone in vials or for further dilution of the solution for intravenous infusion, as precipitation may occur. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of precipitation of ceftriaxone calcium salt (see sections "Contraindications", "Special precautions", "Dosage and administration", "Side effects", and "Incompatibility").

Concomitant use of the drug 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 adjusted appropriately during and after ceftriaxone therapy (see section "Side effects").

There are conflicting data regarding the potential enhancement of nephrotoxic effects 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 results in the Coombs test.

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

Similarly, when glucose in urine is tested by non-enzymatic methods, results may be falsely positive. Therefore, during ceftriaxone therapy, glucose in urine should be tested 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 "Side effects"). Hypersensitivity reactions may also progress to Coomb's syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, administration of 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 agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

Cases of severe skin reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported during ceftriaxone use, which may be life-threatening or fatal; however, the frequency of these events is unknown (see section "Side effects").

Encephalopathy

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

Interaction with calcium-containing medicinal products

Cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys, resulting in fatal outcomes, 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 separate intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering through different infusion sites. 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 at different sites or the infusion system is thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), physicians may consider alternative antibacterial agents that do not carry this precipitation risk. If ceftriaxone use is deemed necessary in such patients, 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 lines should be flushed between administrations (see sections "Contraindications", "Side effects", and "Incompatibilities").

Children

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

Ceftriaxone is contraindicated in premature and full-term newborns 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 antibiotics, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported in both adults and children during ceftriaxone treatment.

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

Prolonged treatment

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

Colitis/overgrowth of resistant microorganisms

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

As with other antibiotics, superinfections caused by microorganisms not susceptible to ceftriaxone may occur.

Severe renal and hepatic impairment

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

Effect on serological test results

Ceftriaxone may cause false-positive results in the Coombs test. Ceftriaxone may also cause false-positive results in galactosemia screening tests (see section "Side effects").

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

Ceftriaxone may falsely lower blood glucose readings obtained by certain blood glucose monitoring systems. Consult the instructions for use of each system. Alternative testing methods should be used if necessary.

Sodium

1 gram of the medicinal product 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 inappropriate for monotherapy in certain types of infections, except when the causative pathogen has 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.

Cholelithiasis

On ultrasound, shadows should raise suspicion of ceftriaxone-calcium salt precipitate formation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in the gallbladder on ultrasound, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering the drug to children. These precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, ceftriaxone-calcium precipitates have been associated with clinical 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 each individual case (see section "Side effects").

Biliary stasis

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

Nephrolithiasis

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

Jarisch–Herxheimer reaction

In some patients with spirochete infections, a Jarisch–Herxheimer reaction may occur shortly after initiating 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.

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 (see section "Preclinical safety data"). Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding

Ceftriaxone passes into breast milk in low concentrations, and no effects on infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization should also be considered. A decision should be made whether to discontinue breastfeeding or discontinue/forego ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, adverse effects (e.g., dizziness) may occur that could impair the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage.

Dosage

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

The recommended doses for specific 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 febrile neutropenic patients 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, 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 ceftriaxone 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 1–2 g daily for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g prior to surgery.

Gonorrhea

500 mg as a single intramuscular dose.

Syphilis

The recommended dose is 500 mg – 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 from 15 days to 12 years of age (<50 kg)

Children with a body weight of 50 kg or more should receive 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 suspected of having a 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, administration of the drug twice daily (with a 12-hour interval) should be considered.

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has failed, 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

The 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.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates up to 41 weeks 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 suspected of having a 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 newborns aged 0–14 days requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose before surgery.

Syphilis

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

Duration of treatment

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

Elderly patients

In patients with normal renal and hepatic function, dose adjustment is not required for elderly patients.

