Tulixson-tz 1125 mg

INSTRUCTION for medical use of the medicinal product Tulixone-TZ 1125 mg (Tulixone-TZ 1125 mg)

Composition:

Active substances: ceftriaxone, tazobactam;

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

Pharmaceutical form. Powder for solution for injection.

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

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

Pharmacological Properties.

Pharmacodynamics.

"Tulixon-TZ 1125 mg" is an antibacterial medicinal product, a fixed combination of a third-generation parenteral cephalosporin antibiotic – sodium ceftriaxone – and a beta-lactamase inhibitor – sodium tazobactam.

Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action. The bactericidal activity of ceftriaxone is due to inhibition of cell membrane synthesis. Ceftriaxone is active in vitro against most Gram-positive and Gram-negative microorganisms. Ceftriaxone is stable against most β-lactamases (both penicillinases and cephalosporinases) of Gram-positive and Gram-negative bacteria. Ceftriaxone is active in vitro against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (methicillin-sensitive), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B), most other species of β-hemolytic streptococci, Streptococci of the viridans group, Streptococcus pneumoniae.

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

Gram-negative aerobes: Acinetobacter lwoffii, Acinetobacter anitratus (mainly A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae, Enterobacter spp. (others)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, 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, mainly 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 are multidrug-resistant 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.

Anaerobes: Bacteroides spp. (bile-sensitive)*, Clostridium spp. (except C. difficile), Fusobacterium nucleatum, Fusobacterium spp. (others), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococcus spp.

* Some isolates of these species are resistant to ceftriaxone, mainly due to β-lactamase production;

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

Note. Many strains of Bacteroides spp., which produce β-lactamases (particularly B. fragilis), are resistant to ceftriaxone. Clostridium difficile is resistant.

Tazobactam is a class III beta-lactamase inhibitor according to the Richmond-Sykes classification: penicillinases and cephalosporinases. It is a derivative of the "penicillin nucleus," sulbactam (sulfone-penicillanic acid). Tazobactam irreversibly inhibits most beta-lactamases produced by clinically important Gram-negative and Gram-positive aerobic and anaerobic bacteria by covalent binding to their enzymes. In particular, tazobactam has a high affinity for binding to plasmid-mediated beta-lactamases, which are often responsible for resistance to penicillins and cephalosporins.

Tazobactam does not inhibit class A enzyme activity.

Additionally, tazobactam does not inhibit the activity of beta-lactamases such as:

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

Pharmacokinetics.

Absorption.

Intramuscular administration

After intramuscular injection, the 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 and is reached within 2–3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma levels are approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma levels 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 increase in mean peak plasma concentration by 8–15% (Cmax) was observed with repeated administration; steady state was achieved in most cases within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is more pronounced 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 of ceftriaxone in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is also detected in low concentrations in breast milk (see section "Use during pregnancy or breastfeeding").

Protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is about 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 only a minor increase in elimination half-life (less than twofold), even in patients with severe renal impairment.

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

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

Elderly patients

In patients aged 75 years and older, the mean elimination half-life is usually 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 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 less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding, and 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.

• Lower respiratory tract infections;
• Acute bacterial otitis media;
• Skin and soft tissue infections;
• Complicated urinary tract infections;
• Bone and joint infections;
• Gonorrhea;
• Septicemia;
• Intra-abdominal infections;
• Meningitis.

Contraindications.

Hypersensitivity to the active substances or to beta-lactamase inhibitors, or to antibiotics belonging to the cephalosporin and penicillin groups. In patients with known hypersensitivity to penicillins, 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 ulcerative colitis, enteritis, or antibiotic-associated colitis.

Ceftriaxone is contraindicated:

in preterm newborns with a postmenstrual age ≤ 41 weeks (gestational age + postnatal age)*;

in full-term newborns (age ≤ 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, due to the risk of precipitation of ceftriaxone-calcium 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 such patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions" 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 interaction.

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to dissolve 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 simultaneously by intravenous route with calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided 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 newborns have been reported. In some cases, venous access and timing of administration of ceftriaxone and calcium-containing solutions differed.

