Sanaxon - 2000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANAXONE – 1000 SANAXONE – 2000 (SANAXONE – 1000) (SANAXONE – 2000)

Composition:

active substance: ceftriaxone;

one vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg or 2000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical 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 certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• decreased outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Clinical breakpoints for susceptibility testing

The clinical breakpoints for minimum inhibitory concentration have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), see Table 1.

Table 1

1 Information on the use of breakpoints in parentheses can be found at: https://www.eucast.org/eucastguidancedocuments/.

2 Isolates susceptible to benzylpenicillin may be considered susceptible to all beta-lactam antibacterial agents for which breakpoints have been defined (including those with footnotes), without further testing. Isolates resistant to benzylpenicillin should 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, for which breakpoints are not defined and which should not be used for the treatment of staphylococcal infections. For orally administered drugs, sufficient exposure at the site of infection must be ensured. If susceptibility to cefotaxime and ceftriaxone is reported for methicillin-susceptible staphylococci, it should be reported as "Susceptible under conditions of increased exposure" (I). Some methicillin-resistant S. aureus isolates 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.

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, Streptococcus group Viridans.

Gram-negative aerobes

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

Species for which acquired resistance may be a problem

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.

Inherently 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 substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean peak plasma concentration (Cmax) 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 in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid 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 only 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 extrarenal clearance due to reduced plasma protein binding and the corresponding increase in total ceftriaxone extrarenal 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, contributing to the observed paradoxical increase in total drug clearance with an increase in volume of distribution paralleling total clearance.

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 decreased glomerular filtration and impaired plasma protein binding. In children, the elimination half-life is shorter than in neonates or adults.

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

Linearity/non-linearity

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

Pharmacokinetic/pharmacodynamic relationship

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

Clinical Characteristics

Indications

The drug should be 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 aged 15 days and older;
• surgical prophylaxis of site infections during surgical procedures;
• management of patients with neutropenia who develop fever suggestive of bacterial infection;
• treatment of 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 possible range of bacterial pathogens is not covered by its spectrum of activity (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 (aged ≤ 28 days):

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

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

Before intramuscular injection of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions" and the lidocaine product information, particularly the "Contraindications" section).

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstituting the drug in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of calcium-ceftriaxone 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 patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown an increased risk of calcium-ceftriaxone salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Side effects", "Incompatibilities").

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 the 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 for increased nephrotoxic effect 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.

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

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

Similarly, false-positive results may occur when glucose in urine 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 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 Cowden 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 immediately discontinued 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.

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

Interaction with calcium-containing drugs

Fatal cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys have been reported in premature and full-term neonates under 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and through separate intravenous infusion systems. According to available scientific data, there are no confirmed cases of intravascular precipitation in patients other than neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medications. In vitro studies have demonstrated 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 different infusion systems or infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered through separate infusion systems at different body sites, or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents not associated with this precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children

The safety and efficacy of ceftriaxone in children, including neonates and infants, 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 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 antibiotics, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during treatment with ceftriaxone in both adults and children.

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

Prolonged therapy

During prolonged treatment, a complete blood count should be performed 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 (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic agents should not be used.

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

Severe renal and hepatic impairment

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

Effect on serological test results

Ceftriaxone may cause false-positive results in the Coombs test. The drug may also lead to 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 assay methods (see section "Side effects"). For patients undergoing hemodialysis, there is no need to adjust the dose after the procedure; however, serum drug concentrations should be monitored, as elimination may be accelerated in these patients.

Sodium

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

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 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 in the lidocaine product instructions must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Gallstone disease

The presence of shadows on ultrasound should raise suspicion of ceftriaxone-calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in the gallbladder on ultrasound, with increased frequency when ceftriaxone is administered at doses of 1 g/day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone-calcium salt may be symptomatic. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue ceftriaxone based on a benefit-risk assessment for the individual patient (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 extensive therapy, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone administration cannot be ruled out as a triggering or contributing factor.

Nephrolithiasis

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (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 the individual patient.

Jarisch–Herxheimer reaction

After initiation of ceftriaxone therapy in patients with spirochetal infections, a Jarisch–Herxheimer reaction (JHR) may occur. This reaction is usually self-limiting or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued due to this reaction.

