Blicef

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BLICEF

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder ranging from almost white to yellowish-white.

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, thereby halting the biosynthesis of the cell wall (peptidoglycan), which 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.

Interpretive criteria for minimum inhibitory concentration (MIC) susceptibility testing for ceftriaxone have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and are available here:

https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

Clinical Efficacy Against Specific Pathogens

The prevalence of acquired resistance may vary geographically and over time for certain species; therefore, local resistance data should be consulted, especially when treating severe infections. If local resistance rates cast doubt on the utility of ceftriaxone, at least for certain types of infections, expert advice should be sought.

Generally Susceptible Organisms

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.

Organisms 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) following 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 (AUC) 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 mg/L and 200 mg/L, respectively. Following intravenous infusions of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80 mg/L, 150 mg/L, and 250 mg/L, respectively.

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations 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 plasma Cmax was observed with repeated dosing, with steady state achieved in most cases 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 (CSF) in patients with bacterial meningitis is up to 25% of the plasma concentration, compared to 2% in patients without meningitis. The Cmax in CSF is reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (see section "Use during pregnancy or breastfeeding").

Plasma Protein Binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the 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 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 renal or hepatic impairment, 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 observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced plasma protein binding and a corresponding increase in total ceftriaxone clearance.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This is also associated with an increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance, with a parallel increase in volume of distribution and 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 continue to rise due to factors such as reduced glomerular filtration and impaired plasma protein binding. In older children, the elimination half-life is shorter than in neonates or adults.

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

Linearity / Non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters—except elimination half-life—are dose-dependent based on total drug concentration and decrease less than proportionally with increasing dose. Non-linearity is observed due to saturation of plasma protein binding and thus affects total plasma ceftriaxone, but not 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 > MIC).

Clinical Characteristics

Indications

The medicinal product Blitcef 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.

Blitcef 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 from 15 days;
• surgical prophylaxis of surgical site infections;
• management of neutropenic patients with fever suspected to be due to bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections is suspected.

Blitcef 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 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 ≤ 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 to be impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions for use" and "Side effects").

* In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin-induced 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 for use"). See the instructions for medical use of lidocaine, particularly contraindications.

Reconstituted 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 Blitcef vials or for further dilution of the reconstituted solution intended for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type administration system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical plasma have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Side effects").

Concomitant use of the drug with oral anticoagulants may enhance the anti-vitamin K effect 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 "Side effects").

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 Coombs' test results.

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

Similarly, false-positive results may occur when glucose in urine 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 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, 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 the event of a severe hypersensitivity reaction, 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, other cephalosporins, or any other type of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam medicinal products.

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 syndrome]), which may be life-threatening or fatal, have been reported during treatment with ceftriaxone; 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 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, there have been no confirmed cases of intravascular precipitation except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that neonates 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 different infusion sites are used. 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 physiological 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 prescribing alternative antibacterial agents that do not carry a similar risk of precipitation. If ceftriaxone use in patients requiring TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate 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 Blitsef 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 Blitsef is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated haemolytic anaemia.

Cases of immune-mediated haemolytic anaemia have been observed in patients receiving cephalosporin-class antibacterial agents, including the medicinal product Blitsef (see section "Side effects"). Severe cases of haemolytic anaemia, including fatal cases, have been reported during treatment with Blitsef in both adults and children.

If a patient develops anaemia during ceftriaxone therapy, cephalosporin-associated anaemia should be considered, and ceftriaxone should be discontinued until the aetiology of the condition is determined.

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 antibacterial agents have been reported during therapy 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 diarrhoea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and administration of appropriate medicinal products against Clostridium difficile should be considered. Medicinal products that inhibit peristalsis 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.

During treatment with the medicinal product Blitsef, the Coombs test may yield false-positive results. Blitsef may also cause false-positive results in galactosaemia testing (see section "Side effects").

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

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

Antibacterial spectrum of activity.

Ceftriaxone has a limited spectrum of antibacterial activity 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 cases of polymicrobial infections where resistant microorganisms are suspected, additional antibiotics should be considered.

Use of lidocaine.

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

Cholelithiasis.

In the presence of shadows on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Shadows, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases with ceftriaxone 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, precipitation of ceftriaxone calcium salt was associated with symptoms. If symptoms occur, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue 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 the medicinal product Blitsef (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. Precipitation in the biliary tract due to Blitsef administration cannot be excluded as an initiating or contributing factor in the development of this condition.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Side effects"). If symptoms occur, an ultrasound examination should be performed. The decision to administer the drug to 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.

