Dyacef

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

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg.

Pharmaceutical form.

Powder for solution for injection.

Main physicochemical properties: crystalline powder from almost white to yellowish-white in color.

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

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

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

Breakpoints for susceptibility testing

Breakpoints for minimal inhibitory concentration have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a. the conclusion on susceptibility is based on susceptibility to cefoxitin;

b. the conclusion on susceptibility is based on susceptibility to penicillin;

c. isolates with minimal inhibitory concentrations exceeding the susceptibility breakpoints are rarely observed. If such isolates are detected, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory;

d. the breakpoints refer to a daily intravenous dose of 1 g × 1 and high dose of 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 a problem

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 after a single intramuscular dose of 1 g is 81 mg/L and is reached within 2–3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

Intravenous administration

After intravenous bolus administration of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.

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, and nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated administration; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues

Ceftriaxone penetrates the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid are achieved 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 during pregnancy or breastfeeding").

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 degree of binding decreases as concentration increases (to 85% at a plasma concentration of 300 mg/L).

Biotransformation

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

Elimination

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

Patients with renal or hepatic impairment

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

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

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

Elderly 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 reduced glomerular filtration and impaired protein binding. In older 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 to a lesser extent than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and thus 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.

Dyacef 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.

Dyacef may be used for:

• treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
• treatment of disseminated Lyme borreliosis (early (Stage II) and late (Stage III)) in adults and children, including newborns aged 15 days and older;
• surgical prophylaxis of surgical site infections;
• management of patients with neutropenia 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.

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

Official recommendations on 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 under these conditions*
• who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone calcium salt (see sections "Special precautions" and "Side effects").

* 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.

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

Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Dyacef 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 infusion system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown an increased risk of ceftriaxone calcium salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Side effects", "Incompatibilities").

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

There are conflicting data regarding the potential for increased nephrotoxic effect of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.

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

No cases of interaction between ceftriaxone and orally administered calcium-containing products or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration) have been reported.

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

Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia testing.

Similarly, false-positive results may occur when glucose in urine is tested by non-enzymatic methods. For this reason, enzymatic methods should be used to determine glucose levels in urine during ceftriaxone therapy.

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

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Coombs' syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). 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 determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

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

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 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, confirmed cases of intravascular precipitation have not been reported 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 different infusion systems or different infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the drugs are administered through separate infusion systems at different body sites, or that the infusion system is thoroughly flushed with physiological saline solution between administrations to prevent precipitation. 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 precipitation. If ceftriaxone use in patients requiring continuous TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", "Pharmacokinetics", and "Incompatibilities").

Children.

The safety and efficacy of Diacef have been established in neonates, infants, and children at 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.

Diacef 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 Diacef (see section "Adverse reactions"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported during ceftriaxone treatment in both adults and children.

If anemia develops 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 performed regularly.

Colitis/overgrowth of resistant microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported with nearly all antibacterials, 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 "Adverse reactions"). 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 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.

When using Diacef, the Coombs test may yield false-positive results. Diacef may also cause false-positive results in galactosemia testing (see section "Adverse reactions").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Diacef therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Adverse reactions").

Sodium.

Each gram of Diacef contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-restricted 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, the use of 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, shadows should raise suspicion of ceftriaxone calcium salt precipitation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in gallbladder ultrasounds, with increased frequency during ceftriaxone administration at doses of 1 g/day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone calcium salt has been 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 "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly due to obstruction of biliary tracts, have been reported in patients receiving Diacef (see section "Adverse reactions"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, or total parenteral nutrition. The formation of precipitates in the biliary tract due to Diacef administration cannot be excluded as an initiating or contributing factor in these events.

Nephrolithiasis.

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

Encephalopathy.

Encephalopathy has been reported during ceftriaxone therapy (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 unused or expired medicinal product:
Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out via a dedicated "waste collection system" where available.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected with 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/abandon ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

Reproductive function studies have not shown any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

During ceftriaxone therapy, adverse reactions such as dizziness may occur, which could affect the ability to drive or operate machinery (see section "Adverse reactions"). Patients should exercise caution when driving or operating machinery.

Dosage and Administration

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.

The doses listed below are general recommendations for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

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

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

** When doses exceeding 2 g per day 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 Dacef may be administered.

Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Dacef may be effective when given intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative prophylaxis of surgical site infections

A single dose of 2 g before surgery.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

The generally recommended doses are 500 mg – 1 g once daily, with dose escalation 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.

Disseminated Lyme borreliosis (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 weighing 50 kg or more should receive the standard adult doses.

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

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

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 Diacef at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Diacef 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

The generally recommended dosage is 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.

Neonates aged 0–14 days

Diacef is contraindicated in preterm neonates 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 must 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 Diacef at a dose of 50 mg/kg may be used.

Prophylaxis of surgical site infections

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

Syphilis

The generally 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 principles of antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or after confirmation of eradication of the bacterial infection.

Elderly patients

If renal and hepatic functions are adequate, dose adjustment in elderly patients is not required.

Patients with hepatic impairment

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

There are no study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the drug's safety and efficacy is recommended.

Patients with severe hepatic and renal dysfunction

In cases of concomitant severe impairment of both renal and hepatic function, careful clinical monitoring of the drug's safety and efficacy is recommended.

Administration method

Intramuscular administration

Diacef can be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle. 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 prescribing information.

Prior to using lidocaine, a sensitivity test should be performed to determine individual susceptibility to this medicinal product.

Intravenous administration

Diacef can be administered by intravenous infusion over at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). Intramuscular administration should be considered only when intravenous administration is not feasible or less suitable for 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 intravenous calcium-containing solutions, including infusion solutions 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 dissolve ceftriaxone in vials or for further dilution of 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 precautions," and "Incompatibilities").

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

Children.

The drug should be administered to children according to the dosing instructions specified in the section "Administration and dosage."

Overdose.

In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis do not effectively reduce excessive plasma concentrations of the drug. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse Reactions.

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

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

Events are classified by frequency as follows:

very common (≥ 1/10);

common (≥ 1/100 to < 1/10);

uncommon (≥ 1/1,000 to < 1/100);

rare (≥ 1/10,000 to < 1/1,000);

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 – Kounis syndrome.

Immune system disorders: frequency not known^a – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^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.

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, chills; rare – swelling, rigors.

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

^a Based on post-marketing reports. Since information on these reactions is voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency; hence, frequency is categorized as not known.

^b See section "Special precautions for use".

^c Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

Cases of 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 term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. 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", "Special precautions for use", and "Pharmacodynamics").

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 also had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized or 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 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—over 30% in some studies. The incidence appears to be lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

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

Incompatibilities.

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

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

Packaging.

1.0 g of powder in glass vials stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap providing a tamper-evident seal.

One vial with the package leaflet is packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

MYLAN LABORATORIES LIMITED – Cephalosporin Division
MYLAN LABORATORIES LIMITED – CEPHA BLOCK

Manufacturer's address.

No. 152/6, 154/11 & 154/16, Doresanipalya, Bilekahalli, Begur Hobli, Bannerghatta Road, Bangalore, IN-560076, India

Marketing Authorisation Holder.

M.BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom