Alcezon

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

Composition:

Active substance: ceftriaxone;

1 vial contains sodium ceftriaxone equivalent to 1 g or 2 g of anhydrous ceftriaxone.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or white-yellow crystalline powder, readily soluble in water.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Resistance

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

• Hydrolysis by 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

Table 1

Breakpoints for minimum inhibitory concentration 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 the susceptibility breakpoints are rarely encountered. If such isolates are observed, repeat testing should be performed, and if confirmed, the isolate 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 that may develop resistance

Gram-positive aerobes

Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.

Gram-negative aerobes

Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.

Anaerobes

Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.

Resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

% Strains producing extended-spectrum beta-lactamases are always resistant.

Pharmacokinetics.

Absorption.

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single 1 g intramuscular dose is 81 mg/L, reached within 2–3 hours after administration. The area under the plasma concentration–time curve after intramuscular administration equals that after intravenous administration of an equivalent dose.

Intravenous administration

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

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated administration; 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 cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (see section "Use during pregnancy or breastfeeding").

Protein binding

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

Biotransformation

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

Elimination

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

Patients with renal or hepatic impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderate increase in half-life in renal impairment is explained by compensatory increase in extrarenal clearance due to reduced protein binding and consequent increase in total extrarenid clearance of 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, leading to a paradoxical increase in total clearance of the drug, with volume of distribution increasing in parallel to total clearance.

Elderly patients

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

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as 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 to a lesser extent than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding and is therefore evident 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 species (i.e., % T > minimum inhibitory concentration).

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

Ceftriaxone 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 precautions").

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 infants ≤ 41 weeks of gestational age (gestational age + postnatal age)*;

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

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

* In vitro studies have shown that ceftriaxone can displace bilirubin from albumin binding, increasing the risk of bilirubin encephalopathy in these patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). See also the instructions for medical use of lidocaine, particularly the "Contraindications" section.

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of 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 patients other than 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 neonatal umbilical plasma have shown that newborns have an increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions", "Incompatibilities").

Concomitant use of ceftriaxone with oral anticoagulants may enhance the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be adjusted appropriately during and after ceftriaxone therapy (see section "Adverse reactions").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).

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

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

Similarly, false-positive results may occur when urine glucose is tested 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.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). In the event of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it should be determined whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

Cases of severe skin reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) have been reported; 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 salt in the lungs and kidneys, some with fatal outcomes, have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitates have been reported, except in newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that newborns are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when different infusion systems or infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered through separate infusion systems 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 parenteral nutrition (PN), healthcare professionals may consider prescribing alternative antibacterial agents that do not carry a similar risk of precipitate formation. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, PN solutions and ceftriaxone may be administered simultaneously, although through different infusion systems and at different body sites. Alternatively, PN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", 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". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

The drug 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 ceftriaxone treatment in both adults and children.

If a patient develops anemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated anemia 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 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 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 test methods (see section "Side effects").

Sodium.

One gram of ceftriaxone contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (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 be administered only intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

On ultrasound imaging, shadows may indicate possible precipitation of ceftriaxone calcium salt. Hypoechoic images, initially misinterpreted as gallstones, have been observed in the gallbladder on ultrasound, with increased frequency during ceftriaxone administration at doses of 1 g/day or higher. Particular caution is advised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, precipitation of ceftriaxone calcium salt has been associated with clinical symptoms. In symptomatic cases, conservative, non-surgical management is recommended, and the physician should decide whether to discontinue the drug based on an individual benefit-risk assessment (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 sludge formation, such as prior extensive therapy, severe illness, or parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone administration cannot be excluded as a triggering or contributing factor in the development of this condition.

Nephrolithiasis.

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

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 performed via a designated "waste collection system" where 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. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the expected benefit outweighs the potential 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. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility.

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

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

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

Administration and Dosage.

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.

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

The recommended doses are listed below. In particularly severe cases, the highest of the recommended doses should be used.

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

Table 2

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

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

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

Acute otitis media

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

Some data suggest that in patients with severe disease or in whom prior therapy has failed, ceftriaxone may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.

Prophylaxis of surgical site infections

2 g as a single dose before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

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

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

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

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

Indications in neonates, infants, and children up to 12 years of age (<50 kg) requiring special dosing regimens

Preoperative prophylaxis of surgical site infections

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

Syphilis

The generally recommended doses for children are 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

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

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or failure of prior therapy, Ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in premature infants with a postmenstrual age (gestational age + postnatal age) of less than 41 weeks.

Table 3

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

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

Indications in neonates aged 0–14 days requiring special dosing regimens

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose before surgery.

Syphilis

The generally recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Duration of treatment

The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone treatment should be continued for 48–72 hours after fever has subsided or after confirmation of eradication of bacterial infection.

Route of administration

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle. No more than 1 g should be injected 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, it is recommended to consult the lidocaine package insert.

The use of lidocaine requires prior sensitivity testing to determine individual susceptibility to this medicinal product.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in infants and children 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 precautions"). Intramuscular administration should be considered when intravenous administration is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.

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

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

Geriatric patients

In the presence of normal renal and hepatic function, dose adjustment in elderly patients is not required.

Patients with hepatic impairment

Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment, provided renal function is normal.

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

Patients with renal impairment

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

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

Patients with severe hepatic and renal dysfunction

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

Children.

The drug is administered to children according to the dosing regimen specified in the section "Dosage and administration".

Overdose.

In case of overdose, hemodialysis or peritoneal dialysis do not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

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

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

Events are classified by frequency as follows:

• Very common (≥ 1/10);
• Common (≥ 1/100 to < 1/10);
• Uncommon (≥ 1/1,000 to < 1/100);
• Rare (≥ 1/10,000 to < 1/1,000);
• Frequency not known (cannot be estimated from available data).

Infections and infestations: Uncommon – genital fungal infections; Rare – pseudomembranous colitis^b; Frequency not known^a – superinfections^b.

Blood and lymphatic system disorders: Common – eosinophilia, leukopenia, thrombocytopenia; Uncommon – granulocytopenia, anemia, coagulation disorders; Frequency not known^a – hemolytic anemia^b, agranulocytosis.

Immune system disorders: Frequency not known^a – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b.

Nervous system disorders: Uncommon – headache, dizziness; 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 – elevated liver enzymes; Frequency not known^a – biliary precipitates^b, kernicterus.

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.

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 testing methods^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."

Infections and infestations.

Cases of diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Adequate 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 precipitates of ceftriaxone calcium salt 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 (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those who are dehydrated. Precipitates may be symptomatic or asymptomatic, and may lead to renal failure and anuria. They 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 incidence rates of precipitate formation with intravenous administration, exceeding 30% in some studies. The incidence appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special Precautions").

Shelf life. 3 years.

Storage conditions.

Store in a light-protected, child-resistant place at a temperature not exceeding 25 °C. The prepared intravenous solution should be used immediately. However, the intramuscular solution remains stable for 1–3 days at room temperature and for 3–10 days in the refrigerator (4 °C). The color of the prepared solution may vary from light yellow to amber. Solutions with such color variations are suitable for use if storage conditions are observed.

Incompatibilities.

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

Ceftriaxone should not be mixed or combined with other medicinal products except those specified in the section "Dosage and Administration". Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, 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.

Vial containing 1 g or 2 g of powder for injection solution, in a cardboard pack.

10 packs in a cardboard box.

Prescription category. Prescription only.

Manufacturer: Sance Laboratories Pvt. Ltd.

Manufacturer’s address.

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

Marketing Authorization Holder.

Alembic Pharmaceuticals Limited.

Address of Marketing Authorization Holder.

Alembic Road, Vadodara - 390003, India.