Infexon - 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INFEXZON - 1000 (INFEXZON - 1000)

Composition:

Active substance: ceftriaxone;

1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1000 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 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.

Breakpoints for susceptibility testing

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

a. Susceptibility conclusion is based on susceptibility to cefoxitin.

b. Susceptibility conclusion is based on susceptibility to penicillin.

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

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

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

Intravenous administration

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

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. 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 is expected in low concentrations 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).

Biotransformation

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

Elimination

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

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

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increase 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 parallel to 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 reduced 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. All major pharmacokinetic parameters based on total drug concentration, except elimination half-life, are dose-dependent, decreasing less 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 medicinal product 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 medicinal product 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 or older;
• surgical prophylaxis of surgical site infections;
• management of neutropenic patients with fever suspected 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 medicinal product should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special 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. 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, since bilirubin binding is likely impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or calcium-containing infusion solutions, due to the risk of precipitation of ceftriaxone calcium salt (see sections "Special warnings and precautions for use" and "Undesirable effects").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, which may lead to development of bilirubin encephalopathy in such patients.

Before intramuscular administration 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 lidocaine product information, 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 the drug in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical plasma have shown an increased risk of ceftriaxone calcium salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special warnings and precautions for use", "Undesirable 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 appropriately adjusted both during and after ceftriaxone therapy (see section "Undesirable 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.

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

Ceftriaxone, like other antibiotics, 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 after concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce ceftriaxone elimination.

Special precautions for use.

Hypersensitivity reactions.

As with all 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 determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, to other cephalosporins, or to 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.

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

Interaction with calcium-containing medicinal products.

In preterm and full-term neonates up to 1 month of age, cases of precipitation of ceftriaxone-calcium salts in the lungs and kidneys with fatal outcomes have been described. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. No confirmed cases of intravascular precipitate formation have been reported in patients other than neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have demonstrated that neonates are at higher risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents that do not carry a similar risk of precipitate formation. If ceftriaxone use in patients requiring continuous parenteral nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and the infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children.

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

Ceftriaxone is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy (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 outcomes, have been reported during treatment with the drug in both adults and children.

If a patient develops anemia during ceftriaxone therapy, cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology of the condition is established.

Prolonged treatment.

During prolonged treatment, a complete blood count should be performed regularly.

Colitis / overgrowth of non-susceptible microorganisms.

Cases of colitis and pseudomembranous colitis associated with the use of antibacterial agents have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "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 not susceptible 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 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. The drug may also cause false-positive results in galactosemia testing (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 test methods (see section "Side effects").

For patients undergoing hemodialysis, there is no need to adjust the dose after the procedure; however, serum drug concentration should be monitored, as elimination may be accelerated in these patients.

Sodium.

Each gram of the medicinal product 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 microorganisms are suspected, the use of additional antibiotics should be considered.

Use of lidocaine.

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

Cholelithiasis.

On ultrasound, shadows should prompt consideration of ceftriaxone-calcium salt precipitate formation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder 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, ceftriaxone-calcium precipitate formation has been associated with symptoms. In case of symptoms, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on a benefit-risk assessment for the individual case (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 drug administration cannot be excluded as an initiating or contributing factor in this disorder.

Nephrolithiasis.

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

Jarisch-Herxheimer reaction.

After initiation of ceftriaxone therapy in some patients with spirochete infection, a Jarisch-Herxheimer reaction may occur. This reaction usually resolves spontaneously or may be managed with symptomatic treatment. Ceftriaxone therapy should not be discontinued if a Jarisch-Herxheimer reaction occurs.

Encephalopathy.

Encephalopathy has been reported with ceftriaxone use (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system (CNS) disorders. If encephalopathy associated with ceftriaxone use is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of unused and expired medicinal product:
Environmental contamination by medicinal products should be minimized. The medicinal product 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 do not indicate direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. During pregnancy, particularly in the first trimester, ceftriaxone may be used only if the benefit outweighs the risk.

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

Fertility. Reproductive function studies have shown no evidence of adverse effects on male or female fertility.

Ability to affect reaction speed when operating vehicles or machinery.

During ceftriaxone therapy, adverse reactions such as dizziness may occur, which may affect the ability to drive or operate complex machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Dosage and administration.

Dosage

The dosage of the medicinal product depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and liver and kidney function.

Recommended dosages according to indications are listed below. In particularly severe cases, the highest dose within the recommended range should be used.

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, it may be advisable to administer the drug twice daily (with a 12-hour interval).

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

Acute otitis media

A single intramuscular dose of 1–2 g of the drug may be used.

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

Preoperative prophylaxis of surgical site infections

2 g as a single dose before surgery.

Gonorrhea

Single 500 mg intramuscular dose.

