Operonix

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OPERONIKS (OPERONIKS)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone – 2 g;

Excipients: none.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: slightly hygroscopic crystalline powder of almost white or yellowish 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) is halted, 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 stably derepressed 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 (MIC) have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a The conclusion on susceptibility is based on susceptibility to cefoxitin;

b The conclusion on susceptibility is based on susceptibility to penicillin;

c Isolates with MICs exceeding the susceptibility breakpoints are rarely encountered; if observed, repeat testing should be performed, and if confirmed, isolates should be sent to a reference laboratory;

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

Clinical efficacy against specific pathogens

The prevalence of resistance among individual species may vary geographically and over time. Local information on microbial resistance should ideally be obtained, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the benefit of using the drug at least questionable for certain 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 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 (Cmax) 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 (AUC) after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of 500 mg and 1 g ceftriaxone, mean peak plasma levels are approximately 120 mg/L and 200 mg/L, respectively. After intravenous infusions of 500 mg, 1 g, and 2 g ceftriaxone, plasma levels are approximately 80 mg/L, 150 mg/L, 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 Cmax was observed upon repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of that in plasma, compared to 2% in patients without meningitis. The Cmax of ceftriaxone in cerebrospinal fluid is achieved 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 degree of binding decreases as concentration increases (to 85% at a plasma concentration of 300 mg/L).

Metabolism

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

Excretion

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 (t1/2) 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 minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

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

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

Elderly patients

In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times 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 reduced glomerular filtration and impaired protein binding. In children, the elimination half-life is shorter than in neonates or adults.

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

Linearity/non-linearity

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

Pharmacokinetic/pharmacodynamic relationship

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

Clinical characteristics.

Indications.

The medicinal product Operonix is used for the treatment of the following infections in adults and children, including 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 medicinal product Operonix 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 suspected to be due to bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections are suspected.

Operonix should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special warnings and precautions for use"). Official recommendations on appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin, or to any of the excipients of the medicinal product. 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 ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*.

In term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing solutions or infusions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special warnings and precautions for use", "Adverse reactions", and "Incompatibilities").

* 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 warnings and precautions for use"), and the instructions for medical use of lidocaine should be consulted, particularly contraindications.

Solutions of ceftriaxone 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 Operonix in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, 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 ceftriaxone-calcium salt precipitation in newborns (see sections "Contraindications", "Special warnings and precautions for use", "Dosage and administration", "Adverse reactions", and "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 appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.

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 (administered intravenously or orally).

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

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

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). 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 ascertain whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

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

Interaction with calcium-containing medicinal products

Fatal cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and 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 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, even when using different infusion systems or administering the drugs into different infusion sites, in patients of any age. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline 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 not associated with such precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous parenteral 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 infusion systems should be flushed between administrations (see sections "Pharmacokinetics", "Contraindications", "Side effects", and "Incompatibilities").

Children

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

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

Immune-mediated hemolytic anemia

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

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, a complete blood count should be performed regularly.

Colitis/overgrowth of resistant microorganisms

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported during treatment 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 treatment (see section "Side effects"). The drug should be discontinued and appropriate therapy against Clostridium difficile should be initiated. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible 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 (see section "Dosage and administration").

Effect on serological test results

The Coombs test may yield false-positive results during ceftriaxone therapy. Ceftriaxone may also cause false-positive results in galactosemia screening tests (see section "Side effects").

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

Ceftriaxone use may cause falsely decreased blood glucose readings with certain glucose monitoring systems. Refer to the instructions for use for each specific system. Alternative testing methods should be used if necessary.

Sodium

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

Antibacterial spectrum

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for monotherapy in certain types of infections, unless the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant microorganisms are suspected, additional antibiotics should be considered.

Use of lidocaine

When lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information specified in the lidocaine product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis

On ultrasound, shadows should raise suspicion of ceftriaxone-calcium salt precipitation. Precipitates mimicking gallstones have been observed on gallbladder ultrasound, with increased frequency at 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, ceftriaxone-calcium salt precipitation has been associated with symptoms. In symptomatic cases, conservative, non-surgical treatment is recommended; the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Side effects").

Cholestasis

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, or total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone use cannot be excluded as an initiating or contributing factor.

Nephrolithiasis

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

Jarisch-Herxheimer reaction (JHR)

The Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone treatment in some patients with spirochetal infections. JHR is usually self-limiting or may be managed symptomatically. Antibiotic treatment should not be discontinued if this reaction occurs.

