Tulixon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TULIXONE (TULIXONE)

Composition:

Active substances: ceftriaxone, sulbactam;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1 g and sulbactam sodium equivalent to sulbactam 500 mg.

Pharmaceutical form. Powder for preparation of solution for injection.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group. Antibacterials for systemic use, other β-lactam antibiotics. Ceftriaxone, combinations. ATC code J01D.

Pharmacological properties.

Pharmacodynamics.

Tulixone is a combination of ceftriaxone and sulbactam sodium.

Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action. The bactericidal activity of ceftriaxone is due to inhibition of cell wall synthesis. Ceftriaxone is active in vitro against most Gram-positive and Gram-negative microorganisms. Ceftriaxone demonstrates high stability against most β-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria. Ceftriaxone is active in vitro and in clinical infections against the following microorganisms (see "Indications"):

Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B), most other β-hemolytic streptococci, Streptococcus viridans, 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 lwoffi, Acinetobacter anitratus (mainly A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alkali-like bacteria, 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, other Moraxella spp., Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, other Pseudomonas spp.*, Providencia rettgeri*, other Providencia spp., Salmonella typhi, Salmonella spp. (non-typhoidal), Serratia marcescens*, other Serratia spp.*, Shigella spp., Vibrio spp., Yersinia enterocolitica, other Yersinia spp.

* 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 several plasmid-mediated β-lactamases.

Note. Many strains of the above-mentioned microorganisms, which are multiply resistant to antibiotics such as aminopenicillins and ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain susceptible to ceftriaxone, except for clinical strains of P. aeruginosa, which are resistant to ceftriaxone. Treponema pallidum is susceptible to ceftriaxone in vitro and in animal studies. Clinical trials have shown that ceftriaxone is effective in the treatment of primary and secondary syphilis.

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

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

Note. Many strains of Bacteroides spp., particularly those producing β-lactamases (e.g., B. fragilis), are resistant to ceftriaxone. Clostridium difficile is resistant.

Sulbactam sodium is a derivative of the basic penicillin nucleus. It is an irreversible inhibitor of beta-lactamase and is used only parenterally. Chemically, it is the sodium sulphonate of penicillinate. It contains 92 mg of sodium (4 mEq) per 1 g. Sulbactam is a highly water-soluble, crystalline, almost white powder. Molecular weight is 255.22.

Sulbactam has no significant intrinsic antibacterial activity, except against Neisseriaceae and Acinetobacter. However, biochemical studies in cell-free bacterial systems have shown that sulbactam is an irreversible inhibitor of the major beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics.

The potential of sulbactam to prevent the degradation of penicillins and cephalosporins by resistant microorganisms has been confirmed by studies on resistant strains in intact microorganisms, where sulbactam demonstrated marked synergy with penicillins and cephalosporins. Since sulbactam also binds to certain penicillin-binding proteins, susceptible strains become more vulnerable to Tulixone than to cefoperazone alone.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

• Lower respiratory tract infections;
• acute bacterial otitis media;
• skin and soft tissue infections;
• kidney and urinary tract infections;
• bone and joint infections;
• sepsis;
• intra-abdominal infections (peritonitis, biliary tract and gastrointestinal tract infections);
• meningitis;
• gonorrhea;
• surgical prophylaxis of infections.

Contraindications.

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

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 in such conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing drugs or calcium-containing infusions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions" and "Adverse reactions").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin encephalopathy in these patients.

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the lidocaine prescribing information, particularly contraindications.

Ceftriaxone solutions 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 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 parenteral nutrition solutions, via a Y-site infusion system. However, in patients other than 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.

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 were different.

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

Ceftriaxone at concentrations up to 1 mM (excess concentrations achieved in vivo after 30-minute intravenous infusion of 2 g ceftriaxone) has been used in combination with calcium at concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma decreased at calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in newborn plasma, which may reflect precipitation of ceftriaxone-calcium salts.

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

Conflicting data exist regarding the potential for aminoglycosides to increase nephrotoxic effects when used concomitantly with cephalosporins. In such cases, careful adherence to clinical monitoring recommendations for aminoglycoside levels (and renal function) is advised.

