Tricef-tz

INSTRUCTION for medical use of the medicinal product TRICEF-TZ (TRICEF-TZ)

Composition:

Active substances: ceftriaxone, tazobactam;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1.0 g, tazobactam sodium equivalent to tazobactam 0.125 g.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder from white to yellow-orange in color.

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

ATC code J01D D54.

Pharmacological Properties

Pharmacodynamics

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

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 bacterial cell lysis and death.

Tazobactam is a beta-lactamase inhibitor of the Richmond-Sykes class III: penicillinases and cephalosporinases. It is a derivative of the "penicillin nucleus", sulphone-penicillanic acid.

Tazobactam irreversibly inhibits most beta-lactamases produced by clinically significant Gram-positive and Gram-negative aerobic and anaerobic bacteria by covalently binding to their enzymes. In particular, tazobactam demonstrates a high degree of binding affinity for plasmid-mediated beta-lactamases, which are often responsible for the development of resistance to penicillin and cephalosporin antibiotics.

Tazobactam does not inhibit enzymes of class A.

In addition, tazobactam does not inhibit the activity of the following beta-lactamases:

• AmpC-type beta-lactamases (produced by Enterobacter spp.);
• serine-based carbapenemases (e.g., carbapenemases produced by Klebsiella pneumoniae);
• metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase);
• Ambler class D beta-lactamases (oxa-carbapenemases).

Resistance

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

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be induced or stably expressed 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 minimum inhibitory concentration (MIC) established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Pathogen	Dilution method (MIC, mg/l)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	˃ 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups A, B, C and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	˃ 2
Streptococci group Viridans	≤ 0.5	˃ 0.5
Haemophilus influenzae	≤ 0.12c.	˃ 0.12
Moraxella catarrhalis	≤ 1	˃ 2
Neisseria gonorrhoeae	≤ 0.12	˃ 0.12
Neisseria meningitidis	≤ 0.12c.	˃ 0.12
Non-species related	≤ 1d.	˃ 2

a. The conclusion on susceptibility was based on susceptibility to cefoxitin.

b. The conclusion on susceptibility was based on susceptibility to penicillin.

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

d. The breakpoints apply to a daily intravenous dose of 1 g x 1 and a high dose of at least 2 g x 1.

Clinical efficacy against specific pathogens

The prevalence of acquired resistance among isolated species may vary by geographical region and over time; therefore, local resistance data are needed, especially in the case of severe infections. Expert advice should be sought if local resistance rates are such that the efficacy of the drug for treating at least some types of infections is questionable.

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 problematic

Gram-positive aerobes

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

Gram-negative aerobes

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

Anaerobes

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

Resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

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

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

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

Pharmacokinetics

Absorption

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single 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 500 mg and 1 g ceftriaxone, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of 500 mg, 1 g, and 2 g ceftriaxone, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with 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 reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also excreted in small concentrations in breast milk (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 increases in extra-renal clearance due to reduced protein binding and a corresponding increase in total extra-renal clearance of ceftriaxone.

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

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 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 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 and decrease to a lesser extent than proportionally with dose. Non-linearity results from saturation of plasma protein binding, and thus is observed for total ceftriaxone in plasma, but not for the free (unbound) fraction.

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

Tritsef-TZ is indicated for the treatment of infections caused by microorganisms sensitive to the drug in adults and children, including full-term newborns (from birth):

• Community-acquired and hospital-acquired pneumonia;

• Acute bacterial otitis media;

• Complicated skin and soft tissue infections;

• Complicated urinary tract infections;

• Bone and joint infections;

• Gonorrhea;

• Bacteremia caused by any of the sensitive bacteria, or suspected association;

• Intra-abdominal infections;

• Bacterial meningitis.

The medicinal product may be used for the treatment of acute exacerbation of chronic obstructive pulmonary disease in adults.

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

Contraindications

Hypersensitivity to the active substances or to beta-lactamase inhibitors, or to antibiotics belonging to the cephalosporin and penicillin groups. In patients with hypersensitivity to penicillin, cross-allergic reactions should be considered possible.

