Denicef

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DENICEF (DENICEF)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone (in the form of ceftriaxone sodium) 1 g;

Excipients: none.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.
Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01DD04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, biosynthesis of the cell wall (peptidoglycan) is halted, leading to bacterial cell lysis and death.

Resistance

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

• Hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacteria.
• Reduced affinity of penicillin-binding proteins for ceftriaxone.
• Decreased outer membrane permeability in Gram-negative bacteria.
• Bacterial efflux pumps.

Clinical breakpoints for susceptibility testing

The minimum inhibitory concentration (MIC) clinical breakpoints have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a. Susceptibility conclusion was based on susceptibility to cefoxitin.

b. Susceptibility conclusion was based on susceptibility to penicillin.

c. Isolates with minimal inhibitory concentrations exceeding susceptibility breakpoints are rare; if observed, repeat testing should be performed and, if confirmed, isolates should be sent to a reference laboratory.

d. Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose, at least 2 g × 1.

Generally susceptible species

Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.

Gram-negative aerobes

Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.

Species for which acquired resistance may be an issue

Gram-positive aerobes

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

Gram-negative aerobes

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

Anaerobes

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

Inherently resistant microorganisms

Gram-positive aerobes

Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes

Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes

Clostridium difficile.

Others

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

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

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

Pharmacokinetics.

Absorption

Intramuscular administration

After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration (Cmax) after a single intramuscular dose of 1 g is 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration–time curve (AUC) after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus injection of 1 g ceftriaxone, the mean peak plasma concentration is approximately 200 mg/L. After intravenous infusion of 1 g ceftriaxone, the plasma concentration is approximately 150 mg/L.

Distribution

The volume of distribution of ceftriaxone is 7–12 L. Concentrations exceeding the minimal inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions. An 8–15% increase in mean Cmax was observed upon repeated administration; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence is expected in low concentrations in breast milk (see section "Use in pregnancy or lactation").

Protein binding

Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the extent of binding decreases with increasing concentration (to 85% at a plasma concentration of 300 mg/L).

Metabolism

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

Elimination

Total plasma clearance of ceftriaxone (bound and unbound) is 10–22 mL/min. Renal clearance is 5–12 mL/min. 50–60% of ceftriaxone is excreted unchanged by the kidneys, primarily via glomerular filtration, and 40–50% is excreted unchanged in bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours.

Patients with renal or hepatic impairment

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The moderate increase in half-life in renal impairment is explained by compensatory increase in extrarenal clearance due to reduced protein binding and the corresponding increase in total extrarenal clearance of ceftriaxone.

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

Geriatric patients

In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times longer than in younger adults.

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as decreased glomerular filtration and impaired protein binding. In children, the elimination half-life is shorter than in neonates or adults.

Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.

Linearity/Non-linearity

The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it is observed for total ceftriaxone in plasma, but not for free (unbound) ceftriaxone.

Pharmacokinetic/Pharmacodynamic relationship

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index that best correlates with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimal inhibitory concentration of ceftriaxone for specific target organisms (i.e., % T > minimal inhibitory concentration).

Clinical characteristics.

Indications.

Ceftriaxone is indicated for the treatment of the following infections in adults and children, including full-term newborns (from birth):

• bacterial meningitis;
• community-acquired pneumonia;
• hospital-acquired pneumonia;
• acute otitis media;
• intra-abdominal infections;
• complicated urinary tract infections (including pyelonephritis);
• bone and joint infections;
• complicated skin and soft tissue infections;
• gonorrhea;
• syphilis;
• bacterial endocarditis.

Ceftriaxone may be used for:

• treatment of acute exacerbations of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme disease [early (Stage II) and late (Stage III)] in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of infection at the site of intervention;
• management of neutropenic patients who develop fever suggestive of bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections, or when there is suspicion of any of the above-mentioned infections.

Ceftriaxone should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by the spectrum of ceftriaxone (see section "Special precautions").

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

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).

Ceftriaxone is contraindicated:

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

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

− with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired in these conditions*;

− who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone calcium salt (see sections "Special precautions", "Adverse reactions").

*In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in such patients.

Before intramuscular injection of ceftriaxone, contraindications to lidocaine must be ruled out if lidocaine is used as a solvent (see section "Special precautions"), see the instructions for medical use of lidocaine, particularly contraindications.

Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Special precautions.

Environmental release of the medicinal product should be minimized. Avoid contamination of sewage systems or household waste.

