Tricef-s

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRICEF-S (TRICEF-S)

Composition:

Active substances: ceftriaxone, sulbactam;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg, sulbactam sodium equivalent to sulbactam 500 mg.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder, white to almost white.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone, combinations. ATC code J01D D54.

Pharmacological Properties

Pharmacodynamics

Tritsef-S is an antibacterial medicinal product, a fixed combination of ceftriaxone sodium—a third-generation cephalosporin antibiotic for parenteral administration—and sulbactam sodium, a beta-lactamase inhibitor.

Ceftriaxone is a parenteral cephalosporin antibiotic of the third generation. Its bactericidal activity is due to inhibition of cell membrane synthesis.

Sulbactam is an irreversible inhibitor of most major beta-lactamases produced by penicillin-resistant microorganisms. Sodium sulbactam is a derivative of the basic penicillin nucleus, an irreversible inhibitor of beta-lactamase, and is used only by parenteral route. Chemically, it is the sodium sulphonate of penicillinate.

It exhibits significant antibacterial activity only against Neisseriaceae, Acinetobacter calcoaceticus, Bacteroides spp., Branhamella catarrhalis, Pseudomonas cepacia. Sulbactam acts synergistically with penicillins and cephalosporins and also binds to certain proteins that inactivate penicillin; therefore, some susceptible strains show increased sensitivity to the combination compared to monotherapy with a beta-lactam antibiotic.

Sulbactam is active against (including strains producing beta-lactamases):

− Gram-positive (aerobic): Staphylococcus aureus (methicillin-sensitive strains), coagulase-negative staphylococci, Streptococcus pyogenes (beta-hemolytic, group A), Streptococcus agalactiae (beta-hemolytic, group B), beta-hemolytic streptococci (excluding groups A and B), Streptococcus viridans, Streptococcus pneumoniae;

Note. Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Additionally, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes are resistant to ceftriaxone.

− Gram-negative (aerobic): Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (others)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, Pseudomonas spp. (others)*, Providencia rettgeri*, Providencia spp. (others), Salmonella typhi, Salmonella spp. (nontyphoidal), Serratia marcescens*, Serratia spp. (others)*, Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others);

* Some isolates of these species are resistant to ceftriaxone, primarily due to chromosomally encoded β-lactamase production.

** Some isolates of these species are resistant to ceftriaxone due to production of multiple plasmid-mediated β-lactamases.

Note. Many strains of the above-mentioned microorganisms, which exhibit multiple resistance to antibiotics such as aminopenicillins and ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain sensitive to ceftriaxone, except for clinical strains of P. aeruginosa resistant to ceftriaxone. Treponema pallidum is sensitive to ceftriaxone in vitro and in animal studies. Tritsef-S, like ceftriaxone, is used for the treatment of gonorrhea and syphilis, as Treponema pallidum is sensitive to ceftriaxone in vitro and in animal experiments.

− Anaerobes: Bacteroides spp. (including some strains of B. fragilis), Clostridium spp. (except C. difficile), Fusobacterium spp. (except F. mortiferum and F. varium), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococcus spp.

Note. Many strains of Bacteroides spp., including B. fragilis, which produce beta-lactamases, as well as Clostridium difficile, are resistant to ceftriaxone.

Since the primary active ingredient of the drug is ceftriaxone, sensitivity to sulbactam is determined based on sensitivity to ceftriaxone, which can be assessed by the disk diffusion method or by serial dilution methods on agar or broth.

Pharmacokinetics

Absorption

Intramuscular administration. After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is 81 mg/L, 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 significantly exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are found in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean peak plasma concentration (Cmax) was observed upon repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningeal inflammation. Peak concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also detected in breast milk in low concentrations (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 extent 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 twofold), even in patients with severe renal impairment.

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

In patients with impaired liver function, 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 seemingly paradoxical increase in total drug clearance, with an increase in volume of distribution parallel to total clearance.

Geriatric patients

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

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired protein binding. In children, the elimination half-life is shorter than in neonates or adults.

