Ceftriaxone-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRIAXONE-DARNITSA (CEFTRIAXONE-DARNITSA)

Composition:

Active substance: ceftriaxone;

1 vial contains 0.5 g or 1 g of sodium ceftriaxone salt, calculated as ceftriaxone.

Excipients: none.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder of almost white or yellowish color.

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

ATC code J01DD04.

Pharmacological properties.

Pharmacodynamics.

Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action.

Microbiology. 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 is highly stable against most β-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria. Ceftriaxone is active in vitro against the following microorganisms and in clinical infections (see section "Indications"):

Gram-positive aerobes. Staphylococcus aureus (methicillin-susceptible), coagulase-negative staphylococci, Streptococcus pyogenes (β-hemolytic, group A), Streptococcus agalactiae (β-hemolytic, group B), β-hemolytic streptococci (groups neither A nor B), Streptococcus viridans, Streptococcus pneumoniae. Methicillin-resistant Staphylococcus spp., which are resistant to cephalosporins, including ceftriaxone, are not susceptible. 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, alcaligenes-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, 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. (non-typhoidal), Serratia marcescens**, Serratia spp. (others)*, Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others).

* Some isolates of these species are resistant to ceftriaxone, primarily due to chromosomally mediated 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 exhibit multiple resistance to antibiotics such as aminopenicillins and ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain susceptible 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. With the exception of clinical strains of P. aeruginosa, which are resistant to ceftriaxone.

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

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

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

Susceptibility to ceftriaxone can be determined by the disk diffusion method or by serial dilution methods on agar or broth, using standardized techniques similar to those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The NCCLS has established the following criteria for interpreting susceptibility test results for ceftriaxone:

Table 1.

	Susceptible	Intermediate	Resistant
Dilution method Inhibitory concentration, mg/l	≤ 8	16–32	≥ 64
Disc method (disc with 30 μg ceftriaxone) Diameter of inhibition zone, mm	≥ 21	20–14	≤ 13

To determine microbial susceptibility, ceftriaxone-containing discs should be used, since in vitro studies have shown that ceftriaxone is active against certain strains resistant when tested with discs intended for the entire cephalosporin group.

Instead of NCCLS standards for determining microbial susceptibility, other well-standardized guidelines such as DIN and ICS may also be used, allowing adequate assessment of susceptibility levels.

Pharmacokinetics.

The pharmacokinetics of ceftriaxone are nonlinear. All major pharmacokinetic parameters based on total drug concentrations, except for half-life, are dose-dependent.

Absorption. Maximum plasma concentration after a single intramuscular injection of 1 g of the drug is 81 mg/L, achieved within 2–3 hours after administration. Single intravenous infusions of 1 g and 2 g of the drug result in plasma concentrations of 168.1 ± 28.2 mg/L and 256.9 ± 16.8 mg/L, respectively, after 30 minutes. The area under the plasma concentration-time curve after intravenous administration is equivalent to that after intramuscular administration. This indicates that the bioavailability of ceftriaxone after intramuscular injection is 100%.

Distribution. The volume of distribution of ceftriaxone ranges from 7 to 12 L. After administration at doses of 1–2 g, ceftriaxone penetrates well into tissues and body fluids. For over 24 hours, its concentrations exceed the minimum inhibitory concentrations for most pathogens by more than 60-fold in over 60 tissues and fluids (including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions).

Following intravenous administration, ceftriaxone rapidly penetrates into cerebrospinal fluid, where bactericidal concentrations against susceptible microorganisms are maintained for 24 hours.

Protein binding. Ceftriaxone reversibly binds to albumin, with the extent of binding decreasing as concentration increases—for example, decreasing from 95% at plasma concentrations below 100 mg/L to 85% at 300 mg/L. Due to lower albumin concentrations in tissue fluid, the fraction of free (unbound) ceftriaxone is higher in tissue fluid than in plasma.

Penetration into specific tissues. Ceftriaxone crosses inflamed meninges in children, including neonates. Twenty-four hours after intravenous administration of ceftriaxone at doses of 50–100 mg/kg body weight (for neonates and infants, respectively), ceftriaxone concentrations in cerebrospinal fluid exceed 1.4 mg/L. Maximum concentrations in cerebrospinal fluid are reached approximately 4 hours after intravenous administration and average about 18 mg/L. In bacterial meningitis, the average concentration of ceftriaxone in cerebrospinal fluid is 17% of the plasma concentration; in aseptic meningitis, it is 4%. In adults with meningitis, administration of a dose of 50 mg/kg body weight results in cerebrospinal fluid concentrations 2–24 hours later that are many times higher than the minimum inhibitory concentrations for the most common causative agents of meningitis.

Ceftriaxone crosses the placental barrier and passes into breast milk in low concentrations.

