Ceftriaxone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE

Composition:

Active substance: ceftriaxone;

1 vial contains 1000 mg of anhydrous ceftriaxone (as sterile ceftriaxone sodium salt).

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antibacterial agents for systemic use. 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 outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Clinical breakpoints for susceptibility testing

Table 1

Clinical 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	≤ 0.12 c	> 0.12
Non-species related	≤ 1d	> 2

a. Susceptibility conclusion is based on susceptibility to cefoxitin.

b. Susceptibility conclusion is based on susceptibility to penicillin.

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

d. Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose of at least 2 g × 1.

Clinical efficacy against specific pathogens

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

Generally susceptible species

Gram-positive aerobes

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

Gram-negative aerobes

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

Species capable of developing resistance

Gram-positive aerobes

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

Gram-negative aerobes

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

Anaerobes

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

Resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

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

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

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

Pharmacokinetics

Absorption

Intramuscular administration. After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration following a single 1 g intramuscular dose is 81 mg/L, reached within 2–3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

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

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations 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 secretion. A mean increase in peak plasma concentration (Cmax) of 8–15% 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 peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (see section "Use during pregnancy or breastfeeding").

Protein binding

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

Biotransformation

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

Elimination

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

Patients with renal or hepatic impairment

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

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

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

Elderly patients

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

Children

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

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

Linearity/non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination 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 unbound (free) fraction.

Pharmacokinetic/pharmacodynamic relationship

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

Preclinical safety data

Animal studies have shown that high doses of the calcium salt of ceftriaxone may lead to the formation of precipitates and concretions in the gallbladder of dogs and monkeys. These effects were reversible. Animal studies did not reveal any toxic effects on the reproductive system or genotoxicity. Carcinogenicity studies with ceftriaxone have not been conducted.

Clinical characteristics

Indications

Ceftriaxone is indicated for the treatment of the following infections in adults and children, including full-term newborns (from birth):

• bacterial meningitis;
• community-acquired pneumonia;
• hospital-acquired pneumonia;
• acute otitis media;
• intra-abdominal infections;
• complicated urinary tract infections (including pyelonephritis);
• bone and joint infections;
• complicated skin and soft tissue infections;
• gonorrhea;
• syphilis;
• bacterial endocarditis.

Ceftriaxone may also be used for:

• treatment of acute exacerbations 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 site infections during surgery;
• management of febrile neutropenic patients with suspected bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.

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

Contraindications

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

Ceftriaxone is contraindicated:

in preterm infants ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

in full-term newborns (≤ 28 days of age):

• 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 solutions or infusions — due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions for use" and "Side effects").

* In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, 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 also the instructions for medical use of lidocaine, particularly the "Contraindications" section.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction

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

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

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

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

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

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

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

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"). In the event of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

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

If symptoms such as rash, skin redness, blistering of lips, eyes or mouth, skin peeling, high fever, flu-like symptoms, elevated liver enzymes in blood tests, increased white blood cell count (eosinophilia), or enlarged lymph nodes (signs of severe skin reactions) occur (see section "Adverse reactions").

If any of the above symptoms occur, the patient should immediately inform their physician.

Jarisch-Herxheimer reaction

In some patients with infections caused by spirochetes, such as Lyme disease, a Jarisch-Herxheimer reaction (fever, chills, headache, muscle pain, and skin rash) may develop shortly after initiation of ceftriaxone therapy. This reaction is usually self-limiting but may sometimes require symptomatic treatment. Antibiotic therapy should not be discontinued if a Jarisch-Herxheimer reaction occurs.

Interaction with calcium-containing drugs

Fatal cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys have been observed in premature and full-term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. To date, no confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing drugs. In vitro studies have shown that neonates have an 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 separate infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered through separate infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous parenteral nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and into 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 ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

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

Immune-mediated hemolytic anemia

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

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

Prolonged treatment

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

Colitis / overgrowth of resistant 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 diarrhea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic drugs should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant to the drug may occur.

Severe renal and hepatic impairment

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

Effect on serological test results

The Coombs test may yield false-positive results during ceftriaxone therapy. Ceftriaxone may also cause false-positive results in galactosemia testing (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 falsely lower blood glucose values obtained with certain blood glucose monitoring systems. In such cases, instructions for use of the respective systems should be consulted. Alternative testing methods should be used if necessary.

Antibacterial spectrum

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as 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 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 considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis

On ultrasound, shadows should raise suspicion of ceftriaxone-calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in gallbladder ultrasound scans, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is advised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone-calcium salt precipitation has been associated with symptoms. If symptoms occur, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on an individual benefit-risk assessment (see section "Adverse reactions").

Biliary stasis

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

Nephrolithiasis

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Adverse reactions"). If symptoms occur, an 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 an individual benefit-risk assessment.

Encephalopathy

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

Important information on excipients. Sodium

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

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 embryo/fetal, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the potential risk.

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

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 reactions such as dizziness may occur, which could affect the ability to drive or operate complex 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.

