Efmerin
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFMERIN (EFMERIN)
Composition:
Active substance: ceftriaxone;
1 vial contains sodium ceftriaxone equivalent to ceftriaxone 1 g or 2 g.
Dosage form. Powder for solution for injection.
Main physicochemical properties: crystalline powder, white to yellowish in color.
Pharmacotherapeutic group.
Antibacterials 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 bacterial cell lysis and 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 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 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 conclusion on susceptibility is based on susceptibility to cefoxitin;
b. The conclusion on susceptibility is based on susceptibility to penicillin;
c. Isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely observed. If such cases occur, repeat testing should be performed, and if confirmed, isolates 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.
Clinical efficacy against specific pathogens
The prevalence of resistance among individual species may vary geographically and over time. Local information on microbial resistance is desirable, especially when treating severe infections. If necessary, expert advice should be sought when local resistance prevalence makes the benefit of using the drug at least questionable for certain types of infections.
Generally susceptible species
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible)1, coagulase-negative staphylococci (methicillin-susceptible)1, 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 epidermidis2, Staphylococcus haemolyticus2, Staphylococcus hominis2.
Gram-negative aerobes
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli3, Klebsiella pneumoniae3, Klebsiella oxytoca3, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.
Initially resistant microorganisms
Gram-positive aerobes
Enterococcus spp., Listeria monocytogenes.
Gram-negative aerobes
Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.
Anaerobes
Clostridium difficile.
Others
Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.
1 All methicillin-resistant staphylococci are resistant to ceftriaxone.
2 Resistance rate >50% in at least one region.
3 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 following a single intramuscular dose of 1 g is 81 mg/L, reached within 2–3 hours after administration. The area under the plasma concentration–time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
Intravenous administration
After intravenous bolus injection of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma concentrations are approximately 120 and 200 mg/L, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g, and 2 g, plasma concentrations are approximately 80, 150, and 250 mg/L, respectively.
Distribution
The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) is observed upon repeated dosing; steady state is generally achieved within 48–72 hours, depending on the route of administration.
Penetration into specific tissues
Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (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 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.
Excretion
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 and hepatic function, the pharmacokinetics of ceftriaxone are only minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.
The relatively moderate increase in half-life in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and the 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 apparent 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 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 reduced glomerular filtration and impaired plasma protein binding. In children, the elimination half-life is shorter than in neonates or adults.
Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.
Linearity/non-linearity
The pharmacokinetics of ceftriaxone are non-linear. All major pharmacokinetic parameters based on total drug concentrations, except elimination half-life, are dose-dependent. Non-linearity results from saturation of plasma protein binding, and thus is 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 minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., %T > MIC).
Clinical characteristics.
Indications.
Ceftriaxone may 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;
- gonorrhoea;
- syphilis;
- bacterial endocarditis.
Efmerin 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 from 15 days;
- surgical prophylaxis of site infections during surgical procedures;
- management of patients with neutropenia who develop fever suspected to be due to bacterial infection;
- treatment of patients with bacteraemia arising from any of the above-mentioned infections, or when there is suspicion of any of the above-mentioned infections.
Efmerin 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 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. 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 of ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*;
in term newborns (≤ 28 days of age):
- with hyperbilirubinaemia, jaundice, hypoalbuminaemia, 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", "Adverse reactions", 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.
Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions", and refer to the medical instructions for lidocaine, especially the section "Contraindications").
Ceftriaxone solutions 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 to reconstitute Efmerin 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 calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type infusion system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion 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 ceftriaxone calcium salt precipitation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions", "Incompatibilities").
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 appropriately adjusted both during and after ceftriaxone therapy (see section "Adverse reactions").
There are conflicting data regarding the potential for increased nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.
In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.
No cases of interaction between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration), have been reported.
Patients receiving ceftriaxone may exhibit false-positive results in the Coombs test.
Ceftriaxone, like other antibiotics, may cause false-positive results in galactosaemia testing.
Similarly, false-positive results may occur when testing for glucose in urine using non-enzymatic methods. For this reason, glucose in urine should be tested using enzymatic methods during ceftriaxone therapy.
