Ontazen – 1000

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ONTAZEN – 1000 (ONTAZEN – 1000)

Composition:

Active substance: ceftriaxone;

1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder from white to yellowish-orange 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. 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 several mechanisms:

• hydrolysis by β-lactamases, including extended-spectrum β-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably expressed in certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• decreased permeability of the outer membrane in Gram-negative bacteria;
• bacterial efflux pumps.

Breakpoints for susceptibility testing.

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

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 such isolates are observed, repeat testing should be performed, and if resistance is 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.

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

Intravenous administration.

After intravenous bolus injection of 500 mg and 1 g of ceftriaxone, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of 500 mg, 1 g, and 2 g of ceftriaxone, 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 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 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 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 transformed 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 prolonged half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in total extrarenal clearance of ceftriaxone.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory 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, 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.

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, decreasing to a lesser extent than proportionally with dose. Non-linearity is observed due to saturation of plasma protein binding and therefore applies to total ceftriaxone in plasma, but not to free (unbound) ceftriaxone.

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 medicinal product should be used for the treatment of the following infections in adults and children, including 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;
• 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 the above-mentioned infections is suspected. The medicinal product should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special precautions").

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

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).

Ceftriaxone is contraindicated in preterm newborns ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;

in term newborns (≤ 28 days of age):

• with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely to be impaired under these conditions*;
• who require (or are expected to require) intravenous administration of calcium-containing products or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions" and "Side effects").

* 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 injection of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the lidocaine product 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 to reconstitute the medicinal product in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type connector. However, in all patients except 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 plasma from adult and newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections "Dosage and administration", "Contraindications", "Special precautions", "Side effects", "Incompatibilities").

Concomitant use of the medicinal product 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 during and after ceftriaxone therapy (see section "Side effects").

There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical monitoring recommendations for 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 interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing medicinal products (for intravenous or oral administration).

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

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

Similarly, false-positive results may occur when glucose in urine is tested by non-enzymatic methods. For this reason, during ceftriaxone therapy, urine glucose should be tested 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 Cowan's syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, ceftriaxone must be discontinued immediately 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 β-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other β-lactam agents.

Severe skin adverse 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 treatment, which may be life-threatening or fatal, although the frequency of these events is unknown (see section "Adverse reactions").

Interaction with medicinal products containing calcium.

Cases of precipitation of ceftriaxone-calcium salt in lungs and kidneys with fatal outcomes have been described in premature and full-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. According to available scientific data, confirmed cases of intravascular precipitates have not been reported except in newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing agents. In vitro studies have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when different infusion systems or different infusion sites are used. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the drugs are administered through different infusion systems at different body sites or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitate formation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous parenteral nutrition is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", "Pharmacokinetics", and "Incompatibilities").

Children.

The safety and efficacy of 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.

Ceftriaxone is contraindicated in premature and full-term newborns 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 ceftriaxone treatment 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 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 "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 resistant to the drug may occur.

Severe renal and hepatic impairment.

In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the medicinal product is recommended (see section "Dosage and administration").

Effect on serological test results.

Administration of ceftriaxone may result in false-positive direct Coombs' test results. Ceftriaxone 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").

Antibacterial spectrum.

Ceftriaxone has a limited antibacterial spectrum and may be inadequate 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, 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 medicinal product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In case of shadows observed on ultrasound, precipitation of ceftriaxone-calcium salt should be considered. Hypoechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency when ceftriaxone is administered at 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 has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide on discontinuation of the drug based on benefit-risk assessment in the individual case (see section "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly caused by biliary tract obstruction, have been reported in patients receiving ceftriaxone (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. It cannot be excluded that precipitation in the biliary tract due to drug administration may be 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 "Adverse reactions"). If symptoms occur, an ultrasound examination should be performed. The decision to use the medicinal product in patients with a history of kidney stones or hypercalciuria should be made by the physician based on benefit-risk assessment in the individual case.

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, but symptomatic treatment may be required. Antibiotic therapy should not be discontinued if a Jarisch-Herxheimer reaction occurs.

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 and expired medicinal product: Environmental contamination by the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed using a designated "waste collection system" if available.

Important information on 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.

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 benefit outweighs the risk.

Breastfeeding. Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization is also possible. A decision on whether to discontinue breastfeeding or discontinue/abandon ceftriaxone therapy should be made, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

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

Ability to affect reaction rate when driving or operating machinery.

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

Administration and dosage.

Dosage

The dosage 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 following dosages are general recommendations for these indications. In particularly severe cases, the highest dose within the recommended range should be used.

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

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

** When doses exceeding 2 g per day are used, consideration should be given to administering the medicinal product 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 medicinal product may be administered. Some data suggest that in cases of severe illness or previous ineffective therapy, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.

Preoperative prevention of surgical site infections.

2 g as a single dose before surgery.

Gonorrhea.

A single intramuscular dose of 500 mg.

Syphilis.

The generally recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, for 10–14 days. Dosage 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.

Neonates, infants, and children from 15 days to 12 years of age (< 50 kg)

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

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

** When doses exceeding 2 g per day are used, 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 dosing 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 of severe illness or previous ineffective therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Prophylaxis of surgical site infections prior to surgery.

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.

Newborns aged 0–14 days.

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

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

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

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

Acute otitis media.

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

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 until eradication of the bacterial infection is confirmed.

Geriatric patients.

In patients with normal renal and hepatic function, dose adjustment is not required for 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 normal.

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) should the daily dose of ceftriaxone not exceed 2 g.

For patients undergoing dialysis, there is no need for additional administration of the drug after dialysis. Ceftriaxone is not eliminated from the body 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 impairment of both renal and hepatic function, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Route of administration.

Intramuscular administration.

The medicinal product may be administered by deep intramuscular injection. Intramuscular injections 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"). For detailed information, refer to the lidocaine medical instructions. The use of lidocaine requires prior testing for individual sensitivity to this medicinal product.

Intravenous administration.

The medicinal product 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 carried out over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). Intramuscular administration should be considered 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 calcium-containing intravenous solutions, including infusion solutions containing calcium, such as parenteral nutrition, due to the risk of precipitation of calcium-ceftriaxone salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or to further dilute the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of calcium-ceftriaxone 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 precautions", and "Incompatibilities").

For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes before 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 (adjusting to a total volume of 40 ml, as specified in the table below).

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

* Ceftriaxone solution 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.

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

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. Hemodialysis or peritoneal dialysis do not reduce excessive drug concentrations in blood plasma. 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*; 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 — elevated 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 syndrome)*.

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 with non-enzymatic methods for glucose testing*.

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

* See section "Special Warnings and Precautions for Use".

** Usually reversible upon discontinuation of ceftriaxone.

Infections and infestations.

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

Precipitates of calcium ceftriaxone 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 precipitates of calcium ceftriaxone salt 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 "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 cumulative doses exceeding 10 grams, and who also had additional risk factors (e.g., limited fluid intake or immobilization). The risk of precipitate formation increases in immobilized or dehydrated patients. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone (see section "Special Warnings and Precautions for Use").

Cases of biliary precipitates of calcium ceftriaxone salt 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—over 30% in some studies. The incidence appears to be lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates typically resolve after discontinuation of ceftriaxone (see section "Special Warnings and Precautions for Use").

Reporting suspected adverse reactions.

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

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 used within 6 hours when stored at temperatures not exceeding 25 °C, or within 24 hours if stored refrigerated (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 "Dosage and Administration", "Special Warnings and Precautions for Use", and "Adverse Reactions").

Packaging.

1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer’s address and site of operation.

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