Metabolism. Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.

Excretion. Total plasma clearance of ceftriaxone is 10–22 mL/min. Renal clearance is 5–12 mL/min. Approximately 50–60% of ceftriaxone is excreted unchanged by the kidneys and 40–50% unchanged via bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours.

Pharmacokinetics in special clinical situations. In neonates, approximately 70% of the dose is excreted by the kidneys. In children during the first 8 days of life, as well as in patients aged 75 years and older, the elimination half-life is on average 2–3 times longer than in younger adults.

In patients with renal or hepatic impairment, the pharmacokinetics of ceftriaxone are only slightly altered, with only a minor increase in half-life observed. If only renal function is impaired, biliary excretion increases; if hepatic function is impaired, renal excretion increases.

Clinical characteristics.

Indications.

Ceftriaxone-Darnitsia is indicated for the treatment of infections caused by microorganisms sensitive to ceftriaxone:

• respiratory tract infections, particularly pneumonia, as well as ear, throat, and nose infections;
• intra-abdominal infections (peritonitis, infections of the 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 immunocompromised patients;
• meningitis;
• disseminated Lyme disease (stages II and III).

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

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

Contraindications.

Hypersensitivity to ceftriaxone or any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated:

In preterm newborns aged ≤ 41 weeks, calculated from gestational age plus postnatal age. In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin encephalopathy in such patients.

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

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

Prior to intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the instructions for medical use of lidocaine, particularly contraindications.

Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Calcium-containing solvents, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of the medicinal product in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type connector. However, in patients other than 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 and neonatal umbilical plasma have shown that newborns are at increased risk of ceftriaxone calcium salt precipitate formation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

Aminoglycosides. Conflicting data exist regarding the potential enhancement of nephrotoxic effects 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.

Nonsteroidal anti-inflammatory drugs, antiplatelet agents, vitamin K antagonists (e.g., warfarin): increased risk of bleeding.

Concomitant use of the medicinal product with oral anticoagulants may enhance the anti-vitamin K 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 appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").

Loop diuretics and nephrotoxic medicinal products – increased risk of nephrotoxicity. No renal function impairment has been observed after concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Antibacterial bacteriostatic agents (chloramphenicol, tetracyclines): may reduce the bactericidal effect of ceftriaxone. In vitro studies have shown antagonistic effects when chloramphenicol was used in combination with ceftriaxone. The clinical significance of these findings is unknown.

Hormonal contraceptives: reduced efficacy of hormonal contraceptives; therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after its completion.

Other β*-lactam antibiotics:* possible development of cross-allergic reactions.

After administration of ethanol, no disulfiram-like effects were observed immediately after ceftriaxone administration.

Ceftriaxone contains an N-methylthiotetrazole group, which may lead to ethanol intolerance or bleeding, as seen with some other cephalosporins.

Probenecid: does not affect tubular secretion of ceftriaxone (unlike other cephalosporins).

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

Ceftriaxone-Darnitsia solution must not be mixed or administered simultaneously with other antimicrobial medicinal products due to pharmaceutical incompatibility.

Ceftriaxone is incompatible and must not be mixed with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Special precautions for use.

Hypersensitivity reactions.

As with all β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). In the event of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to ascertain whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of β-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other β-lactam medicinal products.

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

Jarisch-Herxheimer reaction.

In patients with infections caused by spirochetes, a Jarisch-Herxheimer reaction may occur immediately after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is generally self-limiting or can be managed with symptomatic treatment. Ceftriaxone therapy need not be discontinued if this reaction occurs.

Interaction with calcium-containing medicinal products.

In preterm and full-term neonates under 1 month of age, cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys, sometimes fatal, have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitates except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, 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 replaced with a saline flush between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous nutrition 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", "Side effects", 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". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

The medicinal product is contraindicated in preterm and full-term newborns at risk of developing bilirubin encephalopathy (see section "Contraindications").

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported during ceftriaxone treatment in both adults and children.

If anemia develops in a patient during ceftriaxone therapy, cephalosporin-associated anemia 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 may prolong prothrombin time. Therefore, in suspected vitamin K deficiency, prothrombin time should be monitored.

Colitis/overgrowth of resistant microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported during therapy with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. It is therefore important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant to the drug (e.g., enterococci and Candida strains) may occur.

Ceftriaxone should be used with caution in patients with a history of gastrointestinal disorders, particularly colitis.

Severe renal and hepatic impairment.

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

Effect on serological test results.

Ceftriaxone may cause false-positive results in the Coombs test. The medicinal product may also cause false-positive results in galactosemia screening tests (see section "Side effects").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During ceftriaxone therapy, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").

Sodium.

