Ceftriaxone ananta
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Ceftriaxone Ananta (Ceftriaxone Ananta)
Composition:
Active substance: ceftriaxone;
1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1 g or 2 g.
Pharmaceutical form. Powder for solution for injection.
Main physico-chemical properties: crystalline powder, slightly hygroscopic, almost white or yellowish in 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) is halted, leading to lysis of the bacterial cell and its subsequent death.
Resistance.
Bacterial resistance to ceftriaxone may develop through one or more of the following mechanisms:
- hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be induced 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.
Clinical breakpoints for susceptibility testing
The clinical breakpoints for minimum inhibitory concentration (MIC), as 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 group Viridans |
≤ 0.5 |
˃ 0.5 |
| Haemophilus influenzae |
≤ 0.12c. |
˃ 0.12 |
| Moraxella catarrhalis |
≤ 1 |
˃ 2 |
| Neisseria gonorrhoeae |
≤ 0.12 |
˃ 0.12 |
| Neisseria meningitidis |
≤ 0.12c. |
˃ 0.12 |
| Non-species related |
≤ 1d. |
˃ 2 |
a. The susceptibility conclusion was based on susceptibility to cefoxitin.
b. The susceptibility conclusion was based on susceptibility to penicillin.
c. Rare isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints may occur. In such cases, repeat testing should be performed, and if confirmed, isolates should be sent to a reference laboratory.
d. The breakpoints apply to a daily intravenous dose of 1 g * 1 and a high dose of at least 2 g * 1.
Clinical efficacy against specific pathogens
The prevalence of resistance among specific species may vary geographically and over time. Local information on microbial resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought if local resistance rates are such that the benefit of using the drug, at least for certain types of infections, is questionable.
Generally susceptible species
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.
Gram-negative aerobes
Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.
Species with potential for acquired resistance
Gram-positive aerobes
Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.
Gram-negative aerobes
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.
Resistant microorganisms
Gram-positive aerobes
Enterococcus spp., Listeria monocytogenes.
Gram-negative aerobes
Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.
Anaerobes
Clostridium difficile.
Others
Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
- Resistance frequency is at least 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 (Cmax) after a single 1 g intramuscular dose 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, 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 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 (CSF) in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. The Cmax in CSF is reached approximately 4–6 hours after intravenous administration. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (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).
Metabolism
Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.
Elimination
Total plasma clearance (bound and unbound) of ceftriaxone 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 minimally altered: a slight increase in elimination half-life (less than two-fold) is observed, even in patients with severe renal impairment.
The moderate increase in 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, leading to a paradoxical increase in total drug clearance with an increase in volume of distribution paralleling total clearance.
Elderly patients
In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times longer than in younger adults.
Children
The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired protein binding. In 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. All major pharmacokinetic parameters based on total drug concentrations, except elimination half-life, are dose-dependent. The non-linearity results from saturation of plasma protein binding and is therefore observed for total ceftriaxone in plasma but not for the free (unbound) fraction.
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 MIC of ceftriaxone for specific target organisms (i.e., percentage of T > MIC).
Clinical characteristics.
Indications.
The medicinal product Ceftriaxone Ananta is indicated for the treatment of the following infections in adults and children, including full-term newborns (from birth):
- bacterial meningitis;
- community-acquired pneumonia;
- hospital-acquired pneumonia;
- acute otitis media;
- intra-abdominal infections;
- complicated urinary tract infections (including pyelonephritis);
- bone and joint infections;
- complicated skin and soft tissue infections;
- gonorrhea;
- syphilis;
- bacterial endocarditis.
The medicinal product Ceftriaxone Ananta may be used for:
- treatment of acute exacerbation of chronic obstructive pulmonary disease in adults;
- treatment of disseminated Lyme borreliosis [early (Stage II) and late (Stage III)] in adults and children, including newborns aged 15 days and older;
- surgical prophylaxis of surgical site infections;
- management of neutropenic patients 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 Ceftriaxone Ananta should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens is not covered by the spectrum of ceftriaxone (see section "Special precautions for use").
