Emcef 1000

INSTRUCTIONS for medical use of the medicinal product EMSEPH® 1000 (EMCEPH® 1000)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1000 mg.

Dosage form. Powder for solution for injection.

Main physicochemical properties: crystalline powder from white to yellow-orange in color.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Other β-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins, resulting in the cessation of cell wall (peptidoglycan) biosynthesis, which in turn leads to bacterial cell lysis and death.

Resistance

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

• Hydrolysis by β-lactamases, including extended-spectrum β-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

Table 1

Breakpoints for minimum inhibitory concentration 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 Rare isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints have been observed. If such isolates are detected, repeat testing should be performed and, if confirmed, the isolate should be sent to a reference laboratory.

d Breakpoints apply 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 with potential for acquired resistance

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.

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 β-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, achieved 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 injection 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 substantially exceeding the minimum 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 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 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 in low concentrations is expected 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 extent 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 only a minor increase in elimination half-life (less than twofold), 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, resulting in increased 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 a paradoxical increase in total drug clearance with a parallel increase in volume of distribution.

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 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 and decrease less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore 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 minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., % T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

Emcef**®** 1000 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.

Emcef**®** 1000 may also 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 site infections;
• management of neutropenic patients with fever and suspected bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections is suspected.

Emcef**®** 1000 should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions for use").

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 β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated:

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

• in full-term newborns (≤ 28 days of age):

• 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 salts (see sections "Special precautions for use" and "Adverse reactions").

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

Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). Refer to the lidocaine product information, especially 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 Emcef**®** 1000 in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts 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 that 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 that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Contraindications", "Special precautions for use", "Method and route of administration", "Adverse reactions").

Concomitant use of the medicinal product with oral anticoagulants may enhance the vitamin K-antagonizing 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").

There are conflicting data regarding the potential for increased nephrotoxicity 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 showed antagonistic effects when chloramphenicol was used in combination with ceftriaxone. 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 administration).

False-positive results of the Coombs test may occur in patients receiving ceftriaxone.

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

Similarly, false-positive results may occur when testing for glucose in urine using non-enzymatic methods. For this reason, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

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 β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Cowden syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case 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 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 drugs.

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

Jarisch-Herxheimer reaction (JHR).

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone treatment. JHR is generally self-limiting, but symptomatic treatment may be required. Antibiotic therapy should not be discontinued if such a reaction occurs.

Interaction with calcium-containing medicinal products.

Cases of precipitation of ceftriaxone calcium salt in the lungs and kidneys with fatal outcomes have been observed in preterm and term neonates under 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and via different intravenous infusion systems. No confirmed cases of intravascular precipitate formation have 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 age, even when using separate infusion systems or administering through different infusion sites. However, in patients older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided they are administered through separate infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with physiological saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents that do not carry a similar risk of precipitate formation. If ceftriaxone use in patients requiring continuous parenteral nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", and "Incompatibilities").

Children.

The safety and efficacy of the medicinal product 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.

Emcef® 1000 is contraindicated in preterm and 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 Emcef® 1000 (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported during treatment with the drug in both adults and children.

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

Prolonged therapy.

Complete blood count should be monitored regularly during prolonged treatment.

Colitis/overgrowth of non-susceptible microorganisms.

Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported 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 against Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible to ceftriaxone may occur.

Severe renal and hepatic impairment.

Careful clinical monitoring of safety and efficacy is recommended in cases of severe renal and hepatic impairment (see section "Dosage and administration").

Effect on serological test results.

When using Emcef® 1000, the Coombs test may yield false-positive results. Emcef® 1000 may also cause false-positive results in galactosemia testing (see section "Side effects").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Emcef® 1000 therapy, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").

Sodium.

Each gram of Emcef® 1000 contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Spectrum of antibacterial activity.

Ceftriaxone has a limited spectrum of antibacterial activity 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 in the lidocaine medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In the presence of shadows on ultrasound, the possibility of ceftriaxone calcium salt precipitation should be considered. Shadows, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their incidence increases with ceftriaxone 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. Rarely, precipitation of ceftriaxone calcium salt is accompanied by symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on a benefit-risk assessment for the individual case (see section "Side effects").

Cholestasis.

Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving Emcef® 1000 (see section "Side effects"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior intensive therapy, severe illness, and total parenteral nutrition. Precipitation in the biliary tract due to drug administration cannot be ruled out as an initiating or contributing factor in this disorder.

Nephrolithiasis.

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

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 (CNS) disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonia, seizures), discontinuation of ceftriaxone should be considered.

Disposal of medicinal product.

Disposal of the medicinal product into the environment should be minimized. The medicinal product should not be disposed of via wastewater or household waste. Unused medicinal product after completion of treatment or expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on 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 benefit outweighs the 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 should also be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from 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.

Adverse reactions (e.g., dizziness) may occur during use of the medicinal product, which may affect the ability to drive or operate machinery. Patients should be warned about the possible occurrence of such reactions.