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

No renal function disturbances have been observed with concomitant use of high-dose ceftriaxone and potent diuretics such as furosemide.

No disulfiram-like (antabuse-like) effects have been observed after alcohol consumption immediately following ceftriaxone administration.

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).

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

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

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

Bacteriostatic agents may interfere with the bactericidal action of cephalosporins.

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 does not affect ceftriaxone excretion.

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. Similar reactions have been observed with other cephalosporins. Patients should be cautious about consuming alcoholic beverages during treatment with TuliXon. Ethanol-containing solutions should not be used in artificial nutrition (oral or parenteral).

Special precautions for use.

Under no circumstances should Tulixon be administered with calcium-containing solutions (e.g., Ringer's solution, etc.). Calcium-containing solutions should not be administered within 48 hours after the last dose of ceftriaxone.

Hypersensitivity reactions.

As with other ceftriaxone-containing cephalosporins, anaphylactic reactions (including anaphylactic shock) with fatal outcomes have been reported during the use of Tulixon, even in patients without prior history of such reactions.

Prior to initiating treatment, 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 therapy initiated.

The risk of anaphylactic reactions is increased in patients with a history of anaphylaxis and in those with hypersensitivity reactions to various allergens; therefore, the drug 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 resistant microorganisms.

Diarrhea associated with Clostridium difficile, ranging from mild to severe colitis with fatal outcomes, may occur during treatment with most antibacterial agents, including ceftriaxone and sulbactam. 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.

If Clostridium difficile-associated diarrhea is suspected or confirmed, antibiotic therapy not active against Clostridium difficile should be discontinued.

This diagnosis should be considered in patients who develop diarrhea during or after ceftriaxone therapy (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment against Clostridium difficile should be considered. Antiperistaltic agents should not be used.

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

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.

Cholelithiasis.

Following administration of the drug, usually at doses exceeding standard recommended doses, shadows may be observed on ultrasound examination of the gallbladder, which may be mistaken for gallstones. These are precipitates of ceftriaxone calcium salt, which disappear after completion or discontinuation of ceftriaxone therapy.

Ultrasonographic shadows mistaken for gallstones have been observed in the gallbladder, and their incidence increases with ceftriaxone 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, formation of ceftriaxone calcium salt precipitates may be symptomatic. These changes rarely cause any symptoms. However, conservative treatment is recommended in such cases. If clinical symptoms occur, the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (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 treatment, cholestasis, or biliary sludge formation, including previous extensive therapy, severe illness, and total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone/sulbactam use cannot be ruled out as an initiating or contributing factor in this disorder. The role of precipitates formed by Tulixon in the biliary tract in the development of pancreatitis cannot be excluded.

Nephrolithiasis.

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

Immune-mediated hemolytic anemia has been observed in patients receiving cephalosporins, including ceftriaxone. Cases of severe hemolytic anemia, including fatal cases, have been reported in adults and children. If anemia develops during ceftriaxone therapy, ceftriaxone-induced anemia should be excluded and the drug discontinued until the etiology of anemia is established.

Blood counts should be monitored regularly during prolonged treatment.

Ceftriaxone must not be mixed or co-administered with calcium-containing solutions, even when administered through separate infusion systems. Cases of precipitate formation in the lungs and kidneys of neonates and preterm infants, leading to fatal outcomes, have been reported following simultaneous administration of ceftriaxone and calcium-containing drugs. Cases of intravascular precipitates have also been reported in patients of other age groups after concomitant use of ceftriaxone with intravenous calcium-containing solutions. Therefore, calcium-containing solutions for intravenous administration must not be used in neonates and patients of other age groups within at least 48 hours after the last dose of Tulixon (see section "Contraindications").

Children.

Ceftriaxone, a component of the drug, may displace bilirubin from its binding to serum albumin. Therefore, ceftriaxone is contraindicated in preterm and 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 safety and efficacy of the drug is recommended (see section "Dosage and administration").

In patients with impaired renal function but normal hepatic function, the dose of ceftriaxone/sulbactam does not need to be reduced. In renal failure (creatinine clearance below 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.

In patients with impaired hepatic function but preserved renal function, dose reduction of ceftriaxone/sulbactam is not necessary.

In cases of concomitant severe hepatic and renal disease, serum ceftriaxone concentrations should be monitored regularly. In patients undergoing hemodialysis, the dose of the drug does not need to be adjusted after the procedure.

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

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

In patients undergoing hemodialysis, the dose of the drug does not need to be adjusted after the procedure, but serum drug concentrations should be monitored, as elimination may be accelerated in these patients.

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.

Tulixon should not be administered immediately before delivery in the third trimester of pregnancy due to the increased risk of bilirubin encephalopathy.

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, and no adverse 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 on whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

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.

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

When prescribing Tulkison, official recommendations on antibiotic therapy must be followed, particularly those concerning the prevention of antibiotic resistance.

Solutions should be prepared immediately before use. After adding the solvent, the completeness of dissolution should be visually assessed. Tulkison can be administered intravenously or intramuscularly.

Adults and children aged 12 years and older: the usual dose is 1–2 g (calculated as ceftriaxone) of Tulkison once daily (every 24 hours). In severe infections or infections caused by pathogens with only moderate sensitivity to the drug, the daily dose may be increased to 4 g (calculated as ceftriaxone).

Children

Newborns, infants, and children under 12 years of age

Newborns (up to 2 weeks): 20–50 mg/kg body weight (calculated as ceftriaxone) once daily. Due to immature enzyme systems, the daily dose should not exceed 50 mg/kg body weight. Doses for full-term and preterm infants do not differ.

Tulkison is contraindicated in neonates aged ≤28 days when treatment with intravenous solutions containing calcium is required (or anticipated), including intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of precipitation of calcium-ceftriaxone salts.

Newborns and children aged 15 days to 12 years: 20–80 mg/kg body weight (calculated as ceftriaxone) once daily.

Children with body weight over 50 kg should receive adult doses.

The total daily dose in children should not exceed 2 g (calculated as ceftriaxone).

Intravenous doses of 50 mg/kg (calculated as ceftriaxone) or higher should be administered slowly by infusion over 30–60 minutes.

Elderly patients

Dose adjustment is not required in elderly patients.

Treatment duration

The duration of treatment depends on the course of the disease. As is customary in antibiotic therapy, patients should continue receiving Tulkison for at least 48–72 hours after body temperature normalizes and laboratory tests indicate absence of pathogens.

Combination therapy

Studies have shown synergistic effects between Tulkison and aminoglycosides against many Gram-negative bacteria. Although increased efficacy of such combinations cannot always be predicted, it should be considered in the treatment of severe, life-threatening infections caused by Pseudomonas aeruginosa. Due to physical incompatibility between ceftriaxone and aminoglycosides, they should be administered separately at their recommended doses.

Dosing in special situations

Meningitis

In bacterial meningitis in infants and children aged 15 days to 12 years, treatment should be initiated at a dose of 100 mg/kg (but not exceeding 4 g as ceftriaxone) once daily. Once the causative pathogen is identified and its susceptibility determined, the dose may be adjusted accordingly. Optimal outcomes have been achieved with the following treatment durations:

Gonorrhea (calculated as ceftriaxone). For the treatment of gonorrhea (caused by strains producing or not producing penicillinase), a single intramuscular dose of 250 mg is recommended.

Prophylaxis of surgical infections

For the prevention of postoperative infections in surgery, a single dose of 1–2 g (calculated as ceftriaxone) of Tulixone should be administered 30–90 minutes before the start of surgery, depending on the degree of infection risk. During surgery on the colon and rectum, simultaneous (but separate) administration of Tulixone and one of the 5-nitroimidazoles (e.g., ornidazole) has proven effective.

Renal and hepatic impairment

Dose reduction is not necessary in patients with impaired renal function if hepatic function remains normal.

Dose reduction is not necessary in patients with impaired hepatic function if renal function remains normal. Only in cases of preterminal-stage renal failure (creatinine clearance less than 10 ml/min), the daily dose should not exceed 2 g (calculated as ceftriaxone). In patients with impaired hepatic function and normal renal function, dose adjustment is not required. In cases of concomitant severe renal and hepatic impairment, plasma concentrations of ceftriaxone should be monitored regularly and dosage adjusted as necessary.

