Ultracef

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ULTRACEF

Composition:

active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 0.5 g or 1.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder of white or yellowish color.

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

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This leads to disruption of cell wall (peptidoglycan) biosynthesis, resulting in lysis and death of the bacterial cell.

Resistance

Bacterial resistance to ceftriaxone may be related to the following mechanisms:

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases, and Amp C enzymes, which may be produced or stably derepressed in certain aerobic Gram-negative bacterial species;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• impermeability of the outer membrane of Gram-negative microorganisms;
• bacterial efflux pumps.

Breakpoints for susceptibility testing

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

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 are 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 inferred from 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 agents, adequate 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, increased exposure" (I). Some methicillin-resistant S. aureus isolates are susceptible to ceftaroline and ceftobiprole (see footnotes 6/D and 8/F).
4. Susceptibility of group A, B, C, and G streptococci to cephalosporins is inferred from susceptibility to benzylpenicillin.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance may vary according to geographical region and, for certain species, over time; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Where local resistance prevalence renders the utility of ceftriaxone questionable, at least for certain types of infections, expert consultation should be sought.

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

% Strains producing ESBLs are always resistant

Pharmacokinetics.

Absorption

Following intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma concentrations of ceftriaxone are approximately 120 and 200 mg/L, respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, plasma concentrations of ceftriaxone are approximately 80, 150 and 250 mg/L, respectively. After intramuscular injection, mean peak plasma concentrations of ceftriaxone are approximately half of those observed after intravenous administration of an equivalent dose. Maximum plasma concentration after a single 1 g intramuscular dose is approximately 81 mg/L, achieved 2−3 hours after administration.

The area under the plasma concentration-time curve after intramuscular administration is equivalent to that observed after intravenous administration of an equivalent dose.

Distribution

The volume of distribution of ceftriaxone is 7−12 L. Concentrations significantly exceeding the minimum inhibitory concentrations for most relevant pathogens are achieved in body tissues, including lungs, heart, biliary tract/liver, tonsils, middle ear and nasal mucosa, bones, cerebrospinal fluid, pleural fluid, prostatic secretion and synovial fluid. An 8−15 % increase in mean peak plasma concentration (Cmax) is observed upon repeated administration; steady state is generally achieved within 48−72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is greatest during inflammation of the meninges. Mean peak concentrations of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis are up to 25 % of plasma levels, compared to 2 % of plasma levels in patients without meningeal inflammation. Peak concentration of ceftriaxone in cerebrospinal fluid is reached approximately 4−6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and enters breast milk in low concentrations (see section "Use during pregnancy or breastfeeding").

Plasma protein binding

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

Biotransformation

Ceftriaxone is not systemically metabolized and is converted by intestinal flora into inactive metabolites.

Elimination

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

Patients with impaired renal or hepatic function

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered, with a slightly prolonged elimination half-life (less than 2-fold), even in patients with severe renal impairment.

The relatively small increase in elimination half-life in renal failure is explained by compensatory acceleration of extrarenal clearance due to reduced protein binding and the corresponding increase in total extrarenal clearance of ceftriaxone.

In patients with impaired hepatic function, the elimination half-life of ceftriaxone does not increase due to compensatory acceleration of renal clearance. This is also associated with an increased plasma free fraction of ceftriaxone, contributing to a paradoxical acceleration of total drug clearance, with an increase in volume of distribution parallel to total clearance.

Elderly population

In individuals over 75 years of age, the mean elimination half-life is generally two to three times longer than in younger adults.

Pediatric population

The elimination half-life of ceftriaxone is prolonged in neonates. In children under 14 days of age, free ceftriaxone levels may be further increased by factors such as reduced glomerular filtration and impaired plasma protein binding. In older children, the elimination half-life is shorter than in neonates and adults.

Total plasma clearance and volume of distribution of ceftriaxone in neonates, infants, and older children are higher 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 concentrations, with increases less than proportional to dose. Non-linearity results from saturation of plasma protein binding and therefore applies to total plasma ceftriaxone, not to 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 (MIC) of ceftriaxone for specific target organisms (i.e., % T > MIC).

Preclinical safety data

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

Clinical characteristics.

Indications.