History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems); history of gastrointestinal disorders, particularly non-specific ulcerative colitis, enteritis, or antibiotic-associated colitis.

Ceftriaxone is contraindicated:

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

In full-term newborns (aged ≤ 28 days):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired in such conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions for use" 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-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" and the instructions for medical use of lidocaine, particularly contraindications).

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interactions

Calcium-containing products

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or to dilute reconstituted solution for intravenous administration, due to the risk of precipitation of ceftriaxone-calcium salts. Precipitation of ceftriaxone-calcium 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 connector. However, in patients other than neonates, 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.

A small number of fatal cases due to precipitation of ceftriaxone-calcium salts in the lungs and kidneys of neonates have been reported. In some cases, venous access and timing of administration of ceftriaxone and calcium-containing solutions differed.

In vitro studies using plasma from adult and neonatal umbilical cord blood have demonstrated an increased risk of precipitation of ceftriaxone-calcium salts in neonates (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Adverse reactions", "Incompatibilities").

There are no reports of interaction between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (administered intravenously or orally).

Oral anticoagulants

Concomitant use of the drug with oral anticoagulants may potentiate 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").

Aminoglycosides

Data on the potential for increased nephrotoxic effects of aminoglycosides when administered concomitantly with cephalosporins are conflicting. In such cases, careful adherence to clinical guidelines for monitoring aminoglycoside levels (and renal function) is recommended.

Ceftriaxone must not be mixed with amikacin, vancomycin, fluconazole, and aminoglycosides.

Loop diuretics

No renal function disturbances have been observed when high doses of ceftriaxone are administered concomitantly with potent diuretics such as furosemide.

Bacteriostatic antibiotics (chloramphenicol)

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown. Bacteriostatic agents may interfere with the bactericidal activity of cephalosporins.

Substances used in laboratory tests

False-positive results in the Coombs test may occur in patients receiving ceftriaxone.

Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia testing.

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

Hormonal oral contraceptives

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

Probenecid

Probenecid does not affect the excretion of ceftriaxone.

Alcohol

Ceftriaxone does not contain the N-methylthiotetrazole group, which could cause ethanol intolerance or bleeding associated with some other cephalosporins.

Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol is consumed during and up to 5 days after ceftriaxone therapy. No disulfiram-like (Antabuse-like) effects were observed after alcohol consumption immediately following ceftriaxone administration. Similar reactions have also been observed with other cephalosporins. Patients should be cautious when consuming alcoholic beverages during treatment with Tritsef-TZ. Solutions containing ethanol must not be used during artificial nutrition (oral or parenteral).

Special precautions for use

Hypersensitivity reactions

As with other ceftriaxone-containing cephalosporins, cases of anaphylactic reactions (including anaphylactic shock) with fatal outcomes have been reported, even in the absence of relevant history. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Prior to initiating therapy, it should be established whether the patient has a history of severe hypersensitivity to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. TRICEF-TZ should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs. If allergic reactions occur, the drug should be discontinued immediately and appropriate treatment initiated.

The likelihood of anaphylactic reactions is increased in patients with a history of anaphylaxis and in those with hypersensitivity reactions to various allergens; use with caution in patients predisposed to allergic diathesis.

Cases of severe skin reactions (Stevens–Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported, which may be life-threatening or fatal; however, the frequency of these reactions is unknown (see section "Adverse reactions").

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

Colitis/overgrowth of non-susceptible microorganisms

Diarrhea associated with Clostridium difficile may occur during treatment with most antibacterial agents, including ceftriaxone and tazobactam, ranging from mild to severe colitis with fatal outcome. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Strains of Clostridium difficile that overproduce toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. Clostridium difficile-associated diarrhea should be considered in all patients receiving antibiotics. A detailed medical history should be obtained, as Clostridium difficile-associated diarrhea may occur up to 2 months after completion of antibacterial therapy. Discontinuation of the drug and initiation of appropriate therapy against Clostridium difficile should be considered. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible to the drug may occur.

