Emcef 1000: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EMSEPH® 1000 (EMCEPH® 1000) EMSEPH® 2000 (EMCEPH® 2000)

Composition:

Active substance: ceftriaxone;

One vial contains sodium ceftriaxone equivalent to ceftriaxone 1000 mg or 2000 mg.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antibacterial agents for systemic use. Other beta-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. 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 due to 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 minimum inhibitory concentration, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Pathogen	Dilution method (minimum inhibitory concentration, mg/l)
Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 1	> 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups A, B, C and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	> 2
Viridans group Streptococci	≤ 0.5	> 0.5
Haemophilus influenzae	≤ 0.12c.	> 0.12
Moraxella catarrhalis	≤ 1	> 2
Neisseria gonorrhoeae	≤ 0.12	> 0.12
Neisseria meningitidis	≤ 0.12 c.	> 0.12
Non-species related	≤ 1d.	> 2

a. The conclusion on susceptibility was based on susceptibility to cefoxitin.

b. The conclusion on susceptibility was based on susceptibility to penicillin.

c. Rare isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints may occur. If observed, 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 a 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 that may develop 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. Initially 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 ceftriaxone is 81 mg/L, 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 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 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 secretions. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated dosing; 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 is up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak concentrations in cerebrospinal fluid 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 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 extra-renal clearance due to reduced protein binding and a corresponding increase in total ceftriaxone clearance.

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, contributing to the observed paradoxical increase in total clearance of ceftriaxone, paralleled by an 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.

Pediatric patients

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 plasma 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 ceftriaxone concentration, decreasing to a lesser extent than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone, 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.

The medicinal product should be used 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.

The medicinal product 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 site infections during surgical procedures;
management of patients with neutropenia who have developed fever suggestive of 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.

The medicinal product should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens is not covered by 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 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 to be impaired under these conditions*;
who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions, due to the risk of precipitation of ceftriaxone calcium salt (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 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 for use"). Refer to the lidocaine prescribing information, particularly contraindications.

Ceftriaxone solutions 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 for reconstitution of ceftriaxone in vials or for further dilution of 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 all patients except newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using plasma from adult and newborn umbilical cord blood have shown an increased risk of ceftriaxone calcium salt precipitate formation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Adverse reactions", "Incompatibilities").

Concomitant use of ceftriaxone 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 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.

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 Coombs' test results.

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

Similarly, false-positive results may occur when glucose in urine is tested using non-enzymatic methods. 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 for use.

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 Cowden 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 immediately discontinued and appropriate emergency measures should be initiated. Prior to initiating therapy, it is necessary 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 used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.

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

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 through different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitate formation except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals 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, although through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and the infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").

Children.

The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.

Ceftriaxone 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 ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during treatment with the drug in both adults and children. If a patient develops anemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated anemia should be considered, and ceftriaxone administration should be discontinued until the etiology is established.

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 during therapy 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. Medicinal products that inhibit peristalsis should not be used.

As with other antibacterial agents, superinfections caused by microorganisms resistant to ceftriaxone 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 medicinal product is recommended (see section "Dosage and administration").

Jarisch-Herxheimer reaction.

At the beginning of ceftriaxone therapy, some patients with spirochetal infections may experience a Jarisch-Herxheimer reaction. This reaction is usually self-limiting, or symptomatic treatment may be administered. Ceftriaxone therapy should not be discontinued in case of a Jarisch-Herxheimer reaction.

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 disorders of the central nervous system. If encephalopathy associated with ceftriaxone use is suspected (e.g., decreased level of consciousness, change in mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Effect on serological test results.

During ceftriaxone therapy, the Coombs test may yield false-positive results. Ceftriaxone 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 ceftriaxone therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Side effects").

Spectrum of antibacterial activity.

Ceftriaxone has a limited spectrum of antibacterial activity and may be inappropriate for 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 microorganisms are suspected, the use of additional antibiotics should be considered.

Use of lidocaine.

If 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 medicinal product instructions must be taken into account (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In case of shadows on ultrasound, precipitation of ceftriaxone calcium salt should be considered. Shadows, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, and their frequency increases with ceftriaxone doses of 1 g/day or higher. Particular caution should be exercised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, precipitation of ceftriaxone calcium salt was accompanied by 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 in the individual case (see section "Side effects").

Cholestasis.

Cases of pancreatitis, possibly caused by 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 extensive therapy, severe illness, and total parenteral nutrition. Precipitation in the biliary tract due to the drug use cannot be ruled out as an initiating or contributing factor in the development of this disorder.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Side effects"). In case of symptoms, ultrasound examination should be performed. 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 in the individual case.

Important information about excipients.

Sodium. 1 g of the medicinal product contains 3.6 mmol of sodium. This should be taken into account if the patient is on a sodium-controlled diet.

Disposal of unused and expired medicinal product: Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a dedicated "waste collection system" if 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. During pregnancy, particularly in the first trimester, ceftriaxone should only be used 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. The possibility of sensitization should be considered. 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 not shown evidence of adverse effects on male or female fertility.

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

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

Dosage and Administration

Dosage

The dose of the medicinal product 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).

Ceftriaxone dose*	Frequency of administration**	Indications
1–2 g	Once daily	Community-acquired pneumonia. Acute exacerbation of chronic obstructive pulmonary disease. Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis).
2 g	Once daily	Hospital-acquired pneumonia. Complicated skin and soft tissue infections. Bone and joint infections.
2–4 g	Once daily	Management of patients with neutropenia who have developed fever and are suspected of having a bacterial infection. Bacterial endocarditis. Bacterial meningitis.