Each gram of the medicinal product contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate as monotherapy for certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant microorganisms are suspected, 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 specified in the lidocaine medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

If shadows are observed on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency during ceftriaxone therapy at doses of 1 g/day or higher. Particular caution should be exercised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, precipitation of ceftriaxone calcium salt is associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Side effects").

Cholestasis.

Cases of pancreatitis, possibly due to biliary obstruction, have been reported in patients receiving ceftriaxone (see section "Side effects"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, or total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone use cannot be excluded as an initiating or contributing factor in the development of this condition.

Nephrolithiasis.

Cases of kidney stone formation, resolving after discontinuation of ceftriaxone, have been reported (see section "Side effects"). In symptomatic cases, ultrasound examination should be performed. The decision to use the medicinal product in patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment for each individual case.

Unused medicinal product and/or waste material should be disposed of in accordance with regulatory requirements for medicinal product disposal.

Encephalopathy risk.

Cases of encephalopathy have been reported during ceftriaxone use (see section "Side effects") in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders.

If encephalopathy is suspected to be related to ceftriaxone use (e.g., decreased level of consciousness, changes in mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected 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 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 not shown evidence of adverse effects on male or female fertility.

Ability to influence the speed of reactions when driving or operating machinery.

Appropriate studies have not been conducted. Due to the possibility of side effects such as dizziness, ceftriaxone may affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage.

Adults and children aged 12 years and older: administer 1–2 g of ceftriaxone 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.

Newborns, infants, and children under 12 years of age.

The recommended once-daily dosages are listed below.

Newborns up to 2 weeks of age: 20–50 mg/kg body weight once daily; 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 aged ≤ 28 days who require (or are expected to require) intravenous infusions containing calcium, including continuous intravenous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications").

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

Children weighing more than 50 kg should receive adult doses.

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

Elderly patients.

Dosage adjustment is not required for elderly patients.

Duration of treatment.

The duration of therapy depends on the indication and course of the disease.

Combination therapy.

Studies have shown synergism between ceftriaxone and aminoglycosides against many Gram-negative bacteria. Although increased efficacy of such combinations cannot always be predicted, it should be considered in cases 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.

For bacterial meningitis in infants and children aged 15 days to 12 years, initiate treatment with a dose of 100 mg/kg (but not exceeding 4 g) once daily. Once the causative organism is identified and its susceptibility determined, the dose may be adjusted accordingly. Optimal treatment durations have been as follows:

Table 2.

Neisseria meningitidis	4 days
Haemophilus influenzae	6 days
Streptococcus pneumoniae	7 days

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

Gonorrhea.

For treatment of gonorrhea (caused by penicillinase-producing and non-penicillinase-producing strains), a single intramuscular dose of 250 mg is recommended.

Prophylaxis of infections in surgery.

For prophylaxis of postoperative infections in contaminated or potentially contaminated surgical procedures, a single dose of 1–2 g of ceftriaxone is recommended to be administered 30–90 minutes before the start of surgery, depending on the degree of infection risk. For surgery on the colon and rectum, concomitant administration of ceftriaxone and one of the 5-nitroimidazoles (e.g., ornidazole) has proven effective.

Renal and hepatic impairment.

In patients with renal impairment, dose reduction is not necessary if hepatic function remains normal. Only in pre-terminal renal failure (creatinine clearance less than 10 ml/min), the daily dose should not exceed 2 g.

In patients undergoing dialysis, there is no need for additional drug administration after dialysis. However, serum ceftriaxone concentrations should be monitored, as elimination may be reduced in these patients. The daily dose of the drug in patients on dialysis should not exceed 2 g.

In patients with hepatic impairment, dose reduction is not necessary if renal function remains normal.

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

Preparation of solutions.

Reconstituted solutions should be used immediately after preparation.

Intramuscular injection.

For intramuscular injection, 0.5 g should be dissolved in 2 ml of sterile water for injection, and 1 g should be dissolved in 3.5 ml of 1% lidocaine solution; the injection should be administered into the center of the gluteal muscle. No more than 1 g should be injected at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, it is recommended to refer to the lidocaine instructions for medical use.

The use of lidocaine requires prior testing for individual sensitivity to this medicinal product.

Intravenous injection.

For intravenous injection, 0.5 g of ceftriaxone should be dissolved in 5 ml of sterile water for injection, and 1 g of ceftriaxone in 10 ml of 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 2 g of the drug 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 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.

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. The drug must not be administered intravenously simultaneously with calcium-containing solutions, including prolonged infusions containing calcium, such as parenteral nutrition. However, except in neonates, ceftriaxone and calcium-containing solutions may be administered sequentially if the infusion system is thoroughly flushed between infusions with a compatible solution (see section "Interaction with other medicinal products and other types of interactions").

Children.

The drug can be administered to children according to the dosing regimen specified in the section "Dosage and administration".