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to ceftriaxone or to any other cephalosporin, or to any of the excipients of the medicinal product. 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 ≤ 41 weeks of postmenstrual age (gestational age + postnatal age)*;
in full-term newborns (≤ 28 days of age):
- with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, since bilirubin binding is likely impaired in these conditions*;
- who require (or are expected to require) intravenous administration of calcium-containing solutions or infusions, due to the risk of precipitation of calcium-ceftriaxone salts (see sections "Special precautions for use", "Side effects", and "Incompatibilities").
- 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.
Prior to intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"), and refer also to the instructions for medical use of lidocaine, 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 Ceftriaxone Ananta in vials or for further dilution of reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of calcium-ceftriaxone salts may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site infusion 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 plasma have shown an increased risk of calcium-ceftriaxone salt precipitation in newborns (see sections "Contraindications", "Special precautions for use", "Dosage and administration", "Side effects", and "Incompatibilities").
Concomitant use of the product with oral anticoagulants may potentiate 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 antagonists should be adjusted appropriately both during and after ceftriaxone therapy (see section "Side effects").
There are conflicting data regarding the potential for increased nephrotoxic effect of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.
In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.
No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).
False-positive Coombs' test results may occur in patients receiving ceftriaxone.
Ceftriaxone, like other antibiotics, may cause false-positive results in galactosemia testing.
Similarly, false-positive results may occur when urine glucose is tested by 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 Kounis 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 initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.
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 during ceftriaxone use, which may be life-threatening or fatal; however, 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 reported. 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, there are no confirmed cases of intravascular precipitation in patients other than newborns who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that newborns are at higher 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 older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, 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 precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone administration is deemed necessary in patients requiring continuous parenteral nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines must be flushed between administrations (see sections "Pharmacokinetics", "Contraindications", "Side effects", and "Incompatibilities").
Children.
The safety and efficacy of ceftriaxone in neonates, infants, and children have been established when administered at doses described in the section "Dosage and administration" (see section "Dosage and administration"). Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.
Ceftriaxone Ananta 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 outcomes, have been reported in both adults and children during ceftriaxone therapy.
If anemia develops during ceftriaxone treatment, hemolytic anemia associated with cephalosporin use should be considered, and ceftriaxone should be discontinued until the etiology is determined.
Prolonged treatment.
During prolonged therapy, a complete blood count should be performed regularly.
Colitis/overgrowth of resistant microorganisms.
Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported with nearly all 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"). Administration of the drug should be discontinued and appropriate therapy against Clostridium difficile initiated. Antiperistaltic agents 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 drug is recommended (see section "Dosage and administration").
Effect on serological test results.
Ceftriaxone may cause false-positive results in the Coombs test. Ceftriaxone may also cause false-positive results in galactosemia screening tests (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").
Ceftriaxone may cause falsely low blood glucose readings when measured with certain glucose monitoring systems. Refer to the instructions for use of each specific system. Alternative testing methods should be used if necessary.
Sodium.
Each gram of the medicinal product contains 3.6 mmol of sodium. Caution should be exercised when administering Ceftriaxone Ananta to patients on a sodium-restricted diet.
Spectrum of antibacterial activity.
Ceftriaxone has a limited spectrum of antibacterial activity and may be inappropriate for use as 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 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. 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; the physician should decide whether to discontinue the drug based on a benefit-risk assessment in the individual case (see section "Side effects").
Biliary stasis.
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 ceftriaxone administration cannot be ruled out as an initiating or contributing factor.
Nephrolithiasis.
Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). In case of symptoms, ultrasound examination should be performed. The decision to administer the drug to patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment in the individual case.
Jarisch-Herxheimer reaction (JHR).
In some patients with spirochetosis, a Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone therapy. JHR is generally self-limiting, or symptomatic treatment may be administered. Antibiotic therapy should not be discontinued if this reaction occurs.