Encephalopathy

Encephalopathy has 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, myoclonia, seizures), discontinuation of ceftriaxone should be considered.

Disposal of unused or expired medicinal product

Environmental contamination with the medicinal product should be minimized. The medicinal product 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 ceftriaxone use 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 is excreted in breast milk in low concentrations, and no adverse effects are expected in breastfed infants when used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should also be considered. A decision on whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy should be made, 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 treatment, side effects such as dizziness may occur, which could affect 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, localization, and type of infection, as well as the patient's age and liver and kidney function.

The following dosages are general recommendations for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

Table 1

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

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

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

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

Acute otitis media

A single intramuscular dose of 1–2 g of Operonix may be administered.

Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Operonix may be effective when administered intramuscularly at a dose of 1–2 g once daily for 3 days.

Preoperative prophylaxis of surgical site infections

2 g as a single dose prior to surgery.

Gonorrhea

Single dose – 500 mg intramuscularly.

Syphilis

The recommended total dose is 500 mg – 1 g once daily, increased 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

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

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

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, consideration should be given to administering the drug twice daily (with a 12-hour interval).

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

Acute otitis media

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

Preoperative prophylaxis of surgical site infections

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

Syphilis

The 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 may vary; national or local guidelines should also be considered.

Neonates aged 0–14 days

The medicinal product Operonix is contraindicated in preterm neonates with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

Table 3

* 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 Operonix 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 principles of antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

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

Patients with hepatic impairment

Available data indicate no need for dose adjustment in patients with mild to moderate hepatic impairment, provided renal function is normal.

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

Patients with renal impairment

In patients with renal dysfunction, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in patients with pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.

Patients undergoing dialysis do not require additional doses after 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

Operonix may be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle mass. 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

Operonix 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 neonates and 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 the intravenous route is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.

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

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or 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.

Preparation of solution

For intramuscular injection, dissolve:

• 0.5 g in 2 mL of 1% lidocaine solution;
• 1 g in 3.5 mL of 1% lidocaine solution.

For intravenous injection, dissolve:

• 0.5 g in 5 mL of water for injections;
• 1 g in 10 mL of water for injections.

For intravenous infusion, dissolve 2 g of Operonix in 40 mL of one of the following infusion solutions free of calcium ions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose, 6–10% hydroxyethyl starch, water for injections.

The reconstituted volume of 2 g of Operonix is 1.37 mL in water for injections.

After adding 40 mL of water for injections, the final concentration of the reconstituted solution is 48.34 mg/mL.

Freshly prepared solutions for injection are recommended. The prepared solution (with 1% lidocaine hydrochloride as solvent) is stable for 24 hours when stored at 2–8 °C or for 6 hours at room temperature.

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

The infusion line must be flushed after each administration.

Children.

The drug should be administered to children according to the dosing instructions provided in the section "Dosage and administration".

Overdose.

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

Adverse Reactions

The most commonly observed adverse reactions 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, < 1/10);
• Uncommon (≥ 1/1,000, < 1/100);
• Rare (≥ 1/10,000, < 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^a – Kounis syndrome^b.

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 sludge^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,c.

Skin and subcutaneous tissue disorders: Common – rash; Uncommon – pruritus; Rare – urticaria; Frequency not known^a – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)^b.

Renal and urinary disorders: Rare – hematuria, glucosuria; Frequency not known^a – oliguria, renal precipitates (reversible).

General disorders and administration site conditions: Uncommon – phlebitis, injection site pain, fever; Rare – edema, 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 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 classification as "frequency not known";
^b see section "Special precautions for use";
^c usually reversible upon discontinuation of ceftriaxone.

Infections and infestations

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

Ceftriaxone calcium salt precipitates

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

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses (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 patients or those with dehydration. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special 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 incidence of biliary precipitates with intravenous administration, in some studies exceeding 30%. 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 clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting of adverse reactions

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

Shelf life. 2 years.

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

Storage conditions.

Keep out of reach and sight of children.

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

The reconstituted solution should be used within 6 hours when stored at room temperature and within 24 hours when stored at 2–8 °C.

Incompatibilities.

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

It 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, due to the risk of precipitate formation. Ceftriaxone should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Special precautions for use", "Dosage and administration", and "Adverse reactions").

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

Packaging.

1 vial containing 2 g of powder for solution for injection or infusion in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's address.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorization Holder.

Ananta Medikear Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.