Overdose.

Symptoms: nausea, vomiting, diarrhea, abdominal pain, leukopenia, thrombocytopenia, acute hemolytic anemia, skin, gastrointestinal and hepatic reactions, dyspnea, renal failure, stomatitis, anorexia, transient hearing loss, disorientation.

Treatment: symptomatic and supportive therapy. There is no specific antidote. Hemodialysis and peritoneal dialysis are ineffective.

Adverse Reactions

Auditory and vestibular system disorders: vertigo.

Respiratory, thoracic and mediastinal disorders: possible hypersensitivity reactions of the respiratory tract, including respiratory distress, swelling of the airways, bronchospasm.

Gastrointestinal disorders: stomatitis, glossitis, unformed stools or diarrhea, nausea, vomiting, pancreatitis (possibly due to obstruction of the bile ducts). These adverse reactions are usually mild and often resolve during or after discontinuation of treatment. Cases of pseudomembranous colitis and diarrhea following ceftriaxone administration are mostly caused by Clostridium difficile.

Most of these patients had risk factors for biliary stasis, such as prior surgery, severe illness, or total parenteral nutrition.

The role of ceftriaxone-induced precipitates in the biliary tract in the development of pancreatitis cannot be excluded.

Hepatobiliary disorders: increased serum liver enzymes (AST, ALT, alkaline phosphatase), nuclear jaundice, hepatitis, and cholestatic hepatitis, which are usually reversible upon discontinuation of ceftriaxone (see section "Special precautions for use"). Precipitation of ceftriaxone calcium salt in the gallbladder has been observed (most frequently in patients receiving doses exceeding the recommended standard dose), reversible cholelithiasis in children. In prospective studies in children, various rates of precipitate formation were observed with intravenous administration of the drug, exceeding 30% in some studies. The frequency of precipitate formation is lower when slow infusion (20–30 minutes) is used. This effect is usually asymptomatic, but in rare cases precipitation is accompanied by clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitation is generally reversible after discontinuation of ceftriaxone.

Renal and urinary disorders: oliguria, glucosuria, hematuria. Renal precipitates, primarily in children aged 3 years and older, who were treated with the highest daily doses (80 mg/kg/day and higher) or total doses exceeding 10 g, as well as those with other risk factors such as dehydration or immobilization. Renal precipitate formation may be asymptomatic or clinically evident and is reversible after discontinuation of ceftriaxone. Anuria and renal function impairment have been reported in connection with this.

Nervous system disorders: headache, dizziness, convulsions. There have been reports of convulsions occurring in young children treated with the drug. Encephalopathy is possible, though rare.

Blood and lymphatic system disorders: neutropenia, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia (including hemolytic anemia), prolonged prothrombin time, coagulation disorders, agranulocytosis. Blood counts should be monitored regularly during prolonged therapy.

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

Skin and subcutaneous tissue disorders: allergic skin reactions such as erythema, rash (including maculopapular), urticaria, allergic dermatitis, pruritus, swelling. Multiform erythema, Stevens-Johnson syndrome, Lyell syndrome/toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and rarely, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

General disorders and administration site conditions: chills, pyrexia, increased sweating; erythema, rash, swelling, pruritus, phlebitis, and pain at the injection site may occur after intravenous administration, which can be minimized by slow injection over at least 2–4 minutes. Intramuscular injection without lidocaine is painful.

Infections: genital fungal infections, possible superinfection at various sites caused by yeasts, fungi, or other resistant microorganisms.

Laboratory findings: increased blood creatinine levels, false-positive Coombs test. Like other antibiotics, ceftriaxone may cause false-positive results in galactosemia screening tests. False-positive results may also occur in urine glucose testing; therefore, during treatment with Ceftriaxone-Darnitsia, urine glucose should be tested by enzymatic methods only, if necessary.

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

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or in dehydrated patients. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Cases of ceftriaxone calcium salt precipitate formation in the gallbladder have been reported, primarily in patients who received doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation with intravenous administration of the drug, exceeding 30% in some studies. The frequency of precipitate formation appears to be lower with slow administration (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product registration is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

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.

Ceftriaxone-Darnitsia must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution. Calcium-containing solutions should also not be administered within 48 hours after the last dose of the drug.

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

Do not mix with other solvents except those specified in the section "Dosage and administration".

Packaging.

0.5 g or 1 g of powder in a vial; 1, 5, or 40 vials per package. One vial containing 0.5 g of powder and one ampoule of solvent (Water for Injections-Darnitsia, 5 ml ampoule) per package. One vial containing 1 g of powder and one ampoule of solvent (Water for Injections-Darnitsia, 10 ml ampoule) per package.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsia".

Manufacturer's address and location of business activity.

13 Borispilska Street, Kyiv, 02093, Ukraine.