Encephalopathy

Cases of encephalopathy have been reported during ceftriaxone therapy (see section "Side effects"), 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 should be considered.

Disposal of unused or expired medication

Environmental contamination with the medicinal product should be minimized. The drug must not be disposed of via wastewater or household waste. Disposal should be performed via a designated "waste collection system" if available.

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

Breastfeeding

Ceftriaxone passes into breast milk in low concentrations, and no 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/abandon 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 any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery

During ceftriaxone therapy, side effects such as dizziness may occur, which may 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 drug depends on the severity, sensitivity, location, and type of infection, as well as on the patient's age and liver and kidney function.

The recommended doses listed below (see Tables 2–4) are general guidelines for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

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

Table 2

* 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 (body weight ≥ 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 been ineffective, the drug may be effective when given intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g prior to surgery.

Gonorrhea

A single intramuscular dose of 500 mg.

Syphilis

Recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, administered 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 may vary; national or local guidelines should also be considered.

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

Children with a body weight of 50 kg or more should receive the standard adult doses.

Table 3

* 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 children aged 15 days to 12 years (body weight < 50 kg) requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of the drug at a dose of 50 mg/kg may be administered. Some data suggest that in cases where the child's condition is severe or previous therapy has been ineffective, the drug may be effective when given intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prevention of surgical site infections

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

Syphilis

The generally recommended doses 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. The recommended duration of treatment varies; national or local guidelines should also be considered.

Newborns aged 0–14 days

The drug is contraindicated in premature newborns with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

Table 4

* 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 should be continued for 48–72 hours after the disappearance of signs of systemic illness or until eradication of the bacterial infection has been confirmed.

Elderly patients

If renal and hepatic functions are adequate, 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 study data available for 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 compromised. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

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

Method of administration

Intramuscular administration

The drug 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 administer more than 1 g at a single injection site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, the package leaflet for lidocaine should be consulted.

Intravenous administration

The drug 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 children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special warnings and precautions for use"). Intramuscular administration should be considered when intravenous access is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.

Ceftriaxone is contraindicated in neonates (aged ≤ 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 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 infusion system. Therefore, ceftriaxone must not be mixed or co-administered with solutions containing calcium (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.

Dilution. Depending on the required dose, determine the necessary number of vials. For intravenous or intramuscular administration, add the recommended volume of diluent specified in Table 5 to the vial, then shake the vial well until the contents are completely dissolved.

For intravenous infusion, add 15 mL of diluent to the vial and shake well until the vial contents are completely dissolved.

Withdraw 15 mL of the resulting solution and add it to 25 mL of diluent in an infusion bottle to prepare the patient's dose (to a total volume of 40 mL, as indicated in Table 5).

The solution should be administered by intravenous infusion as described in this section.

Table 5

* Ceftriaxone solution in lidocaine should not be administered intravenously.

If other diluents are used, their compatibility with ceftriaxone must be verified. The resulting solution should be clear and free of foreign particles.

Children

The drug should be administered to children according to the dosage specified in the section "Administration and Dosage".

Overdose

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis does not reduce excessive drug concentrations in plasma. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

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

The frequency of adverse reactions to ceftriaxone was determined based on 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, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not known^a – hemolytic anemia^b, agranulocytosis.

Cardiac disorders: frequency not known – Kounis syndrome.

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

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

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)^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, fever; rare – swelling, chills.

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

^a Based on post-marketing reports. As these reactions are voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency, hence the frequency is categorized as "not known".

^b See section "Special warnings and precautions for use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations

Diarrhea following ceftriaxone administration 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 (see sections "Contraindications", "Special warnings and precautions for use", and "Pharmacodynamics").

Cases of renal precipitates 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 had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special warnings and precautions for use").

Cases of biliary precipitates of ceftriaxone calcium salt have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation following intravenous administration, with some studies reporting over 30%. 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 (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging.

The reconstituted solution should be stored for no more than 6 hours at temperatures not exceeding 25 °C, or 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". Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, as precipitates may form. Ceftriaxone should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special warnings and precautions for use", and "Adverse reactions").

Separate syringes or infusion solutions should be used when combining with other antibiotics.

Packaging

1 vial per cardboard package.

Prescription status

Prescription only.

Manufacturer

Sens Laboratory Pvt. Ltd.

Manufacturer's address and place of business

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