Antibacterial spectrum of activity

Ceftriaxone has a limited antibacterial spectrum and may be inadequate 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.

Cholelithiasis

If shadows are observed on ultrasound, precipitation of ceftriaxone calcium salt should be considered.

Ultrasonographic findings of echogenic material in the gallbladder, sometimes mistaken for gallstones, have been reported, with increased frequency at 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 has been associated with symptoms. In symptomatic cases, conservative non-surgical management is recommended, and the physician should decide whether to discontinue the drug based on benefit-risk assessment (see section "Adverse reactions").

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 biliary stasis, such as prior extensive treatment, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone/tazobactam use cannot be excluded as a triggering or contributing factor.

Nephrolithiasis

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). If symptoms occur, 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 benefit-risk assessment.

Jarisch–Herxheimer reaction

In some patients with infections caused by spirochetes, 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 with ceftriaxone use, 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 TRICEF-TZ 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. Severe hemolytic anemia, including fatal cases, have been reported in both adults and children during ceftriaxone therapy.

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

Prolonged therapy

During prolonged therapy, regular complete blood counts should be performed.

Interaction with calcium-containing products

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, even when administered through different infusion systems.

Fatal cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys have been reported in neonates (term and preterm) under 1 month of age who received ceftriaxone and calcium-containing products simultaneously. Cases of intravascular precipitates have also been reported in patients of other age groups after concomitant administration of ceftriaxone and intravenous calcium-containing solutions. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. Therefore, calcium-containing intravenous solutions must not be administered to neonates and patients of other age groups within at least 48 hours after the last dose of TRICEF-TZ (see section "Contraindications").

No confirmed cases of intravascular precipitates have been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing products. In vitro studies have shown that neonates have an increased risk of ceftriaxone calcium salt precipitation compared to patients of 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 through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are administered through different infusion systems at different body sites or the infusion system is thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents not associated with this precipitation risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion systems flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").

Children

The safety and efficacy of ceftriaxone in neonates, infants, and children have been established at the doses specified in the "Dosage and administration" section. Ceftriaxone, a component of TRICEF-TZ, may displace bilirubin from albumin binding in serum. Therefore, the use of TRICEF-TZ is contraindicated in preterm and term neonates with hyperbilirubinemia at risk of developing bilirubin encephalopathy (see section "Contraindications").

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"). Caution should be exercised when administering ceftriaxone to patients with renal impairment who are concurrently receiving aminoglycosides and diuretics.

Effect on serological test results

Occasionally, false-positive Coombs test results may occur during treatment with TRICEF-TZ. Like other antibiotics, TRICEF-TZ may cause false-positive galactosemia tests. False-positive results may also occur in urine glucose testing; therefore, during treatment with TRICEF-TZ, glucosuria should be assessed only by enzymatic methods if necessary.

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

Sodium

1 g of the medicinal product contains 3.6 mmol (83.03 mg) of sodium, equivalent to 4.15% of the WHO recommended maximum daily intake of 2 g sodium for adults. This should be considered if the patient is on a sodium-restricted diet.

Use of lidocaine

If 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 information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

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 performed 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, peri- or 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 diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. 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 shown no evidence of adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery

There are no data on the effect of ceftriaxone on reaction speed; however, if dizziness occurs, driving and operating complex machinery should be avoided.

Method of Administration and Dosage

Treatment with Tricef-TZ should be initiated only if the patient has a laboratory-confirmed or highly suspected bacterial infection.

Administer intravenously or intramuscularly.

Dosage

The dose of the medicinal product depends on the severity, susceptibility, localization, and type of infection, as well as the patient's age and liver and kidney function.

The recommended doses below are general guidelines 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): 1–2 g (calculated as ceftriaxone) of Tricef-TZ once daily (every 24 hours). In severe cases or infections caused by pathogens with only moderate susceptibility to the drug, the daily dose may be increased up to 4 g (calculated as ceftriaxone).

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

Acute Otitis Media

A single intramuscular dose of 1–2 g of Tricef-TZ (calculated as ceftriaxone) may be administered.

