Tulon 1 g

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TULONE 1G (TULONE 1G)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder, from almost white to yellowish-white in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone.

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, biosynthesis of the cell wall (peptidoglycan) ceases, leading to lysis of the bacterial cell and its death.

Resistance

Bacterial resistance to ceftriaxone may develop 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

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

a. Susceptibility conclusion was based on susceptibility to cefoxitin;

b. Susceptibility conclusion was based on susceptibility to penicillin;

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

d. Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose, 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, Viridans group Streptococci.

Gram-negative aerobes

Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.

Species for which acquired resistance may be a concern

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.

Initially resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile

Others:

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

£ all methicillin-resistant staphylococci are resistant to ceftriaxone;

• resistance frequency >50% in at least one region;

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

Pharmacokinetics.

Absorption

Intramuscular administration

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

Intravenous administration

After intravenous bolus 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 MIC 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 increase (Cmax) of 8–15% has been observed with repeated administration; steady state is generally achieved within 48–72 hours depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence 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 with increasing concentration (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 moderately prolonged half-life in renal impairment is explained by compensatory increased extrarenal clearance due to reduced protein binding and the consequent increase in total ceftriaxone extrarenal clearance.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increased renal clearance. This also results from 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 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 decreased 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; all major pharmacokinetic parameters, except elimination half-life, are dose-dependent. The total drug concentration decreases less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding, which is observed for total ceftriaxone in plasma, but not for 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 MIC of ceftriaxone for specific target organisms (i.e., %T > MIC).

Clinical characteristics.

Indications.

The medicinal product Toulon 1G 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;
• gonorrhoea;
• syphilis;
• bacterial endocarditis.

Toulon 1G may also 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;
• management of patients with neutropenia who develop fever suspected to be of bacterial origin;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.

Toulon 1G 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 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 beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated:

In preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*.

In full-term newborns (≤ 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 drugs or calcium-containing infusions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions for use", "Adverse reactions").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially 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 for use"). Refer to the lidocaine product information, 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 Toulon 1G in vials or for further dilution of reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone-calcium salt may also occur 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 that the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown an increased risk of ceftriaxone-calcium salt precipitation in newborns (see sections "Contraindications", "Special precautions for use", "Dosage and administration", "Adverse reactions", "Incompatibilities").

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

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical guidelines 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 direct Coombs' test results.

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

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

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Coombs syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, treatment with ceftriaxone must be immediately discontinued and appropriate emergency measures should be taken. Prior to initiating therapy, it is essential to ascertain 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 syndrome/toxic epidermal necrolysis) and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), which may be life-threatening or fatal, have been reported; however, the frequency of these reactions 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 outcome 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 precipitate formation 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 administered simultaneously with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents whose use is not associated with such precipitate risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, though through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Pharmacokinetics", "Contraindications", "Side effects", and "Incompatibilities").

Children

The safety and efficacy of Tullon 1G 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.

Tullon 1G is contraindicated in preterm and full-term newborns 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 antibacterial agents of the cephalosporin class, including Tullon 1G (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during treatment in both adults and children.

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

Prolonged treatment

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

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 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

During treatment with Tullon 1G, the Coombs test may yield false-positive results. Tullon 1G 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 the drug, urine glucose levels should be determined using enzymatic analysis methods (see section "Side effects").

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

Sodium

One gram of Tullon 1G contains 3.6 (83.03 mg) mmol of sodium, equivalent to 4.15% of the WHO recommended maximum daily intake of 2 g sodium for adults. This should be considered in patients on a sodium-restricted diet.

Spectrum of antibacterial activity

Ceftriaxone has a limited spectrum of antibacterial activity 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 provided in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis

In case of shadows observed on ultrasound, the possibility of ceftriaxone calcium salt precipitate formation should be considered. Shadows, which were mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency during ceftriaxone administration at doses of 1 g per day or higher. Particular caution should be exercised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, formation of ceftriaxone calcium salt precipitates was accompanied by symptoms. In symptomatic cases, conservative non-surgical treatment is recommended; the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Side effects").

Biliary stasis

Cases of pancreatitis possibly caused by biliary tract obstruction have been reported in patients treated with Tullon 1G (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 Tullon 1G administration cannot be ruled out as an initiating or contributing factor in this disorder.

Nephrolithiasis

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

Jarisch-Herxheimer reaction

In some patients with spirochete infections, a Jarisch-Herxheimer reaction may occur shortly after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is usually self-limiting or may require symptomatic treatment. Antibiotic therapy should not be discontinued if such a reaction occurs.

Encephalopathy

Encephalopathy has been reported during ceftriaxone therapy, particularly in elderly patients with severe renal impairment 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.

Disposal of unused or expired medicinal product

Environmental contamination with the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out via a designated "waste collection system" if available.

Use during pregnancy or breastfeeding.

Pregnancy

Ceftriaxone crosses the placental barrier. Data on the use of ceftriaxone in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. 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 also be considered. A decision whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, dizziness, a possible side effect, may affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Dosage and administration.

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 doses listed below are generally recommended for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

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

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

** When doses exceeding 2 g per day are used, 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 medicinal product Tullon 1G may be administered.

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

Prophylaxis of surgical site infections

2 g as a single dose before surgery.

Gonorrhea

Single dose – 500 mg intramuscularly.

Syphilis

The generally recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be 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 standard adult doses).

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

** When doses exceeding 2 g per day are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Toulon 1G at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Toulon 1G 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 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 considered.

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

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

Neonates aged 0–14 days

The medicinal product Toulon 1G is contraindicated in preterm neonates with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

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

The maximum daily dose of 50 mg/kg 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 Tullon 1G 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. According to general principles of antibiotic therapy, treatment with ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

If renal and hepatic functions are satisfactory, 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 study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in cases of preterminal renal failure (creatinine clearance <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 by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

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

Administration method

Intramuscular administration

Tullon 1G 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 administer more than 1 g at a single injection site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, the lidocaine package insert should be consulted.

Prior to using lidocaine, a sensitivity test should be performed to determine individual susceptibility to this medicinal product.

Intravenous administration

The medicinal product Tullon 1G can be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children under 12 years of age. Intravenous doses in neonates should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications", "Special warnings and precautions for use"). Intramuscular administration should be considered when intravenous administration is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including 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 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 warnings and precautions for use", "Incompatibilities").

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

The prepared solution should be stored for no more than 6 hours at room temperature and no more than 24 hours at 2–8 °C.

Children.

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

Overdose.

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

Side effects.

The most commonly observed adverse reactions during ceftriaxone administration 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 reactions^b, Jarisch–Herxheimer reaction^b.

Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not known^a – seizures^b.

Ear and labyrinth disorders: frequency not known^a – vertigo.

Cardiac disorders: frequency not known – Kounis syndrome^b.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – diarrhea^b, loose stools; uncommon – nausea, vomiting; frequency not known^a – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: common – increased liver enzymes; frequency not known^a – gallbladder precipitates^b, kernicterus; frequency not known – hepatitis^c, cholestatic hepatitis^c, ^b.

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; DRESS syndrome (drug reaction with eosinophilia and systemic symptoms)^b.

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

General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – 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 these reactions are reported voluntarily from an undefined population size, it is not possible to reliably estimate their frequency; therefore, the frequency is categorized as not known.

^b See section "Special precautions for use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations

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

Ceftriaxone calcium salt precipitates

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

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

Injection site reactions

Intramuscular or intravenous administration may be clinically painful. Other injection site reactions include injection site erythema, extravasation, swelling, rash, pruritus, inflammation, induration, and hematoma at the injection site. Complications such as infection at the injection site and abscess formation have been reported.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued 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 in the original packaging at a temperature not exceeding 25 °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", "Side effects").

Packaging.

1 g of powder in a glass vial, 1 vial per cardboard box.

Prescription status.

Prescription-only medicine.

Manufacturer.

Zeiss Pharmaceuticals Pvt. Ltd./Zeiss Pharmaceuticals Pvt. Ltd.;
Swiss Parenterals Ltd./Swiss Parenterals Ltd.

Manufacturer's address and location of operations.

Plot No. 72, EPIP, Phase-І, Jharmajri, Baddi, Distt. Solan, (H. P.), India;
Unit II, Plot No. 402, 412-414 Kerala Industrial Estate, GIDC, Near Bavla, Ahmedabad, Gujarat, 382220, India.