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

Linearity/Non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it 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 minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., %T > minimum inhibitory concentration).

Clinical characteristics

Indications

For the treatment of infections caused by microorganisms sensitive to the components of the medicinal product in adults and children, including term newborns (from birth):

• community-acquired and hospital-acquired pneumonia;

• acute bacterial otitis media;

• complicated skin and soft tissue infections;

• complicated urinary tract infections (including pyelonephritis);

• bone and joint infections;

• intra-abdominal infections;

• bacterial meningitis;

• gonorrhea.

The medicinal product may be used for:

• treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
• treatment of patients with bacteremia associated with any of the above-mentioned infections or when there is suspicion of any of the aforementioned infections;
• preoperative prophylaxis of infections during surgical procedures.

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

Contraindications

Hypersensitivity to sulbactam, ceftriaxone, or 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 term newborns (aged ≤ 28 days):

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

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thereby 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"). Refer to the instructions for medical use of lidocaine, particularly the section "Contraindications".

Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interactions

Solvents containing calcium, such as Ringer's solution, Hartmann's solution, and others, must not be used to dissolve ceftriaxone in vials or to dilute the reconstituted solution for intravenous administration due to the likelihood of precipitation of calcium-ceftriaxone salts. Precipitation of calcium-ceftriaxone salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Ceftriaxone must not be administered intravenously simultaneously with calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site infusion system. However, in all patients except 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 adult and newborn umbilical plasma have shown an increased risk of precipitation of calcium-ceftriaxone salts in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "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 antagonists should be appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").

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

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

No cases of interaction between ceftriaxone and oral calcium-containing agents or between intramuscular ceftriaxone and calcium-containing agents (for intravenous or oral use) have been reported.

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

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

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

Ceftriaxone may reduce the effectiveness of hormonal oral contraceptives. Therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after completion of therapy.

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. However, probenecid reduces tubular secretion of sulbactam, resulting in increased plasma concentration and prolonged elimination half-life, thereby increasing the risk of toxicity.

Alcohol. Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol is consumed during treatment and within 5 days after treatment. No disulfiram-like (antabuse-like) effects were observed after alcohol consumption immediately following ceftriaxone administration. Similar reactions have been observed with other cephalosporins. Patients should be cautious when consuming alcoholic beverages during treatment with Tricef-S. Ethanol-containing solutions must not be used in case of artificial nutrition (oral or parenteral).

Special precautions for use

Hypersensitivity reactions

Serious hypersensitivity reactions, sometimes leading to fatal outcomes, have been reported with the use of beta-lactam antibiotics, including ceftriaxone (see section "Side effects"). Hypersensitivity reactions may also progress to Cowling's syndrome, a severe allergic reaction that can lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, ceftriaxone should 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 other types of beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

Severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported during ceftriaxone treatment. These reactions may be life-threatening or fatal; however, the frequency of such events is unknown (see section "Side effects").

The drug may increase prothrombin time. Therefore, prothrombin time should be monitored in cases of suspected vitamin K deficiency.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction (JHR) may occur shortly after initiation of ceftriaxone therapy in some patients with spirochetal infections. JHR is usually a self-limiting condition that resolves spontaneously or can be managed with symptomatic therapy. Antibiotic treatment should not be discontinued if JHR occurs.

Colitis / overgrowth of resistant microorganisms

Cases of colitis and pseudomembranous colitis associated with antibiotic use have been reported with nearly all antibacterial agents, including ceftriaxone and sulbactam. The severity of these conditions may range from mild to life-threatening.

It is important to consider this diagnosis in patients who develop diarrhea during or after treatment with ceftriaxone and sulbactam (see section "Side effects"). Discontinuation of the drug and initiation of appropriate therapy 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.

Gallstone disease

When shadows are observed on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in gallbladder ultrasounds, with increased frequency when ceftriaxone is administered at doses of 1 g/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, precipitation of ceftriaxone calcium salt has been associated with clinical symptoms. If symptoms occur, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on benefit-risk assessment in the individual case (see section "Side effects").