Some data suggest that in cases of severe illness or ineffective prior therapy, Tricef-TZ may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.

Gonorrhea

For the treatment of gonorrhea, a single intramuscular dose of 500 mg (calculated as ceftriaxone) is recommended.

Children

Neonates (up to 14 days of age) (doses are expressed as ceftriaxone equivalents): 20–50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg body weight.

Contraindicated in preterm neonates with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

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 drug at a dose of 50 mg/kg may be administered.

Children aged 15 days to 12 years (< 50 kg): 50–100 mg/kg body weight once daily.

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

Abdominal infections: 50–80 mg/kg once daily.

Complicated urinary tract infections: 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.

For bacterial meningitis in infants and children aged 15 days to 12 years, treatment should be initiated at a dose of 80–100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily. Once the causative pathogen is identified and its susceptibility determined, the dose may be reduced accordingly.

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 the drug at a dose of 50 mg/kg may be administered. Some data suggest that in cases of severe illness or ineffective prior therapy, Tricef-TZ may be effective when administered intramuscularly at a dose of 50 mg/kg daily for 3 days.

Children with body weight exceeding 50 kg should receive adult doses. The total daily dose for children should not exceed 2 g (calculated as ceftriaxone).

Intravenous doses of 50 mg/kg or higher should be administered by infusion over at least 30–60 minutes.

Treatment Duration

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

Geriatric Patients

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

Patients with Hepatic Impairment

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

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

Patients with Renal Impairment

For patients with mild to moderate renal impairment, there is no need to reduce the dose.

Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose should not exceed 2 g (calculated as ceftriaxone).

Additional doses after dialysis are not required for patients undergoing dialysis. Ceftriaxone is not eliminated by peritoneal or hemodialysis. Careful clinical monitoring of the safety and efficacy of ceftriaxone is recommended.

Patients with Severe Hepatic and Renal Impairment

In cases of concomitant severe renal and hepatic impairment, plasma concentrations of ceftriaxone should be monitored regularly, and the dose should be adjusted as necessary.

Preparation of Solutions

Solutions should be prepared immediately before use.

Intramuscular Injection

For intramuscular injection, the contents of the vial should be dissolved in 3.5 mL of 1% lidocaine solution; the injection should be administered deeply into the gluteal muscle. Tricef-TZ may be administered via deep intramuscular injection. Intramuscular injections should be given into the center of a relatively large muscle. It is recommended not to administer more than 1 g at one site (calculated as ceftriaxone).

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to consult the lidocaine package insert for medical use.

Intravenous Injection

For intravenous injection, dissolve the contents of one vial of Tricef-TZ in 10 mL of sterile water for injection.

Intravenous Infusion

To prepare the infusion solution, dissolve the contents of one vial of Tricef-TZ in 40 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, or water for injection. Due to potential incompatibility, solutions containing Tricef-TZ must not be mixed with solutions containing other antibiotics, either during preparation or administration. Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Tricef-TZ in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitate may form. Precipitation of calcium-ceftriaxone salts may also occur when Tricef-TZ is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, Tricef-TZ must not be administered intravenously simultaneously with calcium-containing solutions (see sections "Contraindications," "Special Warnings," and "Incompatibility"), including long-term infusion solutions containing calcium, such as parenteral nutrition (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Tricef-TZ may be administered via intravenous infusion lasting at least 30 minutes (preferred route) or via slow intravenous injection lasting more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special Warnings"). 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-TZ is contraindicated in neonates (≤ 28 days of age) who require (or are expected to require) intravenous calcium-containing solutions, including infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium-ceftriaxone salts (see section "Contraindications").

Children

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

Tricef-TZ is contraindicated: in preterm neonates with a postmenstrual age ≤ 41 weeks; in term neonates ≤ 28 days of age at risk of developing bilirubin encephalopathy; in term neonates ≤ 28 days of age requiring intravenous calcium therapy (see section "Contraindications").

Overdose

Symptoms: information on cases of overdose in humans is limited.