Encephalopathy.
Encephalopathy has been reported during ceftriaxone therapy (see section "Side effects"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If encephalopathy associated with ceftriaxone use is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.
Disposal of unused or expired medicinal product.
Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a designated 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 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.
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 should be made whether to discontinue breastfeeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
Fertility.
Reproductive function studies have not shown any adverse effects on male or female fertility.
Ability to influence reaction speed when driving or operating machinery.
During ceftriaxone therapy, side effects such as dizziness may occur, which could affect the ability to drive or operate complex machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.
Method of Administration and Dosage.
Dosage
The dosage 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 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 develop fever and are 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, consideration should be given to administering the drug twice daily (with a 12-hour interval).
Indications in adults and children aged 12 years and older (≥ 50 kg) requiring special dosing regimens
Acute otitis media
A single intramuscular dose of 1–2 g of Ceftriaxone Ananta may be administered.
Some data suggest that in severe cases or when prior therapy has failed, Ceftriaxone Ananta may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.
Prophylaxis of surgical site infections
A single dose of 2 g prior to surgery.
Gonorrhoea
Single intramuscular dose of 500 mg.
Syphilis
The usual recommended dose is 500 mg – 1 g once daily, increased to 2 g once daily in cases of neurosyphilis, 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 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.
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 50–80 mg/kg |
Once daily |
Intra-abdominal infections. |
| 50–100 mg/kg |
Once daily |
Complicated skin and soft tissue infections. |
| 80–100 mg/kg |
Once daily |
Bacterial meningitis |
| 100 mg/kg |
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) requiring special dosing regimens
Acute otitis media
For initial treatment of acute otitis media, a single intramuscular injection of Ceftriaxone Ananta at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or when prior therapy has failed, Ceftriaxone Ananta 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
General 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.
Neonates aged 0–14 days
Ceftriaxone Ananta is contraindicated in preterm 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. |
| 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 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 Ananta at a dose of 50 mg/kg may be used.
Preoperative surgical site infection prophylaxis
20–50 mg/kg as a single dose before surgery.
Syphilis
The recommended total dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.
Duration of treatment
The duration of treatment depends on the course of the disease. In accordance with general principles of antibiotic therapy, ceftriaxone should be continued for 48–72 hours after defervescence or until eradication of 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 to 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 severely impaired. Only in patients with preterminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.
There is no need for additional drug administration after dialysis in patients undergoing dialysis. Ceftriaxone is not eliminated by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the drug's safety and efficacy is recommended.
Patients with severe hepatic and renal dysfunction
In cases of concomitant severe renal and hepatic impairment, careful clinical monitoring of the drug's safety and efficacy is recommended.
Administration method
Intramuscular administration
Ceftriaxone Ananta 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.
Intravenous administration
Ceftriaxone Ananta may be administered by intravenous infusion lasting at least 30 minutes (preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion in neonates and children under 12 years of age. In newborns, 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 only when intravenous administration is not feasible or less appropriate for the patient. Doses exceeding 2 g should be administered intravenously.
Ceftriaxone is contraindicated in newborns (≤ 28 days) who require (or are expected to require) treatment with calcium-containing intravenous solutions, including 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 calcium-containing solutions (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").
For preoperative surgical site infection prophylaxis, ceftriaxone should be administered 30–90 minutes before surgery.
Reconstitution instructions
For intramuscular injection, the following should be used:
- 0.5 g in 2 mL of 1% lidocaine solution;
- 1 g in 3.5 mL of 1% lidocaine solution.
For intravenous injection, the following should be used:
- 0.5 g in 5 mL of water for injection;
- 1 g in 10 mL of water for injection.
For intravenous infusion, 2 g of Ceftriaxone Ananta should be dissolved in 40 mL of one of the following calcium-free infusion solutions: 0.9% sodium chloride, 0.45% sodium chloride + 2.5% glucose, 5% glucose, 10% glucose, 6% dextran in 5% glucose solution, 6–10% hydroxyethyl starch, water for injection.
The displacement volume of 2 g of Ceftriaxone Ananta is 1.37 mL in water for injection.
When 40 mL of water for injection is added, the final concentration of the reconstituted solution is 48.34 mg/mL.
Freshly prepared solutions for injection are recommended. The prepared solution (reconstituted with 1% lidocaine hydrochloride solution) is stable for 24 hours when stored at 2–8 °C or for 6 hours at room temperature.
The ceftriaxone solution must not be mixed in the same syringe with any other medicinal products except 1% lidocaine hydrochloride solution (for intramuscular injections only).
The infusion line must be flushed after each administration.
Children.
The medicinal product should be administered to children according to the dosing instructions specified in the section "Posology and method of administration".
Overdose.
In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis do not effectively reduce excessive plasma concentrations of the drug. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse Reactions
The most commonly observed adverse reactions 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 (≥ 1/1000 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 colitisb; frequency not knowna – superinfectionsb.
Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not knowna – hemolytic anemiab, agranulocytosis.
Cardiac disorders: frequency not knowna – Kounis syndromeb.
Immune system disorders: frequency not knowna – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactionsb, Jarisch-Herxheimer reactionb.
Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not knowna – seizures.
Ear and labyrinth disorders: frequency not knowna – vertigo.
Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.
Gastrointestinal disorders: common – diarrheab, loose stools; uncommon – nausea, vomiting; frequency not knowna – pancreatitisb, stomatitis, glossitis.
Hepatobiliary disorders: common – increased liver enzymes; frequency not knowna – precipitates in the gallbladderb, kernicterus, hepatitisc, cholestatic hepatitisb,c.
Skin and subcutaneous tissue disorders: common – rash; uncommon – pruritus; rare – urticaria; frequency not knowna – Stevens-Johnson syndromeb, toxic epidermal necrolysisb, 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 knowna – oliguria, formation of renal precipitates (reversible).
General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – swelling, chills.
Investigations: uncommon – increased blood creatinine levels; frequency not knowna – false-positive Coombs testb, false-positive galactosemia testb, false-positive results with non-enzymatic glucose testsb.
a Based on post-marketing reports. Since these reactions are reported voluntarily from an undefined population size, it is not possible to reliably estimate their frequency, hence the classification as "frequency not known".
b See section "Special precautions for use".
c Usually reversible upon discontinuation of ceftriaxone.
Infections and infestations.
Cases of diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions for use").
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 precipitates of ceftriaxone calcium 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 "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 typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").
Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation with intravenous administration—over 30% in some studies. The incidence of precipitate formation is 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 precautions for use").
Reporting of adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. 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.
Keep out of reach of children.
Store in the original packaging at a temperature not exceeding 25 °C.
The reconstituted solution should be used within 6 hours when stored at a temperature not exceeding 25 °C, or within 24 hours when stored at 2–8 °C.
Incompatibilities.
Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.
It should not be mixed or combined with other medicinal products except those specified in the section "Dosage and administration". Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution, due to the risk of precipitate formation. Ceftriaxone must not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Special precautions for use", "Dosage and administration", and "Adverse reactions").
For combination with other antibiotics, separate syringes or solutions should be used.
Packaging.
Ceftriaxone Ananta, powder for solution for injection, 1 g.
1 g of the medicinal product in a glass vial closed with a rubber stopper and aluminum cap with a "flip-off" component. Packaged in cartons containing one vial or 20 vials.
Ceftriaxone Ananta, powder for solution for injection, 2 g.
2 g of the medicinal product in a glass vial closed with a rubber stopper and aluminum cap with a "flip-off" component. Packaged in cartons containing one vial or 10 vials.
Prescription status.
Prescription only.
Manufacturer.
Ananta Meditech Limited.
Manufacturer's address.
Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udhiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.
Marketing Authorization Holder.
Ananta Meditech Ltd.
Address of Marketing Authorization Holder.
Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.