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 be used:

• for treatment of acute exacerbations of chronic obstructive pulmonary disease in adults;
• for treatment of disseminated Lyme disease [early (stage II) or late (stage III)] in adults and children, including newborns from 15 days of age;
• for surgical prophylaxis of infections at the site of surgical intervention;
• for management of neutropenic patients who develop fever suspected to be due to bacterial infection;
• for treatment of patients with bacteremia, either proven or suspected, associated with any of the infections listed above.

Ceftriaxone should be administered in combination with other antibacterial agents if the suspected range of causative bacteria is not covered by its spectrum of activity.

The decision to prescribe ceftriaxone should be made in accordance with official guidelines for appropriate use of antibacterial agents.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin.

Severe hypersensitivity (e.g., anaphylactic reaction) in history to any other beta-lactam antibacterial agent (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated in preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age).*

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

• with hyperbilirubinemia, jaundice, or hypoalbuminemia or acidosis, as these are conditions in which bilirubin binding is likely impaired;*
• if they have an indication (or are expected to have an indication) for treatment with intravenous calcium or calcium-containing infusions due to the risk of formation of ceftriaxone-calcium precipitates.

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding sites to serum albumin, creating a risk of bilirubin encephalopathy in these patients.

If lidocaine is used as a solvent, the absence of contraindications to lidocaine must be confirmed before administering intramuscular ceftriaxone injection (see section "Contraindications"). See also the instructions for use of lidocaine, particularly the "Contraindications" section.

Solutions of ceftriaxone containing lidocaine must not be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Calcium-containing diluents, such as Ringer's solution or Hartmann's solution, must not be used to dissolve the contents of ceftriaxone vials or for further dilution of reconstituted vial contents for intravenous administration due to the possibility of precipitate formation. Ceftriaxone-calcium precipitate may also form if ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition 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 systems are thoroughly flushed with an appropriate fluid between infusions. In vitro studies using neonatal umbilical cord plasma and adult plasma have shown that newborns have an increased risk of formation of ceftriaxone-calcium deposits.

Concomitant use with oral anticoagulants may potentiate the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, with appropriate dose adjustment of vitamin K antagonist agents during and after ceftriaxone treatment.

Data regarding the potential for increased nephrotoxicity of aminoglycosides when used in combination with cephalosporins are conflicting. In such cases, careful monitoring of aminoglycoside levels (and renal function) is recommended in clinical practice.

An antagonistic effect has been observed in vitro with concomitant use of chloramphenicol and ceftriaxone. The clinical significance of this phenomenon is unknown.

There are no reports of interaction between ceftriaxone and orally administered calcium-containing products, or of interaction between intramuscular ceftriaxone and calcium-containing products (intravenous or oral).

In patients receiving ceftriaxone, the Coombs test may yield false-positive results.

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

In addition, false-positive results may occur with non-enzymatic methods for glucose testing in urine. For this reason, glucose testing in urine during ceftriaxone therapy should be performed using an enzymatic method.

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

Concomitant administration of probenecid does not reduce the elimination of ceftriaxone.

Special precautions for use.

Hypersensitivity reactions

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

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

Jarisch-Herxheimer reaction (JHR)

A Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone treatment in some patients with spirochetal infections. JHR is usually self-limiting, or symptomatic treatment may be administered. Antibiotic therapy should not be discontinued if such a reaction occurs.

Interaction with calcium-containing products

Fatal reactions have been reported in premature and full-term neonates up to 1 month of age, associated with precipitation of ceftriaxone-calcium salts in the lungs and kidneys. In at least one case, ceftriaxone and calcium were administered at different times and via different intravenous systems. There have been no reports of confirmed intravascular precipitates in patients other than neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies have shown that neonates have an increased risk of ceftriaxone-calcium precipitate formation compared to other age groups.

In patients of any age, ceftriaxone must not be mixed or administered simultaneously with any intravenous calcium-containing solution, even via separate lines or infusion at different sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially if different infusion sites are used or if infusion lines are replaced or thoroughly flushed with saline solution between infusions to prevent precipitate formation. If patients require continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers should consider alternative antibacterial therapy that does not carry a similar precipitation risk. If ceftriaxone use is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but via separate infusion systems at different sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion lines should be flushed between administrations.

Paediatric population

The safety and efficacy of ceftriaxone in neonates, infants, and older children have been established for the dosages listed in the section "Dosage and administration".

Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from serum albumin.