The recommended dosages listed below are general guidelines. In particularly severe cases, the highest recommended dose should be used.

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

Table 2

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 with suspected bacterial infection Bacterial endocarditis Bacterial meningitis

* In documented cases of bacteremia, administration of the highest recommended dose may be appropriate.

** When doses exceeding 2 g per day are used, it may be advisable to administer 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 drug may be administered.

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

Surgical site infection prophylaxis

2 g as a single dose prior to surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

The generally recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily for 10–14 days in neurosyphilis. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be considered.

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 taken into account.

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

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

Table 3

Ceftriaxone dose*	Dosing frequency**	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, administration of the highest recommended dose may be appropriate.

** When doses exceeding 2 g per day are used, it may be advisable to administer the drug twice daily (with a 12-hour interval).

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or failure of prior therapy, Ceftriaxone may be effective when administered intramuscularly at 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 generally recommended doses in children are 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 considered.

Disseminated Lyme borreliosis — early (Stage II) and late (Stage III)

50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be taken into account.

Newborns aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates up to 41 weeks postmenstrual age (gestational age + postnatal age).

Table 4

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, administration of the highest recommended dose may be appropriate.

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

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

Acute otitis media

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

Preoperative prophylaxis of surgical site infections

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

Syphilis

The generally recommended dosage 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 defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

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

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 available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

Dose reduction of ceftriaxone is not required in patients with impaired renal function if renal function is not compromised. 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.

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

Patients with severe hepatic and renal dysfunction

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

Administration method

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. The intramuscular injection should be given into the center 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 also recommended to consult the lidocaine product information leaflet.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in infants 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 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) who require (or are expected to require) treatment with intravenous calcium-containing 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 reconstitute ceftriaxone in vials or to further dilute the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration 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 infections, ceftriaxone should be administered 30–90 minutes before surgery.

Instructions for reconstitution of the medicinal product prior to administration are provided in the section "Incompatibilities".

Children

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

Overdose

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis do 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 administration include eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

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

Events are classified by frequency as follows:

very common (≥ 1/10);
common (≥ 1/100, < 1/10);
uncommon (≥ 1/1000, < 1/100);
rare (≥ 1/10000, < 1/1000);
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; frequency not known^a — seizures; rare — encephalopathy.

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

Respiratory, thoracic and mediastinal disorders: rare — bronchospasm.

Gastrointestinal disorders: common — diarrhea^b, loose stools; uncommon — nausea, vomiting; frequency not known^a — pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: common — increased liver enzymes; frequency not known^a — biliary precipitates^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,c.

Skin and subcutaneous tissue disorders: common — rash; uncommon — pruritus; rare — urticaria; frequency not known^a — Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS 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 tests^b.

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

Ceftriaxone therapy may rarely cause impaired consciousness, abnormal movements, agitation, and seizures, particularly in elderly patients with serious renal or neurological disorders.

Description of selected adverse reactions

Infections and infestations

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 premature and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing products. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Cases of precipitate formation in the urinary tract have been reported, primarily in children receiving high doses of ceftriaxone (e.g., ≥ 80 mg/kg/day) or cumulative doses exceeding 10 grams, as well as those with additional risk factors (e.g., limited fluid intake or bed rest). Precipitates may be symptomatic or asymptomatic and may lead to ureteral obstruction and post-renal acute kidney injury. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, mainly in patients receiving doses higher than the standard recommended dose. Prospective studies in children have reported variable incidence rates of precipitate formation with intravenous administration, exceeding 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 clinically with pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals and patients or their legal representatives may report any suspected adverse reactions and/or lack of efficacy of medicinal products from AAR PHARMA FZ-LLS via any convenient method (mail, email, fax, phone, etc.) in paper or electronic form. Reports of adverse reactions and/or lack of efficacy should be sent to the pharmacovigilance department at the following address: Lesya Ukrainky Street, 26, village Shchaslyve, 08325, Ukraine; phone: +38 044-585-64-54, +38 067-441-21-29; email: [email protected], [email protected].

In case of adverse effects or questions regarding the safety of AAR PHARMA FZ-LLS medicinal products, please contact the pharmacovigilance department.

Additionally, adverse reaction reports may be submitted via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging, protected from light. The prepared solution should be stored for no more than 6 hours at temperatures not exceeding 25 °C and for no more than 24 hours in a refrigerator (2–8 °C).

Keep out of reach of children.

Incompatibilities

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

Ceftriaxone should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". In particular, diluents containing calcium (e.g., Ringer's solution, Hartmann's solution) must not be used to reconstitute ceftriaxone vials or for further dilution of reconstituted solution for intravenous administration due to the risk of precipitate formation. Ceftriaxone should not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions for use", and "Adverse reactions").

If combination therapy with another antibiotic and ceftriaxone is planned, the two agents should not be administered in the same syringe or in the same infusion solution.

Packaging. 1 vial of powder per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Cens Lbrcs Pvt. Ltd.

Manufacturer's address and place of business

VI/51B, Post Office No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.