* 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, administration of the medicinal product twice daily (with a 12-hour interval) should be considered.

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

Preoperative surgical site infection prophylaxis

A single dose of 2 g prior to surgery.

Gonorrhoea

A single intramuscular dose of 500 mg.

Syphilis

Recommended doses are 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.

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 from 15 days to 12 years of age (< 50 kg)

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

Ceftriaxone dose*	Dosing frequency**	Indications
50–80 mg/kg	Once daily	Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia.
50–100 mg/kg (maximum 4 g)	Once daily	Complicated skin and soft tissue infections. Bone and joint infections. Management of febrile neutropenic patients with suspected bacterial infection.
80–100 mg/kg (maximum 4 g)	Once daily	Bacterial meningitis.
100 mg/kg (maximum 4 g)	Once daily	Bacterial endocarditis.

* 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, consideration should be given to administering the medicinal product twice daily (with a 12-hour interval).

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of the medicinal product 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, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg once daily for 3 days.

Preoperative prophylaxis of surgical site infections

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

Syphilis

The generally 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.

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

Dose of ceftriaxone*

Frequency of administration

Indications

20–50 mg/kg

Once daily

Intra-abdominal infections

Complicated skin and soft tissue infections

Complicated urinary tract infections (including pyelonephritis)

Community-acquired pneumonia

Hospital-acquired pneumonia

Bone and joint infections

Management of neutropenic patients with fever and suspected bacterial infection

50 mg/kg

Once daily

Bacterial meningitis

Bacterial endocarditis

* 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 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 the fever subsides or after confirmation of eradication of the bacterial infection.

Geriatric patients

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

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 not impaired.

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

Patients with renal impairment

For patients with impaired renal function, dose reduction of ceftriaxone is not required if renal function is not impaired. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 ml/min), the daily dose of ceftriaxone should not exceed 2 g.

Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not eliminated 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

Ceftriaxone may 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 product information. The use of lidocaine requires prior sensitivity testing to determine individual susceptibility to this medicinal product.

Intravenous administration

Ceftriaxone may be administered by intravenous infusion lasting 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 up to 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 administration is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously. Ceftriaxone is contraindicated in neonates (≤ 28 days) if they 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 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 solutions containing calcium (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. Depending on the required dose, determine the necessary number of vials. For intravenous or intramuscular administration, add the recommended volume of diluent as specified in the table below, then shake the vial well until the contents are completely dissolved.

For intravenous infusion, add 15 ml of diluent and shake well until the contents of the vial are completely dissolved.

Withdraw 15 ml of the resulting solution and add it to 25 ml of diluent in an infusion bag to prepare the patient's dose (bringing the total volume to 40 ml, as indicated in the table).

The solution should be administered intravenously as described in this section.

	Powder	Solution for dilution	Volume of solution	Displacement volume
Intramuscular injection	1000 mg	1 % lidocaine for injections*	3.5 ml	0.63 ml
Intravenous injection	1000 mg	Water for injections	10 ml	0.63 ml
Intravenous injection	2000 mg	5 % glucose solution, 0.9 % sodium chloride solution for injections. Sodium chloride and glucose solution for injections (0.45 % sodium chloride and 2.5 % glucose). Dextran 6 % in 5 % glucose solution for injections. Hydroxyethyl starch 6–10 % infusions**	40 ml	1.25 ml

* The solution of ceftriaxone with lidocaine should not be administered intravenously

** 6% infusion: 30 g hydroxyethyl starch, 4.5 g sodium chloride, water for injections up to 500 ml. 10% infusion: 50 g hydroxyethyl starch, 4.5 g sodium chloride, water for injections up to 500 ml.

When using other diluents, compatibility with ceftriaxone must be verified. The resulting solution should be clear and free from foreign particles.

Children.

The medicinal product should be administered to children according to the dosage specified in the section "Administration and dosage".

Overdose.

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

Treatment. In case of overdose, hemodialysis or peritoneal dialysis do not significantly reduce excessive plasma concentrations of ceftriaxone. 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 (≥ 1/1000 to < 1/100);
rare (≥ 1/10,000 to < 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 – Kounine’s syndrome.

Immune system disorders: frequency not known^a – 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 system disorders: rare – bronchospasm.

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

Hepatobiliary disorders: common – increased 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, sweating; 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 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, the frequency is categorized as not known.
^b See section "Special Warnings and 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 Warnings and 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 elimination half-life compared to adults (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacodynamics").

Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they usually resolve after discontinuation of ceftriaxone (see section "Special Warnings and 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 with intravenous ceftriaxone 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 present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special Warnings and Precautions for Use").

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

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

The reconstituted solution should be stored for no more than 6 hours at temperatures not exceeding 25 °C and for no more than 24 hours in the refrigerator (2–8 °C).

Keep out of reach of children.

Incompatibilities.

Ceftriaxone is incompatible with amsacrine, 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, as precipitates may form. Ceftriaxone should not be mixed or administered simultaneously with solutions containing calcium, including total parenteral nutrition solutions (see sections "Dosage and Administration", "Special Warnings and Precautions for Use", and "Adverse Reactions").

Packaging.

1 vial of powder in a cardboard package.

Prescription status.

Prescription only.

Marketing Authorization Holder.

Abhil Formulations Pvt. Ltd.

Address of Marketing Authorization Holder.

17406-A, Minochan Colony, Bathinda-151001, India.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Address of Manufacturer and Site of Manufacturing Activity.

VI/51B, Post Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.