Ontazen-2000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONTAZEN – 2000 (ONTAZEN – 2000)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to 2000 mg of ceftriaxone.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

Antibacterials 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. As a result, biosynthesis of the cell wall (peptidoglycan) is halted, 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 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

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

Pathogen	Dilution method (minimum inhibitory concentration, mg/l)
	Susceptible	Resistant
Enterobacteriaceae	≤ 1	> 2
Staphylococcus spp.	a.	a.
Streptococcus spp. (groups A, B, C and G)	b.	b.
Streptococcus pneumoniae	≤ 0.5c.	> 2
Streptococci (Viridans group)	≤ 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
Not 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. Isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely encountered; if observed, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory;

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

Intravenous administration

After intravenous bolus injection of 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, the 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 secretions. An 8–15% increase in mean 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 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 concentrations in cerebrospinal fluid are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (see section "Use during pregnancy or breastfeeding").

Plasma 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 with increasing concentration (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 moderately increased elimination half-life in renal impairment is explained by compensatory increases in extra-renal clearance due to reduced protein binding and the corresponding increase in total extra-renal clearance of 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, contributing to the observed paradoxical increase in total drug clearance, 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 higher than in younger adults.

Children

The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as decreased glomerular filtration and impaired 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 drug concentration, decreasing less than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it occurs for total ceftriaxone in plasma but not for the free (unbound) fraction.

Pharmacokinetic/pharmacodynamic relationship

As with other β-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 drug 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 drug 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;
• preoperative prophylaxis of surgical site infections;
• management of patients with neutropenia who develop fever suspected to be due to bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections are suspected.

The drug should be prescribed 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 regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-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"). See the lidocaine product information, particularly contraindications.

Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of the drug in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical cord plasma have shown an increased risk of ceftriaxone calcium salt precipitate formation in newborns (see sections "Contraindications", "Special precautions", "Dosage and administration", "Incompatibilities", "Side effects").

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").

Conflicting data exist 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 direct Coombs' test results.

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

Similarly, false-positive results may occur when urine glucose 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 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 "Adverse Reactions"). Hypersensitivity reactions may also progress to Cowden syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse Reactions"). In case of severe hypersensitivity reactions, administration of ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of β-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other β-lactam drugs.

Cases of severe skin reactions (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported, which may be life-threatening or fatal, associated with ceftriaxone therapy; 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 precipitate formation have been reported only in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using separate infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that 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 providers may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone administration is deemed necessary in patients requiring continuous nutrition, 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 "Pharmacokinetics", "Contraindications", "Incompatibilities", and "Adverse Reactions").

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 "Adverse Reactions"). 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, immune-mediated hemolytic anemia associated with cephalosporin use should be considered, and ceftriaxone administration should be discontinued until the etiology is determined.

Prolonged therapy.

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

Colitis/overgrowth of non-susceptible 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 "Adverse Reactions"). Discontinuation of ceftriaxone therapy and administration of appropriate agents against Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be used.

As with other antibacterial agents, superinfections caused by microorganisms not susceptible 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 drug is recommended (see section "Dosage and Administration").

Effect on serological test results.

The Coombs test may yield false-positive results during ceftriaxone therapy. The drug may also cause false-positive results in galactosemia screening tests (see section "Adverse Reactions").

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 "Adverse Reactions").

For patients undergoing hemodialysis, there is no need to adjust the dose after the procedure; however, serum drug concentration should be monitored, as elimination may be accelerated in these patients.

Sodium.

1 g of the drug contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as monotherapy in certain types of infections, unless 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 provided in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

On ultrasound imaging, shadows should raise suspicion of ceftriaxone calcium salt precipitate formation. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency at ceftriaxone doses of 1 g or more per day. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone calcium salt precipitates have been associated with clinical symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuing the drug based on a benefit-risk assessment for the individual case (see section "Adverse Reactions").

Biliary stasis.

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

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse Reactions"). In symptomatic cases, ultrasound examination should be performed. The decision to administer ceftriaxone 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.

Jarisch-Herxheimer reaction.

After initiation of ceftriaxone therapy, the Jarisch-Herxheimer reaction (JHR) may occur in some patients with spirochetal infections. The reaction usually resolves spontaneously or can be managed with symptomatic treatment. Antibiotic therapy should not be discontinued due to this reaction.

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

Breastfeeding period.

Ceftriaxone passes into breast milk in low concentrations, and no adverse effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision on 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 any adverse effects on male or female fertility.

Ability to influence reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Dosage

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

The dosages listed below are generally recommended 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*	Dosing frequency**	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 febrile neutropenic patients suspected of having a bacterial infection Bacterial endocarditis Bacterial meningitis

* 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 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 administered.

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

Preoperative prophylaxis of surgical site infections

Single dose of 2 g administered 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 with a body weight of 50 kg or more should receive the standard adult doses.

Ceftriaxone dose*	Frequency of administration**	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 suspected of 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 drug twice daily (with a 12-hour interval).

Indications in neonates, infants, and children aged 15 days to 12 years (< 50 kg) who require special dosing regimens.

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of the drug at a dose of 50 mg/kg may be used. Some data suggest that in cases where the child's condition is severe or prior therapy has been ineffective, the drug 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 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 considered.

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 varies; national or local guidelines should also be considered.

Neonates aged 0–14 days

The drug is contraindicated in premature neonates with a postmenstrual age of less than 41 weeks (gestational age + chronological age).

Ceftriaxone dose*	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 febrile neutropenic patients with 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 must not be exceeded.

Indications in neonates 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 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 recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after the resolution of fever or confirmation of eradication of the bacterial infection.

Geriatric patients

In patients with normal renal and hepatic function, 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 to moderate hepatic impairment, provided renal function is normal.

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

Patients with renal impairment

In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone. However, in patients with preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.

For patients undergoing dialysis, there is no need for additional administration of the drug after dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Close clinical monitoring of the safety and efficacy of the drug is recommended.

Patients with severe hepatic and renal dysfunction

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

Route of administration

Intramuscular administration

The drug may be administered by deep intramuscular injection. The intramuscular injection should be given into the center of a relatively large muscle mass. It is recommended not to inject more than 1 g at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). For detailed information, the package leaflet for lidocaine should be consulted.

Intravenous administration

The drug may 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. Intravenous doses in neonates 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 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 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.

Dilution . Based on the required dose, determine the necessary number of vials. For intravenous or intramuscular administration, add the recommended volume of diluent as indicated 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 are completely dissolved.

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

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

	Powder	Solution for dilution	Volume of solution, ml	Replacement volume, ml
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 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 in 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.

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

Children.

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

Overdose.

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

Adverse reactions.

The most commonly observed adverse reactions associated with ceftriaxone 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*; frequency not known** – superinfections*.

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

Cardiac disorders: frequency not known – Kounis syndrome.

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

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

Ear and labyrinth disorders: frequency not known** – vertigo.

Respiratory system disorders: rare – bronchospasm.

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

Hepatobiliary disorders: common – increased liver enzymes; frequency not known** – biliary precipitates*, kernicterus, hepatitis**, cholestatic hepatitis*,**.

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

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

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

Investigations: uncommon – increased blood creatinine; frequency not known** – false-positive Coombs test*, false-positive galactosemia test*, false-positive results in non-enzymatic methods for glucose testing*.

** Based on post-marketing reports. Since information on these reactions has been voluntarily reported from an undefined population size, it is not possible to reliably estimate their frequency, hence the classification as "frequency not known."

* See section "Special precautions for use".

** Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

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

Precipitates of ceftriaxone calcium salt.

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 elimination half-life of ceftriaxone compared to adults (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses (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, 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 incidence of precipitate formation with intravenous administration, exceeding 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 typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").

Shelf life.

2 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 stored for no more than 6 hours at temperatures not exceeding 25 °C, or for no more than 24 hours in a refrigerator (2–8 °C).

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 should not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, due to the potential for precipitate formation. Ceftriaxone should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Special precautions for use", "Dosage and administration", "Adverse reactions").

Packaging.

1 vial per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business.

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