In overdose, nausea, vomiting, and diarrhea may occur. High concentrations of β-lactam antibiotics in cerebrospinal fluid may lead to neurological reactions, including seizures.

Treatment: excessive plasma concentrations of ceftriaxone cannot be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Symptomatic treatment is recommended to manage overdose.

Adverse Reactions

Infections and infestations: candidiasis, genital fungal infections, secondary fungal infections, infections caused by resistant microorganisms, superinfections.

Blood and lymphatic system disorders: eosinophilia, neutropenia (associated with prolonged use, reversible), leukopenia, leukocytosis, lymphopenia, granulocytopenia, agranulocytosis, anemia including hemolytic anemia, thrombocytopenia, thrombocytosis, basophilia, prolonged/shortened prothrombin time, coagulation disorders, hypoprothrombinemia, agranulocytosis (less than 500 mm³), predominantly after administration of a cumulative dose of 20 g. Blood counts should be monitored regularly during prolonged therapy.

Gastrointestinal disorders: loose stools, diarrhea, nausea, vomiting, flatulence, stomatitis, taste disturbances, glossitis; pancreatitis possibly developed due to biliary tract obstruction. Precipitates formed by ceftriaxone in the biliary tract may play a role in the development of pancreatitis; pseudomembranous enterocolitis has been reported.

Hepatobiliary disorders: pseudocholelithiasis of the gallbladder, precipitates of ceftriaxone calcium salt in the gallbladder with corresponding symptoms in children, reversible cholelithiasis in children, increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, kernicterus, hepatitis, cholestatic hepatitis.

Skin and subcutaneous tissue disorders: skin rashes; allergic dermatitis; pruritus; urticaria; edema, including angioneurotic edema; acute generalized exanthematous pustulosis, exanthema; exudative multiform erythema; Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell’s syndrome); DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Renal and urinary system disorders: increased blood urea and creatinine levels, oliguria, hematuria, glucosuria; cylindruria, interstitial nephritis; formation of precipitates in the kidneys (usually reversible).

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

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

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.

Immune system disorders: anaphylactic or anaphylactoid reactions, anaphylactic shock, hypersensitivity, Jarisch-Herxheimer reaction.

Ear and labyrinth disorders: vertigo.

General disorders: fever, chills, serum sickness, edema, epistaxis, weakness.

Local reactions: phlebitis, pain, induration along the vein after intravenous administration; pain at the injection site after intramuscular administration. Intramuscular injection without lidocaine is painful.

Effect on laboratory test results

Increased blood creatinine levels. In isolated cases, false-positive results in the Coombs test may occur in patients treated with the drug. As with other antibiotics, the drug may cause false-positive results in galactosemia testing. False-positive results may also occur in urine glucose testing; therefore, during treatment with Tricef-TZ, glucosuria should be assessed only by enzymatic methods if necessary.

Infections and infestations

Cases of diarrhea following ceftriaxone use may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special precautions").

Precipitates of ceftriaxone calcium salt

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

Cases of precipitate formation in the kidneys have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (≥ 80 mg/kg/day), or cumulative doses exceeding 10 g, as well as those with additional risk factors (limited fluid intake, bed rest). The risk of precipitate formation increases in immobilized patients or those with dehydration. Renal precipitate formation may be asymptomatic or clinically evident and may lead to renal failure, which resolves after discontinuation of ceftriaxone therapy.

Cases of precipitate formation of ceftriaxone calcium salt in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown varying incidence rates of precipitate formation, exceeding 30% in some studies. The incidence appears to be lower with slow infusion (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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions

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

Keep out of reach of children.

Incompatibility

Tricef-TZ must not be mixed with calcium-containing solutions, such as Ringer’s solution or Hartmann’s solution, including parenteral nutrition solutions, due to the potential formation of precipitates.

Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides, as well as other antibiotics.

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

Packaging

1125 mg of powder in glass vials stoppered with rubber closures and sealed with aluminum caps with plastic flip-off caps. 1 or 10 vials per cardboard box.

Prescription category. 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 the Marketing Authorization Holder

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