Zoictcef

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

Composition:

Active substance: ceftriaxone;

1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1000 mg.

Dosage 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 β-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 leads to bacterial cell lysis and 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

Table 1

Clinical breakpoints for minimum inhibitory concentration (MIC) as 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 Rare isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints have been observed. If such isolates are detected, repeat testing should be performed, and if resistance is confirmed, the isolate 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 acquired resistance may vary depending on geographical region and, for certain species, over time. Therefore, local information on resistance patterns is desirable, especially when treating severe infections. If local resistance prevalence renders the utility of ceftriaxone at least questionable for certain types of infections, expert advice should be sought.

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 with potential for acquired 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 (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 after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

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

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean plasma Cmax was observed with repeated administration, with steady state 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 reaches up to 25% of the plasma concentration, compared to 2% in patients without meningeal inflammation. The Cmax in cerebrospinal fluid is achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (see section "Use in 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 is not subject to 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 minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderate increase in half-life observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding, resulting in increased extrarenal clearance of total ceftriaxone.

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

Pediatric patients

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as decreased glomerular filtration and impaired protein binding. In older children, the 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 organisms (i.e., %T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

The medicinal product Zocef is 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 Zocef 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 neutropenic patients who develop fever and are suspected of bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections is suspected.

The medicinal product Zocef should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions for use").

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated:

• in preterm newborns with a postmenstrual age (gestational age + postnatal age) ≤ 41 weeks*;
• in full-term newborns (≤ 28 days of age):
  • with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired under these conditions*;
  • who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions for use" and "Side effects").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk 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 precautions for use"). 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 to reconstitute Zocef 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 line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Contraindications", "Special precautions for use", "Method of administration and dosage", "Side effects", "Incompatibilities").

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

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

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

No 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 tests for galactosemia.

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions

As with all beta-lactam antibiotics, severe 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 necessary to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)) have been reported during treatment with ceftriaxone, which may be life-threatening or fatal, although 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 one month of age, cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys with fatal outcome have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitation in patients of other age groups, except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients of 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 through 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, one after another, provided 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 precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone administration is deemed necessary in patients requiring continuous 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 "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". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

The medicinal product Zoicef 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 the medicinal product Zoicef (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.

If anemia develops during ceftriaxone therapy, hemolytic anemia associated with cephalosporin use should be considered, and ceftriaxone therapy should be discontinued until the etiology is established.

Prolonged treatment

Complete blood counts should be performed regularly during prolonged treatment.

Colitis/overgrowth of resistant microorganisms

Cases of colitis and pseudomembranous colitis associated with antibiotic use 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 therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment against Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant 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

When using the medicinal product Zoicef, the Coombs test may yield false-positive results. Ceftriaxone 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 treatment with Zoicef, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").

The presence of ceftriaxone may falsely lower blood glucose values measured by certain blood glucose monitoring systems. Refer to the instructions for use of each system. Alternative testing methods should be used if necessary.

Sodium

The medicinal product Zoicef contains sodium compounds; therefore, caution is advised when prescribing it to 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, 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 in the lidocaine product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis

In case of shadows on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases with ceftriaxone doses of 1 g per day or higher. Particular caution is required when using the drug in children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone calcium salt has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended; the physician should decide whether to discontinue the drug, considering the 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 the medicinal product Zoicef (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 Zoicef administration cannot be excluded as a triggering or contributing factor in this disorder.

Nephrolithiasis

Cases of kidney stone formation that 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 drug in patients with a history of kidney stones or hypercalciuria should be made by the physician, considering the benefit-risk assessment for the individual case.

Jarisch-Herxheimer reaction

In some patients with spirochete infections, such as Lyme disease, Jarisch-Herxheimer reactions (fever, chills, headache, muscle pain, and skin rash) may develop shortly after starting ceftriaxone therapy. Jarisch-Herxheimer reaction usually resolves spontaneously but may occasionally require symptomatic treatment. Antibiotic therapy should not be discontinued if such a 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 disorders of the central nervous system. If encephalopathy associated with ceftriaxone use is suspected (e.g., confusion, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of unused and expired medicinal product

Environmental contamination with the medicinal product should be minimized. The medicinal product should not be disposed of via wastewater or household waste. Any unused medicinal product or expired medicinal product should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal after treatment completion or expiry.