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 Couney's syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In case of severe hypersensitivity reactions, ceftriaxone should be discontinued immediately and appropriate emergency measures should be taken. Prior to initiating therapy, it is necessary to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.
Severe skin reactions (Stevens-Johnson syndrome or Lyell 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.
Fatal cases of precipitation of ceftriaxone-calcium salt in the lungs and kidneys have been reported in preterm and term neonates up to 1 month of age. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, no confirmed cases of intravascular precipitation have been reported except in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates have a higher risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.
Ceftriaxone must not be mixed or administered simultaneously with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with physiological saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider prescribing alternative antibacterial agents whose use is 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, although through different infusion systems and into different body sites. Alternatively, TPN infusions may be paused during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Side effects", "Pharmacokinetics", and "Incompatibilities").
Children.
The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for 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.
Ephemerin is contraindicated in preterm and term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").
Immune-mediated hemolytic anemia.
Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.
If a patient develops anemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology of the condition is established.
Prolonged treatment.
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 treatment 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 treatment (see section "Side effects"). 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 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 drug is recommended (see section "Dosage and administration").
Effect on serological test results.
The Coombs test may yield false-positive results during ceftriaxone treatment. Ceftriaxone may also cause false-positive results in galactosemia testing (see section "Side effects").
False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During ceftriaxone treatment, urine glucose levels should be determined using enzymatic test methods (see section "Side effects").
Ceftriaxone use may cause falsely low blood glucose readings obtained with certain glucose monitoring systems. Consult the instructions for use for each specific system. Alternative testing methods should be used if necessary.
Sodium.
This medicinal product contains 3.6 mmol of sodium. Caution is advised when administering to patients on a sodium-restricted diet.
Antibacterial spectrum.
Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as monotherapy in treating 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.
If lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine medicinal product instructions must be 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, and their frequency increases with ceftriaxone doses of 1 g/day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. 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 discontinuing the drug based on benefit-risk assessment for 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. The formation of precipitates in the biliary tract due to ceftriaxone use cannot be excluded as an initiating or contributing factor in this disorder.
Nephrolithiasis.
Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Side effects"). In symptomatic cases, ultrasound examination should be performed. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician based on benefit-risk assessment for the individual case.
Jarisch-Herxheimer reaction (JHR).
In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur at the beginning of ceftriaxone treatment. JHR is usually self-limiting, or symptomatic treatment may be administered. Antibiotic treatment should not be discontinued if such a reaction occurs.
Encephalopathy.
Encephalopathy has been reported during ceftriaxone use (see section "Side effects"), 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 release of the medicinal product should be minimized. The medicinal product should not be disposed of via wastewater or household waste. A dedicated waste collection system should be used for disposal, 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, peri- and postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.
Breastfeeding.
Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone treatment, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
Fertility.
Reproductive function studies have not revealed any adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery.
During ceftriaxone treatment, side effects such as dizziness may occur, which may affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.
Dosage and Administration
Dosage
The dose of the 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 doses listed below are general recommendations for these indications. In particularly severe cases, the highest dose within the recommended range should be used.
Adults and children aged 12 years and older (≥ 50 kg)
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 1–2 g |
Once daily |
Community-acquired pneumonia. |
| 2 g |
Once daily |
Hospital-acquired pneumonia. |
| 2–4 g |
Once daily |
Management of febrile neutropenic patients suspected of bacterial infection. |
* 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 Efmerin may be administered.
Some data suggest that in cases of severe clinical condition or when prior therapy has been ineffective, ceftriaxone may be effective when given intramuscularly at a dose of 1–2 g once daily for 3 days.
Preoperative surgical site infection prophylaxis
A single dose of 2 g prior to surgery.
Gonorrhea
Single dose – 500 mg intramuscularly.
Syphilis
The generally recommended doses are 500 mg – 1 g once daily, increasing to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III))
2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.