Interaction with other medicinal products and other types of interactions.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Denicef 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-site 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. In vitro studies using adult and neonatal cord plasma have shown an increased risk of ceftriaxone calcium salt precipitation in newborns (see sections "Contraindications", "Special precautions", "Dosage and administration", "Adverse reactions", and "Incompatibilities").

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

Conflicting data exist regarding the potential for increased nephrotoxic effect 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.

An in vitro study using chloramphenicol in combination with ceftriaxone showed antagonistic effects. The clinical significance of these findings is unknown.

No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral use).

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

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

Similarly, when glucose in urine is tested by non-enzymatic methods, results may be falsely positive. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

No renal function impairment has been observed following concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions.

Hypersensitivity reactions

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Coombs syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, administration of 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 beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

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

Interaction with calcium-containing medicinal products

In preterm and full-term neonates up to 1 month of age, cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys with fatal outcomes have been described. 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 formation in patients other than 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 separate infusion systems or different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through separate infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents that do not carry a similar risk of precipitate formation. If ceftriaxone administration is deemed necessary in patients requiring continuous parenteral nutrition, 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 Denicef in neonates, infants, and children have been established with doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like certain other cephalosporins, may displace bilirubin from binding to serum albumin.

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

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

Prolonged treatment

During prolonged treatment, a complete blood count should be monitored regularly.

Colitis/overgrowth of resistant microorganisms

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported during treatment with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is 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 agents should not be used.

As with other antibacterial agents, superinfections 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 Denicef therapy, the Coombs test may yield false-positive results. Denicef may also cause false-positive results in galactosemia testing (see section "Side effects").

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

Sodium

One gram of Denicef contains 3.6 mmol (83 mg) 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 for use as monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant organisms 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 provided in the lidocaine product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis

On ultrasound imaging, shadows should prompt consideration of ceftriaxone calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in the gallbladder on ultrasound, with increased frequency at ceftriaxone doses of 1 g per day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, precipitation of ceftriaxone calcium salt is symptomatic. In symptomatic cases, conservative, non-surgical treatment is recommended. The physician should decide whether to discontinue the drug based on a benefit-risk assessment in the individual case (see section "Side effects").

Biliary stasis

Cases of pancreatitis, possibly due to biliary tract 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 treatment, severe illness, or total parenteral nutrition. Precipitation in the biliary tract due to Denicef administration cannot be excluded as a triggering or contributing factor in the development of this condition.

Nephrolithiasis

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). In case of symptoms, ultrasound examination should be performed. The decision to administer the drug to patients with a history of kidney stones or hypercalciuria should be made by the physician after individual benefit-risk assessment.

Jarisch-Herxheimer reaction (JHR)

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur shortly after initiation of ceftriaxone therapy. JHR is usually self-limiting or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued if JHR occurs.

Encephalopathy

Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), 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.

Use during pregnancy or breastfeeding

Pregnancy

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

Lactation

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 developing diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

During ceftriaxone therapy, side effects such as dizziness may occur, which could impair the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.

Administration and Dosage

Dosage

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

Recommended dosages for indications are listed below. In particularly severe cases, the highest dose within the recommended range should be used.

Adults and children aged 12 years and older (≥50 kg)

*In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

**When doses exceeding 2 g daily are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).

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

Acute otitis media

A single intramuscular dose of 1–2 g of Denicef may be administered.

Some data suggest that Denicef may be effective at a dose of 1–2 g once daily administered intramuscularly for 3 days in severe cases or when prior therapy has been ineffective.

Preoperative prophylaxis of surgical site infections

Single dose of 2 g administered before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

Recommended dose is 500 mg–1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.

Lyme disease (disseminated) [early (Stage II) and late (Stage III)]

2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Children

Neonates, infants, and children aged 15 days to 12 years (˂50 kg)

Children with body weight ≥ 50 kg should receive the standard adult doses.

*In cases of documented bacteremia, consideration should be given to using the highest dose within the recommended range.

**When doses exceeding 2 g per day are used, consider administering the drug twice daily (with a 12-hour interval).

Indications in newborns, infants, and children aged 15 days to 12 years (˂ 50 kg) requiring special dosing regimens:

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Denicef at a dose of 50 mg/kg may be used. Some data suggest that in cases where the child's condition is severe or previous therapy has been ineffective, Denicef may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

Recommended doses are 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.

Disseminated Lyme borreliosis [early (Stage II) and late (Stage III)]

50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.

Newborns aged 0–14 days

Denicef is contraindicated in preterm newborns with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

*In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.

The maximum daily dose of 50 mg/kg should not be exceeded.