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

Immune-mediated haemolytic anaemia

Immune-mediated haemolytic anaemia has been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone. Cases of severe haemolytic anaemia, including fatal outcomes, have been reported during ceftriaxone treatment in both adults and children.

If a patient develops anaemia during ceftriaxone therapy, this may be related to the drug, and ceftriaxone therapy should be discontinued until the aetiology is determined.

Prolonged treatment

During prolonged treatment, periodic complete blood counts should be performed.

Colitis / overgrowth of non-susceptible microorganisms

Colitis and pseudomembranous colitis associated with antibacterial agents have been reported with nearly all antibacterial drugs, including ceftriaxone, with severity ranging from mild to life-threatening. Therefore, if patients develop diarrhoea during or after ceftriaxone administration, this diagnosis should be considered. Discontinuation of ceftriaxone therapy and initiation of specific Clostridium difficile treatment should be considered. Medicinal products that inhibit peristalsis are not recommended.

As with other antibacterial agents, superinfection caused by non-susceptible microorganisms may occur during ceftriaxone use.

Severe renal and hepatic impairment

Clinical monitoring of safety and efficacy is recommended in patients with severe renal or hepatic impairment.

Interference with serological testing

Coombs' test reactions may be distorted, as ceftriaxone may cause false-positive results. Ceftriaxone may also cause false-positive results in galactosemia testing.

Non-enzymatic methods for urine glucose determination may also yield false-positive results. Urine glucose testing during ceftriaxone therapy should be performed using enzymatic methods.

The presence of ceftriaxone may cause falsely low blood glucose readings when certain blood glucose monitoring systems are used. Refer to the instructions for use of each test system. Alternative monitoring methods should be used if necessary.

Sodium

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

Antimicrobial spectrum

Ceftriaxone has a limited antimicrobial spectrum and is not suitable for use as monotherapy in the treatment of certain infections when the causative pathogen has been confirmed. In cases of polymicrobial infections where suspected pathogens include organisms resistant to ceftriaxone, additional antibiotics should be considered.

Use of lidocaine

When lidocaine solution is used as a solvent, ceftriaxone solutions should be used only for intramuscular injection. Prior to administration, contraindications, warnings, and other clinically relevant information provided in the lidocaine product information must be considered. Lidocaine solution must not be administered intravenously.

Gallstone formation

If shadows are observed on ultrasound, the possibility of precipitate formation should be considered. Shadows, which were mistakenly interpreted as gallstones, have been detected on gallbladder sonograms and are reported more frequently with ceftriaxone doses of 1 g per day and higher. Particular attention should be paid to the paediatric population. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, ceftriaxone-calcium precipitates are clinically symptomatic. If clinical symptoms occur, conservative, non-surgical management and discontinuation of ceftriaxone therapy are recommended at the physician’s discretion based on individual benefit-risk assessment.

Biliary sludge

Cases of pancreatitis, likely related to biliary tract obstruction, have been reported in patients receiving ceftriaxone. Most patients had risk factors for biliary stasis and biliary sludge, such as prior therapy, severe illness, and parenteral nutrition. A triggering factor or cofactor for ceftriaxone-related biliary precipitate cannot be excluded.

Renal stone formation

Cases of renal stone formation, which were reversible after discontinuation of ceftriaxone, have been reported. Ultrasound examination should be performed if clinical symptoms are present. Ceftriaxone should be prescribed by a physician on an individual benefit-risk assessment for patients with a history of kidney stones or hypercalciuria.

Encephalopathy

Encephalopathy has been reported during ceftriaxone use (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-related 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 medicinal product: Environmental release of medicinal products should be minimized. Medicinal products must not be disposed of via wastewater or household waste. Disposal should be carried out 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 have not shown direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. Ceftriaxone may be prescribed during pregnancy, including the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding

Ceftriaxone passes into breast milk in low concentrations; however, no effects on breastfed infants are expected with therapeutic doses of ceftriaxone. Nevertheless, the risk of diarrhoea and fungal mucosal infections should not be excluded. The possibility of sensitization must also be considered. The decision on whether to continue or discontinue breastfeeding or to continue or discontinue ceftriaxone therapy should be made after considering the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Reproduction studies have not demonstrated any adverse effects on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone treatment, adverse effects (e.g., dizziness) may occur that could impair the ability to drive or operate machinery, and this should be considered when making decisions about driving or working with 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 doses listed in the tables below are general recommended doses for these indications. In particularly severe cases, consideration should be given to using the highest dose within the recommended range.

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

* In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

** If doses higher than 2 g per day are required, administration of the drug twice daily (at 12-hour intervals) may be considered.

Indications for adults and children aged 12 years and older (≥ 50 kg) requiring specific dosing regimens:

Acute otitis media

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

Preoperative prophylaxis of surgical site infections

2 g as a single dose administered prior to surgery.

Gonorrhea

500 mg as a single intramuscular dose.

Syphilis

The usual recommended doses are 500 mg – 1 g once daily, increased to 2 g once daily for 10–14 days in neurosyphilis. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. Prescribing should follow national or local guidelines.

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 be followed.

Pediatric population

Neonates, infants, and children from 15 days to 12 years of age (<50 kg)

For children with body weight of 50 kg or more, adult doses are generally used.

* In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

** If doses higher than 2 g per day are required, administration of the drug twice daily (at 12-hour intervals) may be considered.

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

Acute otitis media

For initial treatment of acute otitis media, ceftriaxone may be administered as a single intramuscular dose of 50 mg/kg. Some data suggest that in severe cases or when initial therapy has been ineffective, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative surgical site infection prophylaxis

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

Syphilis

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 limited data. Dosing should follow national or local guidelines.

Disseminated Lyme disease (early [stage II] and late [stage III])

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

Neonates aged 0 to 14 days

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

* In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

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

Indications for neonates aged 0 to 14 days requiring specific dosing regimens:

Acute otitis media

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

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose administered 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 limited data. Prescribing should follow national or local guidelines.

Duration of therapy

Duration of therapy depends on the course of the disease. According to general principles of antimicrobial therapy, administration of ceftriaxone should continue for 48–72 hours after normalization of body temperature or confirmation of bacterial eradication.

Elderly patients

Elderly patients without renal or hepatic impairment should receive doses recommended for adults, without need for additional dose adjustment.

Patients with impaired liver function

Available data do not indicate the need for dose adjustment in mild or moderate hepatic impairment, provided renal function is normal.

There are no study data available for patients with severe hepatic impairment.

Patients with impaired kidney function

For patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if liver function is normal. Only in cases of preterminal renal failure (creatinine clearance < 10 mL/min) should the dose of ceftriaxone not exceed 2 g per day.

If patients are undergoing dialysis, no additional dose is required after the dialysis procedure. Ceftriaxone is not removed by peritoneal dialysis or hemodialysis. Careful clinical monitoring of safety and efficacy is recommended.

Patients with severe hepatic and renal dysfunction

For patients with severe renal and hepatic dysfunction, careful clinical monitoring of safety and efficacy of the drug is recommended.

Route of administration

Ceftriaxone may be administered by intravenous infusion over at least 30 minutes (the preferred method), or by slow intravenous injection over 5 minutes, as well as by deep intramuscular injection. Intravenous bolus injection should be performed over at least 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher in neonates and children under 12 years of age must be administered by infusion. To reduce the potential risk of bilirubin encephalopathy, intravenous doses in neonates should be administered as an infusion over at least 60 minutes. Intramuscular injections should be performed into the bulk of a large muscle mass, with no more than 1 g injected at a single site. Intramuscular administration should be considered only when intravenous access is not feasible or less appropriate for the patient. Doses exceeding 2 g must be administered intravenously.

If lidocaine is used as a solvent, the resulting solution must not be administered intravenously. The information provided in the lidocaine package insert must be taken into account.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they have indications (or are expected to have indications) for intravenous administration of calcium-containing solutions, including continuous calcium-containing infusions such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium (see section "Contraindications").

Solvents containing calcium (e.g., Ringer's solution or Hartmann's solution) must not be used to reconstitute the contents of ceftriaxone vials or for further dilution of reconstituted solution for intravenous administration, due to the risk of precipitate formation. A precipitate of ceftriaxone-calcium salt may also form if ceftriaxone is mixed with calcium-containing solutions in the same intravenous line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously.

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

Reconstitution of the medicinal product

The medicinal product is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation of injection and infusion solutions

Freshly prepared solutions are recommended. Storage conditions for the reconstituted medicinal product are described in the section "Storage conditions."

Ceftriaxone dissolves completely in the appropriate solvent within 150 seconds.

Ceftriaxone must not be mixed in the same syringe with any other medicinal product except 1% lidocaine hydrochloride solution (for intramuscular use only). After each administration, the infusion line should be flushed.

Intravenous administration (injection or infusion)

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

Reconstitute the contents of a vial containing 1 g of ceftriaxone with 10 mL of water for injections.

Reconstitute the contents of a vial containing 0.5 g of ceftriaxone with 5 mL of water for injections (for intravenous use).

Gently roll the vial between the palms and visually inspect. The solution should be clear. Do not use the solution if undissolved particles are present. Inject the solution directly into a vein over 5 minutes or via an intravenous infusion line (see section "Incompatibilities").

Alternatively, for intravenous infusion, the reconstituted solution (for the 1 g dose) should be further diluted in 10 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% dextrose solution, or water for injections. The infusion should be administered over at least 30 minutes (see section "Incompatibilities").

Use in the pediatric population

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

Intravenous doses in neonates should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy.

The displacement volume of 1 g of ceftriaxone is 0.71 mL in water for injections and in 1% lidocaine hydrochloride solution. This requires solvent volume compensation to facilitate dosing according to body weight (primarily in children under 12 years of age) when only a portion of the total reconstituted solution is measured and administered. To prepare a final solution concentration of 100 mg/mL, dissolve 1 g of the medicinal product in 9.4 mL of water for injections.

Intramuscular administration

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

Reconstitute the contents of a vial containing 1 g of ceftriaxone with 3.5 mL of 1% lidocaine hydrochloride solution.

Reconstitute the contents of a vial containing 0.5 g of ceftriaxone with 1.7 mL of 1% lidocaine hydrochloride solution.

Gently roll the vial between the palms and visually inspect. The solution should be clear. Do not use the solution if undissolved particles are present. Administer the solution by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at multiple different sites.

Use in the pediatric population

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

The displacement volume of 1 g of ceftriaxone is 0.71 mL in 1% lidocaine hydrochloride solution. This requires solvent volume compensation to facilitate dosing according to body weight (primarily in children under 12 years of age) when only a portion of the total reconstituted solution is measured and administered. To prepare a final solution concentration of 285 mg/mL, dissolve 1 g of ceftriaxone in 2.9 mL of 1% lidocaine hydrochloride solution.

Children.

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

Overdose.

In case of overdose, symptoms such as nausea, vomiting, and diarrhea may occur. Ceftriaxone concentration cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Management of overdose should be symptomatic.

Adverse Reactions

The most commonly reported adverse reactions to ceftriaxone are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and increased levels of liver enzymes.

Data for determining the frequency of adverse drug reactions (ADRs) for ceftriaxone were obtained from clinical studies.

Reactions are classified by frequency as follows:

• Very common (≥ 1/10)
• Common (≥ 1/100 to < 1/10)
• Uncommon (≥ 1/1000 to < 1/100)
• Rare (≥ 1/10000 to < 1/1000)
• Not known (frequency 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^a – Kounis syndrome.

Immune system disorders: Frequency not known^a – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch–Herxheimer reaction (see "Special precautions").

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 enzyme levels; frequency not known^a – gallbladder 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, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see "Special precautions"), acute generalized exanthematous pustulosis.

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 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 information on these reactions is 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 precautions"

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations

Diarrhea following ceftriaxone use may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions").

Precipitates of ceftriaxone calcium salt

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone elimination half-life compared to adults (see sections "Contraindications", "Special precautions", 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 grams, and who had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone (see section "Special precautions").

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

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 36 months.

Storage conditions:
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. After reconstitution, store for no more than 24 hours at 2–8 °C.

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

Solutions containing ceftriaxone should not be mixed with other medicinal products or added to them, 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 co-administered with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications", "Special precautions", "Dosage and administration", and "Adverse reactions").

For combination with other antibiotics, separate syringes or infusion solutions should be used.

Packaging:
0.5 g or 1.0 g of powder for solution for injection in a vial. 1 vial or 10 vials with powder in a cardboard box.

Prescription status: Prescription only.

Manufacturer:
NSPC Hebei Huamin Pharmaceutical Co., Ltd.

Manufacturer's address and place of business:
No. 98 Huan Road, Economic and Technological Development Zone, Shijiazhuang, CH 052165, China.