In vitro studies using adult and neonatal cord plasma have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions", "Incompatibilities").

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 adjusted appropriately 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 practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.

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

When high doses of ceftriaxone are used concomitantly with potent diuretics such as furosemide, no renal function impairment has been observed.

Ceftriaxone contains an N-methylthiotetrazole side chain, which may cause ethanol intolerance and bleeding tendencies, as seen with some other cephalosporins.

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

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).

In patients receiving ceftriaxone, false-positive results in the Coombs test may occur.

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

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

Bacteriostatic agents may interfere with the bactericidal action of cephalosporins.

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.

Probenecid does not affect the elimination of ceftriaxone.

Alcohol. Reactions such as facial flushing, increased sweating, headache, and tachycardia have been reported when alcohol was consumed during and within 5 days after treatment with cefoperazone. No disulfiram-like (antabuse-like) effects have been observed after alcohol consumption immediately following ceftriaxone administration. Similar reactions have been observed with other cephalosporins. Patients should be cautious about consuming alcoholic beverages during treatment with "Tulixson-TZ 1125 mg". Solutions containing ethanol must not be used when artificial nutrition (oral or parenteral) is administered.

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 patients without a relevant history.

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.

If allergic reactions occur, the drug should be discontinued immediately and appropriate treatment initiated.

The risk of anaphylactic reactions is increased in patients with a history of anaphylaxis or those suffering from hypersensitivity reactions to various allergens; therefore, ceftriaxone should be used cautiously in patients with a predisposition to allergic diathesis.

Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of these events is unknown (see section "Adverse reactions").

The drug may increase 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 nearly all antibacterial agents, including ceftriaxone and tazobactam, ranging from mild diarrhea to fatal colitis. Antibacterial agents alter the normal gut flora, leading to overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Clostridium difficile strains 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.

Depending on clinical indications, appropriate fluid and electrolyte replacement, protein supplementation, antibiotic therapy effective against Clostridium difficile, and surgical evaluation should be considered.

Prolonged use of ceftriaxone may lead to difficulties in controlling microorganisms resistant to the drug. Therefore, careful monitoring of patients is required. Appropriate measures should be taken if superinfection occurs.

Antibacterial spectrum.

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 involving microorganisms resistant to ceftriaxone, additional antibiotics should be considered.

Cholelithiasis.

On ultrasound, shadows should prompt consideration of possible precipitation of ceftriaxone calcium salt.

Shadows, mistakenly interpreted as gallstones, have been observed on ultrasound of the gallbladder, with increased frequency during ceftriaxone administration at 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. Rarely, precipitation of ceftriaxone calcium salt has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of 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 therapy, cholestasis, or biliary sludge formation, including severe illness and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone/tazobactam administration cannot be ruled out as a triggering or contributing factor in the development of this disorder.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). In symptomatic cases, 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.

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibiotics, including ceftriaxone. Severe hemolytic anemia, including fatal cases, have been reported in both adults and children during ceftriaxone therapy. If anemia develops during ceftriaxone treatment, hemolytic anemia associated with cephalosporin use should be considered, and ceftriaxone should be discontinued until the etiology is established.

Prolonged therapy.

During prolonged therapy, a complete blood count should be performed regularly.

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, even when administered through different infusion systems. Cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys of full-term and preterm neonates under 1 month of age, resulting in fatal outcomes, have been reported following concomitant administration of ceftriaxone and calcium-containing drugs. Cases of intravascular precipitates have also been reported in patients of other age groups after simultaneous administration of ceftriaxone with 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 for at least 48 hours after the last dose of "Tulixon-TZ 1125 mg" (see section "Contraindications").

Confirmed cases of intravascular precipitates have not been reported except in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing drugs. In vitro studies have shown that neonates have an increased risk of ceftriaxone calcium salt precipitation compared to patients of other age groups.

When administering ceftriaxone to patients of any age, the drug must not be mixed or administered simultaneously with any intravenous solutions containing calcium, 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 the other, provided the drugs are administered through different infusion systems into different body sites or the infusion system is thoroughly flushed with physiological 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 TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").