Patients with hepatic impairment

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

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

Patients with renal impairment

For patients with impaired renal function, dose reduction of ceftriaxone is not required if renal function is not impaired. Only in patients with pre-terminal 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 doses after dialysis. Ceftriaxone is not eliminated 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 impairment

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

Preparation and administration

Intramuscular administration

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

The displacement volume of 1 g of ceftriaxone is 0.71 mL of water for injection and 1% lidocaine hydrochloride solution. When 10 mL of water for injection is added, the final concentration of the solution is 93.37 mg/mL. When 3.5 mL of 1% lidocaine hydrochloride solution is added, the final concentration is 237.53 mg/mL.

When 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

Concentrations for intravenous injection: 100 mg/mL; concentrations for intravenous infusion: 50 mg/mL (for further information, see section "Dosage and administration").

Preparation of injection and infusion solutions

Freshly prepared solutions are recommended.

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

For intravenous administration, 1 g of ceftriaxone should be dissolved in 10 mL of water for injection.

Ceftriaxone may be administered by intravenous infusion over 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, 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 precautions"). Intramuscular administration should be considered only when intravenous access is not feasible or less acceptable 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 precautions", and "Incompatibilities").

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

After reconstitution, the solution is stable for no more than 24 hours at 2–8 °C or no more than 6 hours at 25 °C.

From a microbiological standpoint, the reconstituted medicinal product should be used immediately. If not used immediately, the responsibility for compliance with storage time and conditions lies with the user, and the above-mentioned time limits for maintaining chemical and physical stability during use must not be exceeded.

Children.

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

Overdose.

Symptoms of overdose may include nausea, vomiting, and diarrhea. Ceftriaxone concentrations cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic.

Adverse Reactions

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

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

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), and frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous colitis*; frequency not known – superinfections*.

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

Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions*, Jarisch–Herxheimer reaction*.

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

Ear and labyrinth disorders: frequency not known – vertigo.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – diarrhea*, loose stools; uncommon – nausea, vomiting; frequency not known – pancreatitis*, stomatitis, glossitis.

Hepatobiliary disorders: common – increased liver enzymes; frequency not known – biliary precipitates; frequency not known – hepatitis1, cholestatic hepatitis1,2, nuclear jaundice.

Skin and subcutaneous tissue disorders: common – rash; uncommon – pruritus; rare – urticaria; frequency not known – Stevens–Johnson syndrome*, toxic epidermal necrolysis* (Lyell’s syndrome), erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*.

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

Cardiac disorders: frequency not known – Kounis syndrome.

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

Investigations: uncommon – increased blood creatinine levels; frequency not known – false-positive Coombs test*, false-positive galactosemia test*, false-positive results with non-enzymatic glucose tests*.

* See section "Interaction with other medicinal products and other forms of interaction".

1 Usually reversible upon discontinuation of ceftriaxone.

1,2 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").

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 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 "Pharmacodynamics", "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 the drug (e.g., ≥80 mg/kg/day or total doses exceeding 10 grams) and had additional risk factors (e.g., limited fluid intake, bed rest). Precipitate formation may be symptomatic or asymptomatic and may lead to ureteral obstruction and acute renal failure, which is usually reversible after discontinuation of ceftriaxone (see section "Special precautions for use").

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Incompatibility.

Based on literature data, ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Solutions containing ceftriaxone must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage", nor should they be added to each other. In particular, calcium-containing solutions (e.g., Ringer's solution, Hartmann's solution) must not be used to reconstitute ceftriaxone in the vial or for further dilution of the intravenous solution, as precipitation may occur. Ceftriaxone must not be mixed or co-administered with calcium-containing solutions, including parenteral nutrition (see sections "Contraindications", "Special precautions for use", "Method of administration and dosage", and "Adverse reactions").

If combination therapy with another antibiotic and ceftriaxone is prescribed, administration must not occur in the same syringe or in the same infusion solution.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage".

Packaging. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Mankind Pharma Limited.

Manufacturer's address and location of operations.

Village Kishanpura, P.O. Jamniwal, Tehsil, Paonta Sahib, District Sirmaur 173025, Himachal Pradesh, India.