Biliary stasis

Isolated cases of pancreatitis, possibly due to obstruction of the biliary tract, have been reported in patients receiving ceftriaxone. Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior intensive therapy, severe illness, or total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone administration cannot be ruled out as an initiating or contributing factor in the development of this condition.

Nephrolithiasis

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

Encephalopathy

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), particularly in elderly patients with severe renal impairment or central nervous system disorders. If encephalopathy related to ceftriaxone use is suspected (e.g., confusion, altered mental status, myoclonus, seizures), discontinuation of the medicinal product Tricef-S should be considered.

Immune-mediated hemolytic anemia

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe hemolytic anemia, including fatal cases, have been reported in both adult and pediatric patients during ceftriaxone treatment. If anemia develops during ceftriaxone therapy, cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is established.

Prolonged therapy

Complete blood counts should be monitored regularly during prolonged therapy.

Interaction with calcium-containing medicinal products

Fatal cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys have been described in full-term and preterm neonates under 1 month of age. At least one of these patients received ceftriaxone and calcium at different times and through different intravenous infusion systems.

Confirmed cases of intravascular precipitation have been reported only in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have demonstrated an increased risk of ceftriaxone calcium salt precipitation in neonates compared to patients in 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 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, provided they are given through different infusion systems at different body sites or the infusion system is thoroughly flushed with saline 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 this precipitation risk. If ceftriaxone use in patients requiring continuous TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and at different body sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", and "Incompatibilities").

Children

The safety and efficacy of the medicinal product in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Ceftriaxone, a component of the medicinal product, may displace bilirubin from albumin binding sites in serum. Therefore, ceftriaxone is contraindicated in preterm and term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Severe renal and hepatic impairment

Careful clinical monitoring of safety and efficacy is recommended in cases of severe renal and hepatic impairment (see section "Dosage and administration").

Effect on serological test results

Occasionally, false-positive Coombs test results may occur during treatment with the drug. Like other antibiotics, Tricef-S may cause false-positive galactosemia screening tests (see section "Side effects"). False-positive results may also occur when testing urine glucose using non-enzymatic methods. Urine glucose levels should be determined using enzymatic methods during treatment with the drug (see section "Side effects").

Ceftriaxone use may cause falsely low blood glucose readings with certain glucose monitoring systems. Refer to the instructions for use of each specific monitoring system. Alternative testing methods should be used if necessary.

Sodium content

1 gram of the medicinal product contains 3.6 mmol of sodium. This should be taken into account if the patient is on a sodium-controlled diet.

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 in the lidocaine product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Disposal of unused or expired medicinal product

Environmental release of 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

Ceftriaxone and sulbactam cross the placental barrier. Data on the use of ceftriaxone/sulbactam in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryo/fetal, peri- or postnatal development. Ceftriaxone/sulbactam may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.

Breastfeeding

Ceftriaxone and sulbactam are 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. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

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

Administration and Dosage

Treatment with the medicinal product should be initiated only if there is laboratory confirmation or a well-founded suspicion of bacterial infection in the patient.

Administer intravenously or intramuscularly.

Dosage

The dose of the medicinal product depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and hepatic and renal function.

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

Adults and children aged 12 years and older (with body weight ≥ 50 kg): 1–4 g (calculated as ceftriaxone) once daily.

Community-acquired pneumonia: 1–2 g once daily.

Acute exacerbation of chronic obstructive pulmonary disease: 1–2 g once daily.

Intra-abdominal infections: 1–2 g once daily.

Complicated urinary tract infections (including pyelonephritis): 1–2 g once daily.

Hospital-acquired pneumonia: 2 g once daily.

Complicated skin and soft tissue infections: 2 g once daily.

Bone and joint infections: 2 g once daily.

Bacterial meningitis: 2–4 g once daily.

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

When doses exceeding 2 g (calculated as ceftriaxone) 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 (with body weight ≥ 50 kg) requiring special dosing regimens

Acute otitis media. A single intramuscular dose of 1–2 g of the medicinal product Tricef-S (calculated as ceftriaxone) may be administered.