Indications in newborns aged 0–14 days requiring special dosing regimens:

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Denicef at a dose of 50 mg/kg may be used.

Preoperative prophylaxis of surgical site infections

20–50 mg/kg as a single dose before surgery.

Syphilis

The recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Duration of treatment

The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone treatment should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

In patients with normal renal and hepatic function, dose adjustment is not required in the elderly.

Patients with hepatic impairment

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

There are no data from studies in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

Dose reduction of ceftriaxone is not required in patients with impaired renal function, provided renal function is not severely compromised. Only in cases of preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.

There is no need for additional doses in patients undergoing dialysis after dialysis. Ceftriaxone is not removed by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

In cases of concomitant severe hepatic and renal dysfunction, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Route of administration

Intramuscular administration

Denicef can be administered by deep intramuscular injection. The injection should be given into the center of a relatively large muscle mass. It is recommended not to inject more than 1 g 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, refer to the lidocaine package insert.

Intravenous administration

Denicef can be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over not more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special warnings and precautions for use"). Intramuscular administration should be considered when intravenous access is not feasible or less acceptable to the patient. Doses exceeding 2 g should be administered intravenously.

Ceftriaxone is contraindicated in neonates (≤ 28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including intravenous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone calcium salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or to further dilute the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").

For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes before surgery.

Reconstitution instructions

For intramuscular injection, reconstitute:

• 1 g with 3.5 mL of 1% lidocaine solution.

For intravenous injection, reconstitute:

• 1 g with 10 mL of water for injections.

Freshly prepared solutions for injection are recommended. The prepared solution (with 1% lidocaine hydrochloride as solvent) is stable for 24 hours when stored at 2–8 °C or for 6 hours when stored at 15–25 °C.

Do not mix the ceftriaxone solution in the same syringe with any other medicinal products except 1% lidocaine hydrochloride solution (for intramuscular injections only).

The infusion line must be flushed after each administration.

Children.

The drug is administered to children according to the dosing regimen specified in the section "Method of administration and dosage."

Overdose.

In case of overdose, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.

Side effects

The most commonly observed adverse reactions during the use of ceftriaxone are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

The frequency of adverse reactions to ceftriaxone was determined based on data from clinical trials.

Events are classified by frequency as follows:

• very common (≥ 1/10);
• common (≥ 1/100, < 1/10);
• uncommon (≥ 1/1000, < 1/100);
• rare (≥ 1/10,000, < 1/1000);
• frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous colitis^b; frequency not known^a – superinfections^b.

Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not known^a – hemolytic anemia^b, agranulocytosis.

Cardiac disorders: frequency not known^a – Kounis syndrome^b.

Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch–Herxheimer reaction^b.

Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not known^a – seizures.

Ear and labyrinth disorders: frequency not known^a – vertigo.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – diarrhea^b, loose stools; uncommon – nausea, vomiting; frequency not known^a – pancreatitis^b, stomatitis, glossitis.

Hepatobiliary disorders: common – elevated liver enzymes; frequency not known^a – biliary precipitates^b, kernicterus, hepatitis^c, cholestatic hepatitis^b,c.

Skin and subcutaneous tissue disorders: common – rash; uncommon – pruritus; rare – urticaria; frequency not known^a – Stevens–Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)^b.

Renal and urinary disorders: rare – hematuria, glucosuria; frequency not known^a – oliguria, renal precipitates (reversible).

General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – edema, chills.

Investigations: uncommon – increased blood creatinine levels; frequency not known^a – false-positive Coombs test^b, false-positive galactosemia test^b, false-positive non-enzymatic glucose tests^b.

^a Based on post-marketing reports. Since information on these reactions is voluntarily reported and the number of patients is not defined, it is not possible to reliably estimate their frequency; therefore, frequency is categorized as "not known".

^b See section "Special precautions for use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations

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

Ceftriaxone calcium salt precipitates

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 ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Contraindications" and "Special precautions for use").

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

Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation following intravenous administration, with some studies reporting over 30%. The incidence is 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. Precipitates typically 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 continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Keep out of reach of children.

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

The reconstituted solution should be used within 6 hours at room temperature or within 24 hours when stored at 2–8 °C.

Incompatibilities.

Denicef is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Denicef must not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". Denicef must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, due to the potential for precipitate formation. Denicef must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Special precautions for use", "Dosage and administration", and "Side effects").

For combination with other antibiotics, separate syringes or solutions should be used.

Packaging.

1 g of powder for injection solution in a vial, 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer’s address and place of business.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing authorization holder.

Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.