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 initiation of ceftriaxone therapy. The 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 during ceftriaxone therapy (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If encephalopathy associated with ceftriaxone use is suspected (e.g., confusion, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Sodium.

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

Disposal of medicinal product and expired medicinal product.

Medicinal product entry into the external environment should be minimized. Avoid disposal into sewage systems or household waste. Any unused medicinal product after completion of treatment or after expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

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, peri- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, 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 diarrhoea and fungal mucosal infections cannot be excluded. Sensitization is possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abandon 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 not shown any adverse effects on male or female fertility.

Ability to influence 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.

Method of 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.

The generally 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 inadequate response to prior therapy, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g administered preoperatively.

Gonorrhoea

The single dose is 500 mg administered intramuscularly.

Syphilis

The generally recommended doses are 500 mg – 1 g once daily, with dose escalation 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 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 considered.

Children

Neonates, infants, and children aged from 15 days to 12 years (<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 neonates, 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 pediatric doses are 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dose recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

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

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

Neonates aged 0–14 days

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

Table 4

*In cases 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 newborns aged 0–14 days requiring special dosing regimens

Acute otitis media

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

Preoperative surgical site infection prophylaxis

20–50 mg/kg as a single dose prior to 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 defervescence or until eradication of bacterial infection is confirmed.

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 that dose adjustment is not necessary in patients with mild or 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

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 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 dysfunction

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

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. It is recommended not to inject more than 1 g at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, refer to the lidocaine product information.

Intravenous administration

Ceftriaxone may 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 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 intravenous calcium-containing 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 reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone-calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with solutions containing calcium (see sections "Contraindications", "Special precautions", and "Incompatibilities").

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

Dilution. 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 by intravenous infusion as described in this section.

Table 5

*Ceftriaxone solution in lidocaine should not be administered intravenously.

When using other diluents, compatibility with ceftriaxone must be checked. The resulting solution must be clear and free from foreign particles.

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 will not reduce excessive drug concentrations in blood plasma. 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 (≥ 1/1000 to < 1/100)
Rare (≥ 1/10,000 to < 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^b.

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.

Cardiac disorders: Frequency not known: Kounis syndrome.

Ear and labyrinth disorders: Frequency not known^a: vertigo.

Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm.

Gastrointestinal disorders: Common: loose stools, diarrhea^b; Uncommon: nausea, vomiting; Frequency not known^a: pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: Common: elevated liver enzymes; Frequency not known: gallbladder precipitates, nuclear jaundice, hepatitis, cholestatic hepatitis.

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

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

General disorders and administration site conditions: Uncommon: phlebitis, injection site pain, malaise; Rare: edema, chills.

Investigations: Uncommon: increased blood creatinine; Frequency not known^a: false-positive Coombs test^b, false-positive galactosemia test^b, false-positive results in non-enzymatic glucose testing methods^b.

^a Based on post-marketing reports. As these reactions are reported voluntarily, their frequency cannot be reliably estimated.
^b See section "Special Warnings and Precautions for Use".
^c Usually reversible upon discontinuation of the medicinal product Blitsef.

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

Description of selected adverse reactions

Infections and infestations

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

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 products. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Contraindications", "Special Warnings and Precautions for Use").

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of the medicinal product (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special Warnings and 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. According to prospective studies in children, the incidence of precipitate formation after intravenous administration varied—exceeding 30% in some studies. The rate of precipitate formation appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present clinically with pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special Warnings and Precautions for Use").

Injection site reactions

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

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

Incompatibilities.

Blitsef must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution.

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

It should not be mixed with solvents other than those specified in the section "Dosage and Administration".

Ceftriaxone must not be mixed or co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Special Warnings and Precautions for Use", "Dosage and Administration", and "Adverse Reactions").

Packaging.

1.0 g of powder in glass vials stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap providing tamper-evidence.

1 or 10 vials with the instruction for medical use in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

Zeus Pharmaceuticals Pvt. Ltd.

Manufacturer's address.

Plot No. 72, EPZ, Phase-1, Jharmajri, Baddi, Solan District, Himachal Pradesh, India.

Marketing Authorization Holder. AAR PHARMA FZ-LLC.

Address of the Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates / Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates.