Ceftriaxone-bhffz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE-BCPP

Composition:

Active substance: ceftriaxone;

One vial contains ceftriaxone (as sterile ceftriaxone sodium) 500 mg or 1000 mg.

Dosage form. Powder for solution for injection.

Main physicochemical properties: crystalline powder of nearly white or slightly yellow color, slightly hygroscopic.

Pharmacotherapeutic group. Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC Code J01D D04.

Pharmacological Properties.

Pharmacodynamics.

Ceftriaxone is a semisynthetic antibiotic of the beta-lactam group, a third-generation cephalosporin; it exerts a bactericidal effect, the mechanism of which is associated with inhibition of transpeptidase enzyme activity and disruption of peptidoglycan biosynthesis in the microbial cell wall; it has a broad spectrum of activity.

Active against gram-positive aerobes: Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae, beta-hemolytic group A streptococci (S. pyogenes), group B streptococci (S. agalactiae), Viridans group, non-enterococcal group D streptococci; gram-negative aerobes: E. coli, H. influenzae, H. parainfluenzae, Klebsiella spp. (including K. pneumoniae), Morganella morganii, Neisseria gonorrhoeae (including penicillinase-producing strains), Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Salmonella spp. (including S. typhi), Serratia spp. (including S. marcescens), Shigella spp., Yersinia spp. (including Y. enterocolitica), Treponema pallidum; anaerobes: Bacteroides spp. (including some strains of B. fragilis), Clostridium spp. (however, most strains of C. difficile are resistant), Peptococcus spp., Peptostreptococcus spp., Fusobacterium spp. (except F. mortiferum and F. varium). The drug is active against microorganisms resistant to penicillins, first-generation cephalosporins, and aminoglycosides.

Resistant to the drug are: methicillin-resistant staphylococci; most strains of enterococci (including S. faecalis) and group D streptococci; many strains of beta-lactamase-producing Bacteroides spp. (B. fragilis).

Pharmacokinetics.

After intramuscular administration, the bioavailability of ceftriaxone is 100%; its maximum plasma concentration is reached within 2–3 hours. After intravenous administration, the drug rapidly penetrates into tissue fluid, where bactericidal concentrations against susceptible microorganisms are maintained for 24 hours. Ceftriaxone reversibly binds to plasma albumin. This binding is inversely proportional to concentration: for example, at a serum concentration of less than 100 mg/L, ceftriaxone binding to proteins is 95%, while at a concentration of 300 mg/L, it is only 85%. Due to the lower albumin content in interstitial fluid, the concentration of ceftriaxone in this fluid is higher than in blood serum.

Ceftriaxone penetrates well into organs and body fluids (peritoneal, pleural, cerebrospinal, synovial), into bone tissue, crosses the placenta, and in small amounts (3–4%) passes into breast milk. In children, including newborns, with meningitis, the drug penetrates into inflamed meninges, and its concentration in cerebrospinal fluid reaches 17% of the plasma concentration.

The drug is excreted unchanged by 50–60% via the kidneys and 40–50% via bile. In renal insufficiency, the pharmacokinetics of the drug is almost unchanged, with only a slight increase in elimination half-life. With impaired kidney function, biliary excretion increases, while in the presence of liver pathology, renal excretion of ceftriaxone increases. The elimination half-life in healthy adults is approximately 8 hours; in newborns under 8 days of age and in individuals aged 75 years and older, it increases by 2–3 times.

Clinical characteristics.

Indications.

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:

• respiratory tract infections, especially pneumonia, as well as ear, throat, and nose infections;
• intra-abdominal infections (peritonitis, infections of biliary tract and gastrointestinal tract);
• kidney and urinary tract infections;
• genital infections, including gonorrhea;
• sepsis;
• bone, joint, soft tissue, skin infections, and wound infections;
• infections in patients with impaired immune defense;
• meningitis;
• disseminated Lyme borreliosis (Stage II and Stage III).

Perioperative prophylaxis of infections during surgical procedures on gastrointestinal organs, biliary tract, urinary tract, and during gynecological procedures, but only in cases of potential or known contamination.

When prescribing ceftriaxone, official recommendations on antibiotic therapy and recommendations on prevention of antibiotic resistance should be followed.

Contraindications.

• Hypersensitivity to ceftriaxone, to any cephalosporin antibiotic, or to lidocaine (for intramuscular administration).
• History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, carbapenems).
• Premature newborns with a postmenstrual age of less than 41 weeks (gestational age + postnatal age)*.
• Term newborns (up to 28 days of life):
  • with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis (in these conditions, bilirubin binding to blood proteins is reduced)*;
  • requiring (or expected to require) intravenous administration of calcium-containing solutions or drugs due to the risk of ceftriaxone-calcium precipitate formation in lungs and kidneys (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" and the lidocaine instructions for medical use, especially contraindications).

Ceftriaxone solutions containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Calcium-containing products. Due to the risk of precipitation of ceftriaxone-calcium salts, calcium-containing solutions such as Ringer's solution or Hartmann's solution must not be used to reconstitute the drug in vials or to further dilute reconstituted solution for intravenous administration.

Ceftriaxone-calcium precipitates may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site infusion system. However, in all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult plasma and neonatal umbilical cord plasma have shown that newborns have an increased risk of ceftriaxone-calcium precipitate formation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

There are no reports of interaction between ceftriaxone and oral calcium-containing drugs, or between ceftriaxone administered intramuscularly and calcium-containing drugs administered intravenously or orally.

Nonsteroidal anti-inflammatory drugs, antiplatelet agents, vitamin K antagonists (such as warfarin). Increased risk of bleeding. Potentiation of the effect of vitamin K antagonists. Frequent monitoring of the international normalized ratio (INR) is recommended, and dosage of vitamin K antagonists should be adjusted accordingly during and after ceftriaxone treatment (see section "Adverse reactions").

Aminoglycosides. Data regarding potential enhancement of aminoglycoside nephrotoxicity when used concomitantly with cephalosporins are conflicting. In such cases, careful clinical monitoring of aminoglycoside levels and renal function is required.

If combination therapy is necessary, the drugs should be administered separately at different sites and must not be mixed in the same syringe or in the same infusion solution due to physicochemical incompatibility.

Bacteriostatic antibiotics (chloramphenicol, tetracyclines). Possible reduction of the bactericidal effect of ceftriaxone.

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

Other beta-lactam antibiotics. Cross-allergic reactions may occur.

Loop diuretics. No renal function disturbances have been observed when high doses of ceftriaxone and potent diuretics (e.g., furosemide) are used concomitantly.

Probenecid. Does not affect tubular secretion of ceftriaxone (in contrast to other cephalosporins).

Hormonal contraceptives. As with other antibiotics, the efficacy of hormonal contraceptives may be reduced; therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after its completion.

Ethanol. No disulfiram-like effects have been observed. Ceftriaxone contains an N-methylthiotetrazole side chain, which could theoretically cause ethanol intolerance or bleeding, as seen with some other cephalosporins.

As with other antibiotics, ceftriaxone may reduce the therapeutic effect of the typhoid vaccine, but this effect applies only to the attenuated Ty21a strain.

Substances used in laboratory tests. False-positive urine glucose test results may occur when using Benedict's or Fehling's solution.

Ceftriaxone is incompatible and must not be mixed in the same container or administered simultaneously with amsacrine, vancomycin, fluconazole, aminoglycosides.

Special precautions for use.

Hypersensitivity reactions.

As with other cephalosporins and beta-lactam antibiotics, there have been reports of severe acute hypersensitivity reactions (including anaphylactic shock), sometimes fatal, even in patients with no prior history of such reactions. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). If such reactions occur, the drug should be discontinued immediately and adrenaline (epinephrine), glucocorticoids, and appropriate emergency measures should be administered.

Prior to initiating therapy, patients should be questioned about previous history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other beta-lactam antibiotics. Cross-allergic reactions between penicillins and cephalosporins are possible. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

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

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.

Interaction with calcium-containing products.

Cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys with fatal outcomes have been reported in premature and full-term neonates up to 1 month of age. In at least one of these cases, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. To date, there have been no confirmed cases of intravascular precipitates in patients other than newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies have shown that neonates have an increased risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone should not be mixed or co-administered with any calcium-containing intravenous solutions in patients of any age, even when using separate 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 that the drugs are administered through different infusion systems into different body sites or that the infusion system is replaced or thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider alternative antibacterial therapy not associated with such precipitation risk. If ceftriaxone use in patients requiring TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines should be 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 for the doses described in the section "Dosage and administration". Ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

Ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been reported in patients receiving cephalosporins, including ceftriaxone (see section "Adverse reactions"). Severe cases of hemolytic anemia (including fatal cases) have been reported during ceftriaxone treatment in both adults and children. If anemia develops during treatment, this diagnosis should be considered and the antibiotic discontinued until the etiology of anemia is determined.

Prolonged therapy.

During prolonged treatment with the drug, regular monitoring of complete blood count is recommended.

Colitis/overgrowth of resistant microorganisms.

Cases of antibiotic-associated colitis/pseudomembranous colitis have been reported with the use of nearly all antibacterial agents, including ceftriaxone. The severity of symptoms may range from mild to life-threatening; therefore, it is important to consider this diagnosis in all patients who develop diarrhea during or after ceftriaxone administration (see section "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of specific therapy against Clostridium difficile may be necessary. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfection caused by microorganisms resistant to the drug may occur.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended (see section "Dosage and administration").

Effect on serological test results.

During ceftriaxone use, the Coombs test may yield false-positive results. Ceftriaxone may also cause false-positive results in galactosemia screening tests and in non-enzymatic methods for glucose determination in urine. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Adverse reactions").

Sodium.

Each gram of the drug contains 3.6 mmol (83.03 mg) of sodium, which should be taken into account for patients on a sodium-controlled diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inadequate as monotherapy for certain types of infections, except when the causative pathogen has been confirmed (see section "Dosage and administration"). In cases of polymicrobial infections where resistant organisms are suspected, the need for additional antibiotics should be considered.

Use of lidocaine.

When lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information should be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

On ultrasound, shadows should raise suspicion of ceftriaxone-calcium salt precipitates. Such shadows, mistaken for gallstones, have been observed in gallbladder ultrasound scans and occur more frequently with ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering the drug to children. These precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, ceftriaxone-calcium precipitates have been associated with symptoms. The risk of precipitate formation increases with treatment duration exceeding 14 days, renal impairment, dehydration, or parenteral nutrition. Conservative, non-surgical treatment is recommended if symptoms occur. The physician should consider discontinuing the drug, weighing the benefit-risk ratio in each individual case (see section "Adverse reactions").

Cholestasis.

Cases of pancreatitis possibly caused by biliary tract obstruction have been reported during ceftriaxone use. Most patients had risk factors for cholestasis and biliary sludge, such as prior extensive therapy, severe illness, or total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone use cannot be excluded as a trigger or cofactor for this complication.

Nephrolithiasis.

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Adverse reactions"). Ultrasound examination is recommended if symptoms occur. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician, considering the benefit-risk ratio in each individual case.

Encephalopathy.

Cases of encephalopathy have been reported during ceftriaxone use (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of medicinal product.

Environmental contamination should be minimized. The drug should not enter sewage systems or household waste. Unused medicinal product after completion of treatment or expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on its use in pregnant women are limited. 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 when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

Reproductive function studies have shown no evidence of adverse effects on male or female fertility.

Ability to drive or operate machinery.

Appropriate studies have not been conducted. Ceftriaxone may affect the ability to drive or operate machinery due to possible adverse reactions such as dizziness.

Method of Administration and Dosage

Before initiating therapy, it is necessary to exclude the presence of hypersensitivity to the antibiotic and to lidocaine (in case of intramuscular administration) by performing a skin test.

The daily dose for adults and children aged 12 years and older is 1–2 g of the drug once daily (every 24 hours). In severe infections or infections caused by pathogens with only moderate sensitivity to ceftriaxone, the daily dose may be increased up to 4 g. For doses exceeding 2 g/day, the drug may be administered twice daily (every 12 hours).

Children

• Neonates (up to 14 days of age) and preterm infants (from 41 weeks of corrected age): 20–50 mg/kg body weight once daily, administered over at least 60 minutes to prevent displacement of bilirubin from albumin binding and reduce the potential risk of bilirubin encephalopathy. Due to immature enzyme systems, the daily dose should not exceed 50 mg/kg body weight. There is no difference in dosing between full-term and preterm infants.

Ceftriaxone is contraindicated in neonates (≤28 days of age) when there is (or expected) need for intravenous calcium-containing solutions, including continuous intravenous calcium infusions such as parenteral nutrition, due to the risk of ceftriaxone-calcium precipitate formation (see section "Contraindications").

• Children aged 15 days to 12 years: 20–80 mg/kg body weight once daily. Doses exceeding 80 mg/kg body weight should be avoided (except in cases of meningitis) due to increased risk of biliary precipitates.
• Children with body weight over 50 kg should receive adult doses.

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

Elderly patients: dosing corresponds to that for adults; dose adjustment is not required provided hepatic and renal function are satisfactory.

Duration of treatment with ceftriaxone depends on the course of the disease. The drug should be continued (as with any antibiotic therapy) for 48–72 hours after disappearance of clinical symptoms and confirmation of therapeutic effect by bacteriological testing.

Combination therapy. Data exist on synergy when ceftriaxone is used concomitantly with aminoglycosides against many Gram-negative microorganisms. Although the enhanced efficacy of such combinations cannot always be predicted, it should be considered in life-threatening infections caused by Pseudomonas aeruginosa. Due to physical incompatibility between ceftriaxone and aminoglycosides, they should be administered separately at recommended doses.

Dosing in special situations.

In bacterial meningitis in infants and children aged 15 days to 12 years, treatment should be initiated at a dose of 100 mg/kg body weight (but not exceeding 4 g) once daily. After pathogen identification and determination of its susceptibility, the dose may be reduced accordingly. For neonates up to 2 weeks of age, the dose should not exceed 50 mg/kg/day.

Optimal treatment outcomes were achieved with the following treatment durations:

Lyme disease: 50 mg/kg (maximum daily dose – 2 g) once daily for 14 days in adults and children.

Gonorrhea (caused by penicillinase-producing and non-penicillinase-producing strains): a single intramuscular dose of 250 mg is recommended.

Prophylaxis of surgical infections.

For prophylaxis of postoperative infections in contaminated or potentially contaminated surgical procedures, a single dose of 1–2 g of ceftriaxone should be administered 30–90 minutes before the start of surgery, depending on the degree of infection risk. For surgery on the colon and rectum, a 5-nitroimidazole agent (e.g., ornidazole) should be administered simultaneously (but separately).

Patients with impaired renal function and normal hepatic function do not require dose reduction. Only in preterminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose not exceed 2 g.

Patients undergoing hemodialysis do not require additional doses after dialysis. Serum ceftriaxone concentrations should be monitored for possible dose adjustment, as elimination may be reduced in these patients.

The daily dose of ceftriaxone in patients undergoing hemodialysis should not exceed 2 g.

Patients with impaired hepatic function and normal renal function do not require dose reduction.

In cases of concomitant severe renal and hepatic impairment, plasma ceftriaxone concentrations should be monitored regularly and dosage adjusted as necessary, as ceftriaxone elimination may be reduced.

Preparation of solutions.

Solutions should be prepared immediately before use. After adding the diluent, visual inspection should be performed to confirm complete dissolution. Depending on concentration and storage duration, the color of solutions may vary from pale yellow to yellow. This property of the active substance does not affect the efficacy or tolerability of the drug.

Ceftriaxone should be administered intravenously or intramuscularly. Intramuscular administration should be considered only if intravenous administration is not feasible or less suitable for the patient. Doses ≥ 2 g should be administered intravenously.

Intramuscular injection.

For intramuscular injection, the contents of a 0.5 g vial of ceftriaxone should be dissolved in 2 mL of 1 % lidocaine solution, and the contents of a 1 g vial in 3.5 mL of 1 % lidocaine solution (after prior sensitivity testing to lidocaine).

The solution should be injected deeply into the center of a relatively large muscle mass, with no more than 1 g administered at one site.

Solutions containing lidocaine must not be administered intravenously! (see section "Contraindications"). For detailed information, refer to the lidocaine instructions for medical use.

Intravenous administration.

For intravenous injection, the contents of a 0.5 g vial should be dissolved in 5 mL of water for injections, and the contents of a 1 g vial in 10 mL of water for injections. Administer slowly over 2–4 minutes.

Intravenous infusion should last at least 30 minutes. To prepare the solution, 2 g of ceftriaxone should be dissolved in 40 mL of one of the following infusion solutions not containing calcium ions:

• 0.9 % sodium chloride solution;
• 5 % glucose solution;
• 0.45 % sodium chloride solution + 2.5 % glucose solution;
• 10 % glucose solution;
• 6 % dextran in 5 % glucose solution;
• sterile water for injections.

Due to possible incompatibility, solutions containing ceftriaxone must not be mixed with solutions containing other antibiotics, either during preparation or administration.

However, 2 g of ceftriaxone and 1 g of ornidazole are physically and chemically compatible in 250 mL of 0.9 % sodium chloride solution or glucose solution.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or to dilute reconstituted solutions for intravenous administration, as precipitation of ceftriaxone-calcium may occur. Formation of ceftriaxone-calcium precipitates may also occur when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Therefore, 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 system. However, in all patients except neonates, ceftriaxone and calcium-containing solutions may be administered sequentially if the infusion system is thoroughly flushed between infusions with a compatible solution (see "Interaction with other medicinal products and other forms of interaction").

Freshly prepared solutions retain their physical and chemical stability for 8 hours at 25 °C and for 24 hours at 2–8 °C.

Children.

The drug should be administered to children according to the dosages specified in the section "Method of administration and dosage."

Overdose.

Symptoms: nausea, vomiting, diarrhea, and increased manifestations of adverse reactions may occur.

Treatment: symptomatic and supportive therapy should be administered. Hemodialysis and peritoneal dialysis are ineffective (do not reduce excessive drug concentrations in plasma). There is no specific antidote.

Adverse Reactions

Gastrointestinal tract: diarrhoea, dyspepsia, nausea, vomiting, stomatitis, glossitis, dysgeusia, abdominal pain, decreased appetite (usually mild, resolve during or after discontinuation of therapy); pancreatitis (possibly due to obstruction of biliary ducts).

Hepatobiliary system: precipitation of calcium salts of ceftriaxone in the gallbladder*; increased levels of bilirubin, liver transaminases, alkaline phosphatase in plasma, hepatic dysfunction, hepatitis¹, cholestatic hepatitis^1,2, kernicterus.

Hematopoietic system: eosinophilia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, granulocytopenia, anemia including hemolytic anemia, prolonged prothrombin time, epistaxis, coagulopathies, agranulocytosis (usually after 10 days of treatment and cumulative dose of ceftriaxone ≥ 20 g).

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

Ears and balance organs: vertigo.

Urinary system: increased blood creatinine levels, cylindruria, glucosuria, hematuria, oliguria, precipitation of ceftriaxone in kidneys (usually reversible), anuria, renal failure, acute tubular necrosis.

Skin and subcutaneous tissue: increased sweating, flushing, allergic skin reactions (including urticaria, dermatitis, maculopapular rash or exanthema), pruritus, multiform exudative erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), acute generalized exanthematous pustulosis.

Cardiovascular system: Kounis syndrome.

Immune system: hypersensitivity reactions, anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, serum sickness, Jarisch-Herxheimer reaction.

Respiratory disorders: bronchospasm, allergic pneumonitis.

Infections and infestations: possible genital fungal infections, superinfection development, pseudomembranous colitis.

General disorders and administration site reactions: phlebitis/thrombophlebitis with intravenous administration, pain and/or infiltration at injection site, drug fever, skin and joint swelling, chills.

Laboratory tests: hyperazotemia, false-positive Coombs test results, galactosemia test results, and glucose in urine when tested by non-enzymatic methods.

¹ Usually reversible upon discontinuation of ceftriaxone
² See section "Special precautions for use"

Infections and infestations.

Diarrhoea following ceftriaxone administration may be associated with overgrowth of Clostridium difficile.

Therapeutic management should include adequate fluid and electrolyte replacement (see section "Special precautions for use").

* Precipitation of calcium salts of ceftriaxone.

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. Post-mortem examinations revealed precipitates of calcium salts of ceftriaxone in 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 for use").

Cases of precipitate formation in kidneys have been reported, primarily in children aged 3 years and older receiving high daily doses (≥ 80 mg/kg/day), cumulative doses exceeding 10 g, or with additional risk factors (limited fluid intake, dehydration, immobility, bed rest). Precipitate formation may be symptomatic or asymptomatic and may lead to renal failure and anuria. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of precipitation of calcium salts of ceftriaxone in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In prospective studies of ceftriaxone in children, the incidence of precipitate formation after intravenous administration varied—over 30% in some studies. Slower infusion (over 20–30 minutes) appears to reduce the incidence of precipitate formation. 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. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Do not mix with other medicinal products in the same syringe or intravenous administration system.

Pharmaceutically incompatible with other antimicrobial agents. Do not mix the reconstituted solution in the same container with other antibiotics or with calcium-containing solutions (such as Hartmann’s or Ringer’s solutions).

Incompatible with amsacrine, vancomycin, fluconazole, labetalol, aminoglycosides, and other antibiotics.

Packaging. Powder for injection solution 500 mg. One vial of powder; one vial per pack; one vial of powder with solvent (water for injection) 5 mL in ampoule in a carton with cardboard divider.

Powder for injection solution 1000 mg. One vial of powder; one vial per pack; one vial of powder with solvent (water for injection) 5 mL or 10 mL in ampoule in a carton with cardboard divider; one vial of powder with solvent (lidocaine hydrochloride injection solution, 10 mg/mL) 3.5 mL in ampoule in a carton with cardboard divider.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company “Scientific and Production Center “Boryspil Chemical and Pharmaceutical Plant”.

Manufacturer’s address.

17 Myru Street, Kyiv, 03134, Ukraine.