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

Lactation

Ceftriaxone is excreted in breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision on whether to discontinue breastfeeding or 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.

Adverse reactions (e.g., dizziness) may occur during treatment, which may affect the ability to drive or operate machinery (see section "Side effects"). Patients should be warned about driving or operating machinery.

Administration and dosage.

Dosage

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

The generally recommended dosages 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, consideration should be given to administering 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 administered.

Some data suggest that in severe patient condition or after failure of prior therapy, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.

Prophylaxis of surgical site infections

2 g as a single dose prior to surgery.

Gonorrhea

Single dose of 500 mg intramuscularly.

Syphilis

The generally recommended doses are 500 mg – 1 g once daily, with dose escalation up to 2 g once daily for 10–14 days in 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 varies; national or local guidelines should also be considered.

Children

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

Children with body weight < 50 kg should receive the usual adult doses.

Table 3

* 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 newborns, infants, and children aged 15 days to 12 years (<50 kg) requiring special dosage 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. 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.

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.

Newborns aged 0–14 days

Ceftriaxone is contraindicated in preterm infants up to 41 weeks postmenstrual age (gestational age + postnatal age).

Table 4

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

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 the medicinal product Zoicef 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 should be continued for 48–72 hours after fever has subsided or after confirmation of eradication of the bacterial infection.

Geriatric patients

In patients with normal renal and hepatic function, dose 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 for 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 renal function is not compromised. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

Patients undergoing dialysis do not require additional doses after dialysis. Ceftriaxone is not eliminated from the body 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 renal and hepatic dysfunction, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Administration method

Intramuscular administration

Ceftriaxone can be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle. It is recommended not to 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, the package leaflet for lidocaine should be consulted.

Intravenous administration

Ceftriaxone can be administered by intravenous infusion over 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 up to 12 years of age. Intravenous doses in neonates 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 suitable for the patient. Doses exceeding 2 g must be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they 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 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 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 precautions", and "Incompatibilities").

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

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

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

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

The solution should be administered intravenously as described in this section.

Table 5

* A solution of ceftriaxone with lidocaine should not be administered intravenously.

When using other diluents, compatibility with ceftriaxone must be checked. The resulting solution should be clear and free from particulate matter.

Children.

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

Overdose.

In case of overdose, nausea, vomiting, and diarrhea may occur.

In case of overdose, hemodialysis or peritoneal dialysis does not reduce the excessive concentration of the drug in plasma. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone use include: eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

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

Adverse reactions are classified by frequency as follows:

• very common (≥ 1/10);
• common (≥ 1/100, < 1/10);
• uncommon (≥ 1/1000, < 1/100);
• rare (≥ 1/10,000, < 1/1000);
• 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^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 – elevated liver enzymes; frequency not known^a – precipitates in the gallbladder^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, formation of precipitates in the kidneys (reversible).

Cardiac disorders: frequency not known – Kounis syndrome.

General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – swelling, chills.

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

^a Based on post-marketing reports. Since these reactions are reported voluntarily, their frequency cannot be reliably estimated.
^b See section "Special precautions for use".
^c Usually reversible upon discontinuation of Zoicef.

Administration of ceftriaxone, particularly in elderly patients with serious renal or neurological disorders, may rarely cause disturbances in consciousness, abnormal movements, agitation, and seizures.

Description of selected adverse reactions

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 for use").

Precipitates of ceftriaxone calcium salt

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 products. 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 "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 g, and who also had additional risk factors (e.g., limited fluid intake or bed rest). 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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence rates of precipitate formation with intravenous administration, exceeding 30% in some studies. The incidence appears to be 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 for use").

Injection site reactions

Intramuscular injection is clinically painful. Other injection site reactions include injection site erythema, extravasation at injection site, swelling at injection site, rash at injection site, pruritus at injection site, inflammation at injection site, induration at injection site, and hematoma at injection site. Rarely, complications including infection and abscess at the injection site have been reported.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

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

The reconstituted solution should be 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 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 "Special precautions for use", "Dosage and administration", and "Adverse reactions").

Packaging.

1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business.

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