Dosage and Administration

Dosage

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

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

The general recommended doses are listed below. In particularly severe cases, the highest of the recommended doses should be used.

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

Table 2

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

** 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 the drug may be used.

Some data suggest that in patients with severe disease or after failure of prior therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.

Preoperative prophylaxis of surgical site infections

Single dose of 2 g administered preoperatively.

Gonorrhea

Single intramuscular dose of 500 mg.

Syphilis

Recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily for 10–14 days in neurosyphilis. 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 varies; national or local guidelines should also be considered.

Children

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

Table 3

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

** 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 neonates, infants, and children up to 12 years of age (< 50 kg) requiring special dosing regimens

Preoperative prophylaxis of surgical site infections

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

Syphilis

Recommended pediatric dose: 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. Recommended treatment duration may vary; national or local guidelines should also be considered.

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or failure of prior therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Neonates aged 0–14 days

Ceftriaxone is contraindicated in preterm neonates up to 41 weeks of gestational age (gestational age + postnatal age).

Table 4

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

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 ceftriaxone 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 should be continued for 48–72 hours after defervescence or until eradication of bacterial infection is confirmed.

Geriatric patients

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

Patients with hepatic impairment

Available data indicate no need for dose adjustment in patients with mild to moderate hepatic impairment, provided renal function is normal.

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

Patients with renal impairment

Dose reduction of ceftriaxone is not necessary in patients with impaired renal function if renal function is not compromised. Only in patients with pre-terminal stage 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 after dialysis. Ceftriaxone is not removed by peritoneal dialysis or hemodialysis. Careful clinical monitoring of safety and efficacy is recommended.

Patients with severe hepatic and renal dysfunction

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

Route of administration

Intramuscular administration

The medicinal product can be administered by deep intramuscular injection. The injection should be given into the center of a relatively large muscle. It is recommended not to administer more than 1 g at a single injection site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to consult the instructions for medical use of lidocaine.

Intravenous administration

The drug may be administered by intravenous infusion lasting at least 30 minutes (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 to 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 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 reconstitute 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 warnings and precautions for use", and "Incompatibilities").

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

Preparation instructions

Concentration for intravenous injection: 100 mg/mL.

Concentration for intravenous infusion: 50 mg/mL.

For information on storage of the reconstituted solution, see section "Storage conditions".

Ceftriaxone must not be mixed in the same syringe with any other medicinal product except 1% lidocaine hydrochloride solution (for intramuscular use only). The infusion line should be flushed after each administration of the drug.

For intravenous injection, 1 g of ceftriaxone should be dissolved in 10 mL of water for injections. The injection should be administered directly into a vein or into an intravenous infusion system over more than 5 minutes.

For intramuscular injection, 1 g of ceftriaxone should be dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The medicinal product should be administered by deep intramuscular injection. Doses exceeding 1 g should be divided and administered at more than one injection site.

Children.

The medicinal product is administered to children according to the dosing instructions specified in the section "Posology and method of administration".

Overdose

In case of overdose, nausea, vomiting, and diarrhea may occur.

Hemodialysis or peritoneal dialysis do not reduce drug concentrations. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse reactions.

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

Infections and infestations: fungal genital infections, pseudomembranous colitis, superinfections.

Blood and lymphatic system disorders: eosinophilia, leukopenia, thrombocytopenia, granulocytopenia, anemia, hemolytic anemia, coagulation disorders, agranulocytosis.

Cardiac disorders: Kounis syndrome.

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

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

Ear and labyrinth disorders: vertigo.

Respiratory system disorders: bronchospasm.

Gastrointestinal disorders: loose stools, diarrhea, nausea, vomiting, pancreatitis, stomatitis, glossitis.

Hepatobiliary disorders: elevated liver enzymes, biliary precipitates, nuclear jaundice, hepatitis¹, cholestatic hepatitis^1,2.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders: hematuria, glucosuria, oliguria, formation of renal precipitates (reversible).

General disorders and administration site conditions: phlebitis, injection site pain; fever, chills, swelling.

Investigations: increased blood creatinine levels, false-positive Coombs test results, false-positive galactosemia test results, false-positive results with non-enzymatic methods for glucose determination.

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

Infections and infestations.

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

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

Cases of renal 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 g, and who 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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

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 with intravenous administration—over 30% in some studies. The incidence appears lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may cause clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

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

Incompatibilities.

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 co-administered with solutions containing calcium, including parenteral nutrition solutions (see sections "Special precautions", "Dosage and administration", and "Adverse reactions").

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

It should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration".

It is incompatible with solutions containing other antibiotics.

Packaging.

1000 mg of powder in a vial. 1 vial in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Nectar Lifesciences Limited - Unit VI.

Manufacturer's address and site of operations.

Village Bhatoli Kalan, near Jharmajri, E.P.I.P., P.O. Barotiwala, Tehsil Baddi, District Solan, Himachal Pradesh, 174103, India.