Some data suggest that in cases of severe condition or previous ineffective therapy, Tricef-S may be effective when administered intramuscularly at a dose of 1–2 g (calculated as ceftriaxone) daily for 3 days.

Perioperative prophylaxis of surgical site infections: A single dose of 2 g (calculated as ceftriaxone) before surgery.

Gonorrhea: A single intramuscular dose of 500 mg (calculated as ceftriaxone).

Children

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

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

Intra-abdominal infections: 50–80 mg/kg once daily.

Complicated urinary tract infections (including pyelonephritis): 50–80 mg/kg once daily.

Community-acquired and hospital-acquired pneumonia: 50–80 mg/kg once daily.

Complicated skin and soft tissue infections: 50–100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily.

Bone and joint infections: 50–100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily.

Bacterial meningitis: 80–100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily.

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

When doses exceeding 2 g (calculated as ceftriaxone) 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 (with body weight < 50 kg) requiring special dosing regimens:

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Tricef-S at a dose of 50 mg/kg (calculated as ceftriaxone) may be used. Some data suggest that in cases of severe condition or previous ineffective therapy, Tricef-S may be effective when administered intramuscularly at a dose of 50 mg/kg (calculated as ceftriaxone) daily for 3 days.

Perioperative prophylaxis of surgical site infections: 50–80 mg/kg (calculated as ceftriaxone) as a single dose before surgery.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates aged less than 41 weeks gestational age (gestational age + chronological age).

The recommended doses for neonates aged 0–14 days (calculated as ceftriaxone) are listed below.

Intra-abdominal infections: 20–50 mg/kg once daily.

Complicated skin and soft tissue infections: 20–50 mg/kg once daily.

Complicated urinary tract infections (including pyelonephritis): 20–50 mg/kg once daily.

Community-acquired and hospital-acquired pneumonia: 20–50 mg/kg once daily.

Bone and joint infections: 20–50 mg/kg once daily.

Bacterial meningitis: 50 mg/kg once daily.

In cases of documented 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 neonates 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 at a dose of 50 mg/kg (calculated as ceftriaxone) may be used.

Perioperative prophylaxis of surgical site infections: 20–50 mg/kg (calculated as ceftriaxone) as a single dose before surgery.

Duration of treatment

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

Elderly patients

In the presence of adequate 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 study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

Patients with impaired renal function do not require dose reduction of ceftriaxone if hepatic function is normal. Only in patients with pre-terminal renal failure (creatinine clearance less than 10 ml/min) should the daily dose not exceed 2 g (calculated as ceftriaxone).

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 impairment

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.

Administration method

Intramuscular administration

The medicinal product Tricef-S 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 (calculated as ceftriaxone) 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, refer to the lidocaine product information.

Intravenous administration

The medicinal product Tricef-S 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 infants and children up to 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 suitable for the patient. Doses exceeding 2 g should be administered intravenously. Tricef-S is contraindicated in neonates (≤ 28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (see section "Contraindications"). Solvents containing calcium, such as Ringer's solution or Hartmann's solution and others, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of calcium salts of ceftriaxone may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special precautions", and "Incompatibilities").

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

Solution preparation instructions

Freshly prepared solutions are recommended.

The solution of ceftriaxone should not be mixed in the same syringe with any other medicinal products except 1% lidocaine hydrochloride solution (for intramuscular injections only).

The infusion system should be flushed after each administration.

For intramuscular injection, the vial contents should be dissolved in 3.5 ml of 1% lidocaine solution.

For intravenous injection, the contents of one vial of Tricef-S should be dissolved in 10 ml of sterile water for injection.

For intravenous infusion, the vial contents of Tricef-S should be dissolved in 40 ml of one of the following infusion solutions free of calcium ions: 0.9% sodium chloride solution, 0.45% sodium chloride solution + 2.5% glucose solution, 5% glucose solution, 10% glucose solution, 6% dextran in 5% glucose solution, water for injection.

Children.

Administer to children according to the recommendations in the section "Administration and Dosage".