Children
Neonates, infants, and children from 15 days to 12 years of age (˂ 50 kg)
Children with a body weight of 50 kg or more should receive 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 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 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 the drug at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or after ineffective prior therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg once daily for 3 days.
Preoperative prophylaxis of surgical site infections
50–80 mg/kg as a single dose before surgery.
Syphilis
The generally recommended dosage is 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 varies; national or local guidelines should also be considered.
Neonates up to 14 days of age
Ephmerin is contraindicated in preterm neonates aged ≤ 41 weeks postmenstrual age (gestational age + postnatal 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 neonates under 14 days of age requiring special dosing regimens.
Acute otitis media
For initial treatment of acute otitis media, a single intramuscular injection of Efmeryn 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 fever has subsided or after confirmation of eradication of the bacterial infection.
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 if renal function is normal.
There are no study data available for patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment
Dose reduction of ceftriaxone is not required in patients with impaired renal function if renal function is not compromised. Only in cases of pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.
Patients undergoing dialysis do not require additional doses 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.
Administration method
Intramuscular administration
Efmeryn can 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 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 product information.
Intravenous administration
Efmeryn can be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over not 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 infants and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special precautions"). Intramuscular administration should be considered when intravenous access 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 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 precautions", and "Incompatibilities").
For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes prior to surgery.
Reconstitution instructions
For intramuscular injection, dissolve:
- 0.5 g in 2 mL of 1% lidocaine solution;
- 1 g in 3.5 mL of 1% lidocaine solution.
For intravenous injection, dissolve:
- 0.5 g in 5 mL of water for injections;
- 1 g in 10 mL of water for injections.
For intravenous infusion, dissolve 2 g of Efmeryn 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 injections.
The displacement volume of 2 g of Efmeryn is 1.37 mL in water for injections.
When 40 mL of water for injections is added, the final concentration of the reconstituted solution is 48.34 mg/mL.
Freshly prepared solutions for injection are recommended. The prepared solution (using 1% lidocaine hydrochloride as solvent) 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 drugs except 1% lidocaine hydrochloride solution (for intramuscular injections only).
The infusion line must be flushed after each administration.
Children
The drug should be used in children according to the dosing instructions specified in the section "Dosage and administration".
Overdose
In case of overdose, nausea, vomiting, and diarrhea may occur. Hemodialysis or peritoneal dialysis does 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 – biliary precipitatesb, 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, renal precipitates (reversible).
General disorders and administration site conditions: uncommon – phlebitis, injection site pain, fever; rare – swelling, chills.
Investigations: uncommon – increased blood creatinine; frequency not knowna – false-positive Coombs testb, false-positive galactosemia testb, false-positive results with non-enzymatic glucose testing methodsb.
a Based on post-marketing reports. Since these reactions are voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency; hence, the frequency is described as 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").
Ceftriaxone calcium salt precipitates.
Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing 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 ceftriaxone elimination half-life compared to adults (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").
Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses of the drug (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those who are dehydrated. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they 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 incidence rates of precipitate formation following intravenous administration, with some studies reporting rates exceeding 30%. The incidence 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 typically resolve after discontinuation of ceftriaxone (see section "Special precautions for use").
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.
Shelf life.
2 years.
Storage conditions.
Keep out of reach and sight of children.
Store in the original packaging at a temperature not exceeding 25 °C.
Reconstituted solution should be used within 6 hours at room temperature or within 24 hours if 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 should not be mixed or administered simultaneously with solutions containing calcium, including parenteral nutrition solutions (see sections "Dosage and administration", "Special precautions for use", and "Adverse reactions").
When co-administering with other antibiotics, separate syringes or solutions should be used.
Packaging.
1 g or 2 g of the medicinal product in a glass vial closed with a rubber stopper and aluminum cap with flip-off seal, one vial per carton.
Prescription status.
Prescription only.
Manufacturer.
Ananta Medicare Limited.
Manufacturer's address.
Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udiog Vihar, Sri Ganganagar-335002 (Rajasthan), India.
Marketing Authorization Holder.
Ananta Medicare Ltd.
Address of the Marketing Authorization Holder and/or its representative.
Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.