Syphilis

Recommended dose is 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 considered.

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 taken into account.

Children

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

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

* 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) may be appropriate.

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 the drug at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or after ineffective prior therapy, the drug may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prophylaxis of surgical site infections

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

Syphilis

Recommended dose is 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

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

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

Neonates aged 0–14 days

The medicinal product is contraindicated in preterm neonates under 41 weeks of gestational age (gestational age + postnatal age).

* 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.

Surgical 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 taken into account.

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 resolution of fever symptoms or confirmation of eradication of bacterial infection.

Geriatric patients

In the presence of normal renal and hepatic function, dosage adjustment in elderly patients 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 available in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

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

If the patient is undergoing dialysis, there is no need for additional administration of the drug after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal impairment

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

Administration method

Intramuscular administration

The drug may be administered by deep intramuscular injection. Intramuscular injections 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"). It is also recommended to consult the instructions for medical use of lidocaine.

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 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"). Intramuscular administration should be considered when intravenous administration 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 calcium-containing intravenous solutions, including infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (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 calcium salts of ceftriaxone 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 "Incompatibilities").

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

Recommended solution concentrations:

• concentration for intravenous injection: 100 mg/mL,
• concentration for intravenous infusion: 50 mg/mL.

Preparation of injection and infusion solutions:

Freshly prepared solutions are recommended.

The drug must not be mixed in the same syringe with any other medicinal product except 1% lidocaine hydrochloride solution (for intramuscular injection only).

The infusion line must be flushed after each administration.

Preparation of solutions for administration

For intravenous injection: Dissolve 1 g of the drug in 10 mL of water for injections. The solution should be administered over 5 minutes directly into a vein or through an intravenous infusion line.

For intramuscular injection: Dissolve 1 g of the drug in 3.5 mL of 1% lidocaine hydrochloride solution. The solution should be administered by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at more than one site. The displacement volume of 1 g of the drug is 0.71 mL in water for injections and in 1% lidocaine hydrochloride solution. When 10 mL of water for injections is added, the final concentration of the reconstituted solution is 93.37 mg/mL. When 3.5 mL of 1% lidocaine hydrochloride solution is added, the final concentration of the reconstituted solution is 237.53 mg/mL.

Children.

The drug should be administered to children according to the dosing instructions specified 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 the use of ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

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

Events are classified according to 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 colitisb; frequency not knowna — superinfectionsb.

Blood and lymphatic system disorders: common — eosinophilia, leucopenia, thrombocytopenia; uncommon — granulocytopenia, anemia, coagulation disorders; frequency not knowna — hemolytic anemiab, agranulocytosis.

Cardiac disorders: frequency not known — Kounis syndrome.

Immune system disorders: frequency not knowna — anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactionsb, Jarisch–Herxheimer reactionb.

Nervous system disorders: uncommon — headache, dizziness; rare — encephalopathy; frequency not knowna — seizures.

Ear and labyrinth disorders: frequency not knowna — vertigo.

Respiratory, thoracic and mediastinal disorders: rare — bronchospasm.

Gastrointestinal disorders: common — diarrheab, loose stools; uncommon — nausea, vomiting; frequency not knowna — pancreatitisb, stomatitis, glossitis.

Hepatobiliary disorders: common — elevated liver enzymes; frequency not knowna — biliary precipitatesb, nuclear jaundice, hepatitisc, cholestatic hepatitisb,c.

Skin and subcutaneous tissue disorders: common — rash; uncommon — pruritus; rare — urticaria; frequency not knowna — Stevens–Johnson syndromeb, toxic epidermal necrolysisb, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS)b.

Renal and urinary disorders: rare — hematuria, glucosuria; frequency not knowna — oliguria, renal precipitates (reversible).

General disorders and administration site conditions: uncommon — phlebitis, injection site pain, sweating; rare — edema, chills.

Investigations: uncommon — increased blood creatinine; frequency not knowna — false-positive Coombs testb, false-positive galactosemia testb, false-positive results with non-enzymatic glucose testsb.

a Based on post-marketing reports. Since these reactions are reported voluntarily and the size of the population exposed is unknown, 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.

Cases of diarrhea following ceftriaxone administration 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 medications. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who also 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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

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 with intravenous administration—over 30% in some studies. The incidence appears lower with slow infusion (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 precautions").

Shelf life.

2 years.

Storage conditions.

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

The prepared solution should be used within 6 hours when stored at temperatures not exceeding 25 °C, or within 24 hours if stored in a refrigerator (2–8 °C).

Keep out of reach of children.

Incompatibilities.

Ceftriaxone is incompatible withamsacrine, 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 should 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 "Dosage and administration", "Special precautions", and "Adverse reactions").

Packaging.

1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, P.O. Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.