Children.

Ceftriaxone, a component of the drug, may displace bilirubin from its binding to serum albumin. Therefore, ceftriaxone is contraindicated in preterm and full-term neonates with hyperbilirubinemia who are 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 drug's safety and efficacy is recommended (see section "Dosage and administration").

For patients with impaired renal function but normal hepatic function, dose adjustment of ceftriaxone/tazobactam is not required. However, in patients with renal impairment (creatinine clearance below 10 ml/min), the daily dose of ceftriaxone should not exceed 2 g.

For patients with impaired hepatic function but preserved renal function, dose adjustment of ceftriaxone/tazobactam is not necessary.

In cases of concomitant severe hepatic and renal impairment, serum ceftriaxone concentrations should be monitored regularly. For patients undergoing hemodialysis, dose adjustment after the procedure is not required.

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

Effect on serological test results.

Occasionally, patients treated with "Tulixon-TZ 1125 mg" may exhibit false-positive Coombs test results. Like other antibiotics, "Tulixon-TZ 1125 mg" may cause false-positive galactosemia test results. False-positive results may also occur in urine glucose testing; therefore, during treatment with "Tulixon-TZ 1125 mg", glucosuria, if necessary, should be assessed only by enzymatic methods.

For patients undergoing hemodialysis, dose adjustment after the procedure is not required, but serum drug concentration should be monitored, as elimination may be accelerated in these patients.

Sodium.

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

Use of lidocaine as solvent.

If lidocaine solution is used as a solvent, ceftriaxone may be administered only by intramuscular injection. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine package insert must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Disposal of unused or expired drug:

Environmental contamination with medicinal products should be minimized. The drug 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 the embryo/fetus or peri- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, but no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision 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 revealed any 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 or operating machinery should be avoided.

Administration and Dosage

Administer intravenously or intramuscularly.

Dosage

The dose of the medicinal product depends on the severity, susceptibility, localization, and type of infection, as well as on 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 "Tulixon-TZ 1125 mg" once daily (every 24 hours). In severe cases or when pathogens have only moderate sensitivity 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 "Tulixon-TZ 1125 mg" (calculated as ceftriaxone) may be administered.

Some data suggest that in cases of severe illness or when prior therapy has been ineffective, "Tulixon-TZ 1125 mg" 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 given in terms of ceftriaxone): 20–50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg body weight. Contraindicated in premature neonates with postmenstrual age 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.

Lower respiratory tract infections: 50–80 mg/kg once daily.

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

Complicated urinary tract infections: 50–80 mg/kg once daily.

Skin and soft tissue infections: 50–100 mg/kg (but not more than 4 g calculated as ceftriaxone) once daily.

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

For bacterial meningitis in infants and children aged 15 days to 12 years, initiate treatment with a dose of 80–100 mg/kg (but not more than 4 g calculated as ceftriaxone) once daily. Once the causative organism is identified and its sensitivity 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 when prior therapy has been ineffective, "Tulixon-TZ 1125 mg" 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 drug should be continued for 48–72 hours after the resolution of fever or confirmation of eradication of the 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

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) should the daily dose not exceed 2 g (calculated as ceftriaxone).

Patients with severe hepatic and renal dysfunction

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

Careful clinical monitoring of the safety and efficacy of the medicinal product is recommended when both severe renal and hepatic functions are impaired.

Patients undergoing hemodialysis 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 medicinal product is recommended. However, serum concentrations of ceftriaxone should be monitored to consider possible dose adjustments, as elimination rate may be reduced in these patients. The daily dose of "Tulixon-TZ 1125 mg" for patients on hemodialysis should not exceed 2 g (calculated as ceftriaxone).

Preparation of solutions

Prepare solutions immediately before use.

Intramuscular injection

For intramuscular injection, dissolve the contents of the vial in 3.5 mL of 1% lidocaine solution; inject deeply into the gluteal muscle. "Tulixon-TZ 1125 mg" may be administered by deep intramuscular injection. Intramuscular injection should be administered 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 instructions for medical use of lidocaine.

Intravenous injection

For intravenous injection, dissolve the contents of one vial of "Tulixon-TZ 1125 mg" in 10 mL of sterile water for injection.

Intravenous infusion

To prepare the solution for infusion, dissolve the contents of the vial of "Tulixon-TZ 1125 mg" in 40 mL of one of the following infusion solutions free of calcium ions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, water for injection. Due to possible incompatibility, solutions containing "Tulixon-TZ 1125 mg" 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 dissolve "Tulixon-TZ 1125 mg" in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitate may form. Precipitation of calcium salts of ceftriaxone may also occur when "Tulixon-TZ 1125 mg" is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, "Tulixon-TZ 1125 mg" must not be administered intravenously simultaneously with calcium-containing solutions (see sections "Contraindications", "Special precautions", and "Incompatibility"), including long-term infusion solutions containing calcium, such as parenteral nutrition (see "Interaction with other medicinal products and other forms of interaction").

"Tulixon-TZ 1125 mg" may be administered by intravenous infusion over at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion to 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 precautions"). Intramuscular administration should be considered when intravenous access is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.

"Tulixon-TZ 1125 mg" is contraindicated in neonates (≤ 28 days of age) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (see section "Contraindications").

Children

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

"Tulixon-TZ 1125 mg" is contraindicated for use in neonates aged ≤ 28 days if there is a need (or expected need) for treatment with intravenous calcium-containing solutions, including intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (see "Administration and dosage").

Cases of precipitation in the lungs and kidneys leading to fatal outcomes have been reported in neonates and premature infants following concomitant administration of ceftriaxone and calcium-containing drugs. In some of these cases, the same intravenous infusion systems were used for "Tulixon-TZ 1125 mg" and calcium-containing solutions, and precipitate formation was observed in some infusion systems.

Overdose

Symptoms: Limited information is available on cases of overdose in humans.

In overdose, nausea, vomiting, and diarrhea may occur. High concentrations of β-lactam antibiotics in cerebrospinal fluid may cause 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 for managing overdose cases.

Adverse Reactions

Infections and infestations: candidiasis, fungal genital tract 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, anemia including hemolytic anemia, thrombocytopenia, thrombocytosis, basophilia, increased/decreased prothrombin time, coagulation disorders, hypoprothrombinemia, agranulocytosis (less than 500 mm³), predominantly after administration of a total dose exceeding 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 contribute to pancreatitis; pseudomembranous enterocolitis has been reported.

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

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).

Renal and urinary system disorders: increased blood urea and creatinine concentrations, oliguria, hematuria, glucosuria; cylindruria, interstitial nephritis.

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

Cardiac disorders: increased or decreased blood pressure, palpitations.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.

Immune system disorders: anaphylactic or anaphylactoid reactions, anaphylactic shock, hypersensitivity.

Ear and labyrinth disorders: vertigo.

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

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

Effect on laboratory test results.

Elevated serum creatinine levels. Rarely, false-positive results in the Coombs test may occur in patients treated with this 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 ceftriaxone/tazobactam therapy, urine glucose should be determined only by enzymatic methods if necessary.

Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special precautions").

Precipitates of calcium ceftriaxone salt.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing products. Autopsy findings revealed precipitates of calcium ceftriaxone 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 (≥ 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 who are dehydrated. Renal precipitate formation may be asymptomatic or clinically evident and may lead to renal failure, which resolves after discontinuation of ceftriaxone therapy.

Cases of calcium ceftriaxone salt precipitate formation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence of precipitate formation following intravenous administration—over 30% in some studies. The frequency of precipitate formation appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may cause clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. After discontinuation of ceftriaxone, precipitates usually resolve (see section "Special precautions").

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

The reconstituted solution remains stable for 6 hours at room temperature or 24 hours at 2–8 °C.

Incompatibilities.

"Tulixon-TZ 1125 mg" 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.

1 vial of 1125 mg powder for injection solution per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Zeiss Pharmaceuticals Pvt. Ltd.;
Swiss Parenterals Ltd.

Manufacturer's address and place of business.

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