Tricef-S is contraindicated in: preterm neonates aged ≤ 41 weeks gestational age; term neonates aged ≤ 28 days at risk of developing bilirubin encephalopathy; term neonates aged ≤ 28 days who require intravenous calcium-containing medications or infusions of calcium-containing solutions (see section "Contraindications").

Overdose

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

Excess plasma concentrations of ceftriaxone cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Symptomatic treatment is recommended for cases of overdose.

Adverse Reactions

Sulbactam in combination with ceftriaxone is generally well tolerated.

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

Infections and infestations: fungal genital infections, superinfections², pseudomembranous colitis².

Blood and lymphatic system disorders: eosinophilia, neutropenia (associated with prolonged use, reversible), leukopenia, leukocytosis, lymphopenia, granulocytopenia, anemia, hemolytic anemia², thrombocytopenia, thrombocytosis, basophilia, prolonged/shortened prothrombin time, coagulation disorders, agranulocytosis.

Gastrointestinal disorders: loose stools, diarrhea², nausea, vomiting, flatulence, taste disturbances, stomatitis, glossitis, pancreatitis², gastrointestinal bleeding.

Hepatobiliary disorders: pseudocholelithiasis of the gallbladder, gallbladder precipitates, reversible cholelithiasis in children, elevated liver enzymes, nuclear jaundice, hepatitis¹, cholestatic hepatitis^1,2.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, edema including angioedema, acute generalized exanthematous pustulosis, exanthema, erythema multiforme, Stevens-Johnson syndrome², toxic epidermal necrolysis², DRESS syndrome (drug reaction with eosinophilia and systemic symptoms)².

Renal and urinary system disorders: oliguria, hematuria, glucosuria, cylindruria, interstitial nephritis, renal precipitates (reversible).

Nervous system disorders: headache, dizziness, seizures, encephalopathy.

Cardiac disorders: increased or decreased blood pressure, palpitations, Kounis syndrome.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.

Immune system disorders: anaphylactic reactions, anaphylactoid reactions, anaphylactic shock, hypersensitivity², Jarisch-Herxheimer reaction².

Ear and labyrinth disorders: vertigo.

General disorders and administration site conditions: phlebitis, pain at injection site, pyrexia, swelling, chills.

Laboratory test abnormalities: increased serum creatinine, false-positive Coombs test², false-positive galactosemia test², false-positive results in non-enzymatic methods for glucose determination².

¹ Usually reversible upon discontinuation of ceftriaxone.

² See section "Special precautions for use".

Infections and infestations

Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Adequate 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 full-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 attributed to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions for use").

Cases of renal precipitates have been reported, primarily in children receiving high daily doses (≥ 80 mg/kg/day) or cumulative doses exceeding 10 g, as well as those with additional risk factors (limited fluid intake, bed rest). Renal precipitate formation may be asymptomatic or clinically evident and may lead to renal failure, which resolves after discontinuation of ceftriaxone therapy (see section "Special precautions for use").

Ceftriaxone-calcium salt precipitates in the gallbladder have been reported, predominantly in patients receiving doses higher than the standard recommended dose. In children, prospective studies have reported varying incidence rates of gallbladder precipitates, 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").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or 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 and sight of children.

Incompatibilities

Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution, Hartmann's solution, or others, due to the potential formation of precipitates. Ceftriaxone should not be mixed or co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions for use", and "Adverse reactions").

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

Do not mix or add to other medicinal products except those specified in the section "Dosage and administration".

If combination therapy with ceftriaxone and another antibiotic is planned, these drugs must not be mixed in the same syringe or in the same infusion solution.

Packaging

1500 mg of powder in glass vials stoppered with rubber closures and sealed with aluminum caps with plastic flip-off tops. 1 or 10 vials per cardboard box.

Prescription status: Prescription only.

Manufacturer: Zeiss Pharmaceuticals Pvt. Ltd.

Manufacturer's address: Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India

Marketing Authorization Holder: AAR PHARMA FZ-LLC

Address of Marketing Authorization Holder: Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates