Cefort: detailed information

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

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 1 g or 2 g.

Dosage form. Powder for solution for injection or infusion.

Main physicochemical properties: slightly hygroscopic crystalline powder of almost white or yellowish colour in vials.

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, resulting in the cessation of cell wall (peptidoglycan) biosynthesis, which in turn leads to bacterial cell lysis and death.

Resistance

Bacterial resistance to ceftriaxone may develop through one or more of the following mechanisms:

hydrolysis by β-lactamases, including extended-spectrum β-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably expressed in certain aerobic Gram-negative bacteria;
reduced affinity of penicillin-binding proteins for ceftriaxone;
decreased outer membrane permeability in Gram-negative bacteria;
bacterial efflux pumps.

Breakpoints for susceptibility testing

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

Table 1

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

a Susceptibility conclusion based on susceptibility to cefoxitin.

b Susceptibility conclusion based on susceptibility to penicillin.

c Rare isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints have been observed. If such isolates are detected, repeat testing should be performed, and if confirmed, isolates should be sent to a reference laboratory.

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

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary geographically and over time for individual species, and local resistance data are desirable, especially when treating severe infections. Expert consultation should be sought when local resistance prevalence raises doubts about the usefulness of ceftriaxone for at least some types of infections.

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 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 of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration–time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

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

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations exceeding the minimum inhibitory concentrations for most clinically significant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed upon repeated administration; 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 that in plasma, 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 is expected in breast milk (see section "Use during pregnancy or breastfeeding").

Protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the extent 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 of ceftriaxone is 10–22 mL/min. Renal clearance is 5–12 mL/min. 50–60% of ceftriaxone is excreted unchanged by the kidneys and 40–50% unchanged via 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 dysfunction, 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 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 ceftriaxone extrarenal clearance.

In patients with hepatic dysfunction, 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 volume of distribution increasing in parallel with total clearance.

Elderly patients

In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times higher 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 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

Ceftriaxone pharmacokinetics are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration and decline to a lesser extent than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone.

Pharmacokinetic/pharmacodynamic relationship

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

Cefort may be used for:

treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
treatment of disseminated Lyme borreliosis (early (Stage II) and late (Stage III)) in adults and children, including newborns aged 15 days and older;
surgical prophylaxis of surgical site infections;
management of patients with neutropenia who develop fever and are suspected of having a bacterial infection;
treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.

Cefort should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens falls outside 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 hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Cefort is contraindicated:

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

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin-induced encephalopathy in such patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see the lidocaine product information, particularly contraindications).

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Cefort 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 calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site system. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and neonatal cord plasma have shown that neonates are at increased risk of ceftriaxone-calcium salt precipitation.

Concomitant use of ceftriaxone with oral anticoagulants may potentiate the anti-vitamin K effect and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be appropriately adjusted during and after ceftriaxone therapy.

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 interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).

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

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

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

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

Concomitant administration of probenecid does not reduce ceftriaxone elimination.

Special precautions for use.

Hypersensitivity reactions.

As with all β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of β-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other β-lactam drugs.

Serious skin adverse reactions (including Stevens-Johnson syndrome, Lyell’s syndrome/toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported, which may be life-threatening or fatal; however, the frequency of these events is unknown.

Interaction with medicinal products containing calcium.

In preterm and full-term neonates up to 1 month of age, cases of precipitation of calcium ceftriaxone salt in the lungs and kidneys with fatal outcomes have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitation have been reported except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates 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 the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and the infusion systems should be flushed between administrations.

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.

Ceftriaxone is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy.

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone. Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.

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

Prolonged treatment.

During prolonged treatment, complete blood counts 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 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. Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic medicinal products 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 safety and efficacy of the drug is recommended.

Effect on serological test results.

Cefort may yield false-positive results in the Coombs test. Cefort may also cause false-positive results in tests for galactosemia.

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Cefort therapy, urine glucose levels should be determined using enzymatic test methods.

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. 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 provided in the lidocaine product information must be considered. Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In case of shadows observed on ultrasound, precipitation of calcium ceftriaxone salt should be considered. Precipitates, which were falsely interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases with ceftriaxone doses of 1 g or higher per day. Particular caution is required when administering the drug to 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 whether to discontinue the drug based on a benefit-risk assessment for the individual case.

Cholestasis.

Cases of pancreatitis, possibly caused by biliary tract obstruction, have been reported in patients receiving ceftriaxone. Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive treatment, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to Cefort administration cannot be ruled out as an initiating or contributing factor in this disorder.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported. In symptomatic cases, 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 for the individual case.

Jarisch-Herxheimer reaction.

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction may occur shortly after initiating ceftriaxone therapy. The Jarisch-Herxheimer reaction is typically self-limiting or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if this 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 ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonia, seizures), discontinuation of ceftriaxone should be considered.

Sodium.

One gram of Cefort contains 3.6 mmol of sodium. Caution is advised when administering the drug to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on the use of ceftriaxone in pregnant women are limited. During pregnancy, particularly in the first trimester, ceftriaxone should be used only if the benefit outweighs the risk.

Breastfeeding.

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

Fertility.

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

Ability to affect reaction speed when driving vehicles or operating machinery.

Adverse reactions (e.g., dizziness) may occur during treatment with the drug, which may impair the ability to drive vehicles or operate machinery. Patients should be warned about the potential risk of driving vehicles or operating machinery.

Dosage and Administration.

Dosage

The dose of the drug 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 listed below are general guidelines. In particularly severe cases, the highest of the recommended doses 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, consideration should be given to using the highest recommended dose.

** 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 drug may be administered.

Some data suggest that in patients with severe disease or inadequate response to prior therapy, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.

Prophylaxis of surgical site infections

A single dose of 2 g prior to surgery.

Gonorrhea

A single intramuscular dose of 500 mg.

Syphilis

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

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

2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Children

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

For children with body weight < 50 kg, the usual adult doses should be administered.

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, consideration should be given to using the highest recommended dose.

** 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

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

The generally recommended doses for 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 taken into account.

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

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Cefort 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 administered intramuscularly at 50 mg/kg per day for 3 days may be effective.

Neonates aged 0–14 days

Cefort is contraindicated in preterm neonates with a postmenstrual age (gestational age + postnatal age) of less than 41 weeks.

Table 3

Ceftriaxone dose*

Frequency of administration

Indications

20–50 mg/kg

Once daily

Intra-abdominal infections

Complicated skin and soft tissue infections

Complicated urinary tract infections (including pyelonephritis)

Community-acquired pneumonia

Hospital-acquired pneumonia

Bone and joint infections

Management of neutropenic patients with fever 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 recommended dose.

The maximum daily dose of 50 mg/kg should 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 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 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 recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after fever subsides or after confirmation of eradication of bacterial infection.

Elderly patients

Dose adjustment is not required in elderly patients.

Patients with hepatic impairment

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

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

Patients with renal impairment

Dose reduction of ceftriaxone is not necessary in patients with impaired renal function if hepatic function is not impaired. Only in pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

There is no need to administer an additional dose after dialysis in patients undergoing dialysis. Ceftriaxone is not removed by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

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

Route of administration

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"). For detailed information, refer to the lidocaine package insert.

Intravenous administration

Ceftriaxone may 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, 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 warnings and precautions for use"). Intramuscular administration should be considered when intravenous access is not feasible or less appropriate for the patient. Doses exceeding 2 g should be administered intravenously.

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

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

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

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone use are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and elevated liver enzymes.

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

Events are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), frequency not known (cannot be estimated from available data).

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

Blood and lymphatic system disorders: common – eosinophilia, leucopenia, thrombocytopenia; uncommon – granulocytopenia, anaemia, coagulation disorders; frequency not known^a – haemolytic anaemia^b, agranulocytosis.

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

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 – diarrhoea^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).

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

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

Cardiac disorders: frequency not known – Kounis syndrome.

Investigations: uncommon – increased blood creatinine; frequency not known^a – false-positive Coombs test^b, false-positive galactosaemia test^b, false-positive non-enzymatic glucose tests^b.

^a Based on post-marketing reports. Since these reactions are reported voluntarily from an undefined population, it is not possible to reliably estimate their frequency, hence they are categorized as frequency not known.

^b See section "Special Warnings and Precautions for Use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

Cases of diarrhoea following ceftriaxone use may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special Warnings and Precautions for Use").

Ceftriaxone calcium salt precipitates.

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

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 g, and who also had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those who are dehydrated. Precipitates may be symptomatic or asymptomatic, and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone.

Cases of biliary precipitates of ceftriaxone calcium salt have been reported, primarily in patients receiving doses higher than the standard recommended dose. Prospective studies in children have shown variable incidence rates of biliary precipitates following intravenous administration—over 30% in some studies. The incidence appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with the national reporting system.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

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

The ceftriaxone solution should not be mixed or combined with other medicinal products except those specified in the section "Dosage and Administration". Ceftriaxone must not be mixed in the same container with calcium-containing solutions such as Ringer's solution or Hartmann's solution for parenteral nutrition due to the risk of precipitate formation.

Ceftriaxone should not be mixed or co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Contraindications", "Dosage and Administration", "Special Warnings and Precautions for Use", and "Adverse Reactions").

When combining with other antibiotics, mixing in the same syringe or infusion solution is not permitted.

This medicinal product should not be mixed with other medicinal products except those specified in the section "Dosage and Administration".

Packaging.

Vial; 1 or 10 vials per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

ANTIBIOTICE SA
ANTIBIOTICE SA

Manufacturer's address and place of business.

1, Valea Lupului Street, 707410, Iasi, Romania