Patients undergoing hemodialysis do not require additional doses of the drug after dialysis. However, serum concentrations of ceftriaxone should be monitored for possible dose adjustment due to potentially reduced elimination rates in these patients. The daily dose of Tulixone in patients undergoing hemodialysis should not exceed 2 g (calculated as ceftriaxone).

Preparation of solutions

Solutions should be prepared immediately before use.

Freshly prepared solutions retain their physical and chemical stability for 6 hours at room temperature or for 24 hours at 2–8 °C. Depending on concentration and storage duration, the color of the solution may vary from pale yellow to amber. This property of the active ingredient does not affect the drug's efficacy or tolerability.

Intramuscular injection

For intramuscular injection, dissolve 1.5 g of the drug in 3.5 ml of 1% lidocaine solution; administer deeply into the gluteal muscle. It is recommended not to inject more than 1 g per buttock (calculated as ceftriaxone).

Solutions containing lidocaine must not be administered intravenously.

Intravenous injection

For intravenous injection, dissolve the contents of one Tulixone vial in 10 ml of sterile water for injection; administer slowly intravenously over 2–4 minutes.

Intravenous infusion

Intravenous infusion should last at least 30 minutes. To prepare the infusion solution, dissolve 3 g of Tulixone 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, 6–10% hydroxyethyl starch, water for injection. Due to possible incompatibility, solutions containing Tulixone 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 Tulixone in vials or to dilute the reconstituted solution for intravenous infusion, due to the risk of forming precipitates of ceftriaxone calcium salts. Precipitation of ceftriaxone calcium salts may also occur when Tulixone is mixed with calcium-containing solutions in the same intravenous infusion system. Tulixone must not be administered intravenously simultaneously with calcium-containing solutions, including prolonged infusions containing calcium, such as parenteral nutrition (see "Interaction with other medicinal products and other types of interactions").

Children

Use in children (see section "Method of administration and dosage").

Tulixone is contraindicated in neonates aged ≤ 28 days when treatment with intravenous calcium-containing solutions, including intravenous infusions containing calcium (e.g., parenteral nutrition), is necessary or expected, due to the risk of forming ceftriaxone calcium salt precipitates (see "Method of administration and dosage").

Cases of precipitate formation 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 products. In some of these cases, the same intravenous infusion systems were used for administering both Tulixone and calcium-containing solutions, and precipitate formation was observed in some infusion systems.

Overdose.

Symptoms: limited information is available on cases of drug 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: candidomycosis, fungal genital tract infections, secondary fungal infections, and 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), mainly after administration of a total dose exceeding 20 g. Blood count should be monitored regularly during prolonged treatment.

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 have contributed to the development of pancreatitis; cases of pseudomembranous enterocolitis have 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 polymorphic erythema; Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell's syndrome).

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

Neurological disorders: headache, dizziness, tremor, convulsions.

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 the injection site. Intramuscular injection without using lidocaine is painful.

Effect on laboratory test results.

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

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

Calcium ceftriaxone salt precipitates.

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

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (≥ 80 mg/kg/day), cumulative doses exceeding 10 g, or had 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 reversible renal failure after discontinuation of ceftriaxone therapy.

Cases of calcium ceftriaxone salt precipitate formation in the gallbladder have been reported, mainly in patients receiving doses higher than the standard recommended dose. Prospective studies in children have shown variable rates of precipitate formation with intravenous administration—over 30% in some studies. The incidence of precipitate formation 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. After discontinuation of ceftriaxone, precipitates usually resolve (see section "Special precautions").

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a dry, protected from light and inaccessible to children place.

Incompatibilities.

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

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

Do not mix with other solvents except those specified in the section "Administration and dosage".

Packaging.

1.5 g powder in 20 ml glass vials, stoppered with rubber stoppers and sealed with aluminum caps with flip-off plastic caps. One vial per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Zyss Pharmaceuticals Pvt. Ltd.;
Swiss Parenterals Ltd.

Manufacturer's address and place of business.

Plot No. 72, EPIP, Phase-1, Jharmajri, Baddi, Solan District, Himachal Pradesh, India;
Unit II, Plot 402, 412-414 Kerala Industrial Estate, GIDC, Near Bavla, Ahmedabad, Gujarat, 382220, India