Alvococ
UkraineTable of Contents
INSTRUCTIONS for medical use of the medicinal product ALVOCOC (ALVOCOC)
Composition:
Active substance: ceftriaxone;
1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1 g.
Pharmaceutical form. Powder for solution for injection.
Main physico-chemical properties: crystalline powder of nearly white or yellowish color. Slightly hygroscopic.
Pharmacotherapeutic group.
Antibacterial agents for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action.
Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, biosynthesis of the cell wall (peptidoglycan) ceases, leading to lysis and death of the bacterial cell. 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 permeability of the outer membrane in gram-negative bacteria.
- Bacterial efflux pumps.
Breakpoints for susceptibility testing
Breakpoints for minimum inhibitory concentration have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):
| Pathogen |
Dilution method (minimum inhibitory concentration, mg/l) |
|
| Susceptible |
Resistant |
|
| Enterobacteriaceae |
≤ 1 |
> 2 |
| Staphylococcus spp. |
a |
a |
| Streptococcus spp. (groups A, B, C and G) |
b |
b |
| Streptococcus pneumoniae |
≤ 0.5c |
> 2 |
| Viridans group Streptococci |
≤ 0.5 |
> 0.5 |
| Haemophilus influenzae |
≤ 0.12c |
> 0.12 |
| Moraxella catarrhalis |
≤ 1 |
> 2 |
| Neisseria gonorrhoeae |
≤ 0.12 |
> 0.12 |
| Neisseria meningitidis |
≤ 0.12 c |
> 0.12 |
| Non-species related |
≤ 1d |
> 2 |
a susceptibility conclusion was based on susceptibility to cefoxitin;
b susceptibility conclusion was based on susceptibility to penicillin;
c isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely observed; if such isolates are detected, repeat testing should be performed, and if confirmed, the isolate should be sent to a reference laboratory;
d breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose of at least 2 g × 1.
Clinical efficacy against specific pathogens
The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Expert consultation should be sought if local resistance prevalence renders the utility of ceftriaxone at least questionable for certain types of infections.
Generally susceptible species.
Gram-positive aerobes.
Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.
Gram-negative aerobes.
Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.
Species for which acquired resistance may be problematic.
Gram-positive aerobes.
Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.
Gram-negative aerobes.
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes.
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.*
Initially resistant microorganisms.
Gram-positive aerobes.
Enterococcus spp., Listeria monocytogenes.
Gram-negative aerobes.
Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.
Anaerobes.
Clostridium difficile.
Others:
Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
- Resistance frequency >50% in at least one region.
% Strains producing extended-spectrum beta-lactamases are always resistant.
Pharmacokinetics.
Absorption.
Intramuscular administration.
After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is 81 mg/L, achieved 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 ranges from 7 to 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 (CSF) in patients with bacterial meningitis reaches up to 25% of the plasma concentration, compared to 2% in patients without meningitis. Peak CSF concentrations are achieved approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and low concentrations are expected in breast milk (see section "Use during pregnancy or breastfeeding").
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.
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 minimally altered, with a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment. The relatively modest 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 ceftriaxone extrarenal clearance.
In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, contributing to the observed paradoxical increase in total clearance, 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 older children, the elimination half-life is shorter than in neonates or adults.
Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.
Linearity/non-linearity.
The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with dose. Non-linearity arises from saturation of plasma protein binding; thus, it 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 > minimum inhibitory concentration).
Clinical characteristics.
Indications.
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.
Alvokok 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 are suspected.
Alvokok should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions").
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems).
Ceftriaxone is contraindicated:
In preterm newborns aged ≤ 41 weeks postmenstrual age (gestational age + postnatal age)*.
In full-term newborns (aged ≤ 28 days):
- with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired under these conditions*;
- who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salt (see sections "Special precautions" and "Adverse reactions").
* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the risk of bilirubin encephalopathy in these patients.
Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions"). Refer to the medical instructions for 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 Alvokok in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salt may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site connector. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn cord plasma have shown an increased risk of ceftriaxone-calcium salt precipitation in newborns (see sections "Contraindications", "Special precautions", "Method of administration and dosage", "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 drugs or between intramuscular ceftriaxone and calcium-containing drugs (administered intravenously or orally) have been reported.
Patients receiving ceftriaxone may exhibit false-positive results in the Coombs test. Like other antibiotics, ceftriaxone may cause false-positive results in galactosemia testing.
Similarly, when glucose in urine is tested by non-enzymatic methods, results may be falsely positive. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.
No renal function impairment has been observed after concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).
Concomitant administration of probenecid does not reduce ceftriaxone excretion.
Special precautions for use.
Hypersensitivity reactions.
As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Coombs 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 discontinued immediately and appropriate emergency measures should be taken. 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 administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs.
Serious skin adverse reactions (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) and reactions 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").
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 therapy should not be discontinued if such a reaction occurs.
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, confirmed cases of intravascular precipitation have only been observed in neonates who received ceftriaxone and calcium-containing solutions or any other calcium-containing medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium salt precipitation compared to patients in other age groups.
Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering the drugs into different infusion sites. However, in patients older than 28 days, 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 thoroughly flushed with saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may consider prescribing alternative antibacterial agents that do not carry such precipitation risk. If ceftriaxone use in patients requiring continuous nutrition is deemed necessary, 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 systems should be flushed between administrations (see sections "Pharmacokinetics", "Contraindications", "Side effects", "Incompatibilities").
Children.
The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin. Alvoqoc is contraindicated in preterm and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").
Immune-mediated hemolytic anemia.
Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during ceftriaxone treatment in both adults and children.
If a patient develops anemia during ceftriaxone therapy, diagnosis of cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology of the condition is established.
Prolonged therapy.
Complete blood counts should be performed regularly during prolonged therapy. Colitis/overgrowth of non-susceptible microorganisms.
Cases of colitis and pseudomembranous colitis associated with antibiotic use 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 therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and administration of appropriate agents against Clostridium difficile should be considered. Antiperistaltic medicinal products 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.
Careful clinical monitoring of the drug's safety and efficacy is recommended in cases of severe renal and hepatic impairment (see section "Dosage and administration").
Impact on serological test results.
The Coombs test may yield false-positive results during Alvoqoc therapy. Alvoqoc 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 Alvoqoc therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Side effects").
Ceftriaxone use may cause falsely low blood glucose readings 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 Alvoqoc contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.
Antibacterial spectrum.
Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as monotherapy in 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.
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.
Shadows on ultrasound should raise suspicion of ceftriaxone calcium salt precipitation. Precipitates mimicking gallstones have been observed on gallbladder ultrasound, with increased frequency at ceftriaxone doses of 1 g per day or higher. Particular caution is required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, ceftriaxone calcium salt precipitation has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Side effects").
Biliary stasis.
Cases of pancreatitis, possibly due to 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 Alvoqoc use cannot be ruled out as an initiating or contributing factor in this condition.
Nephrolithiasis.
Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (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 a benefit-risk assessment for the individual case.
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. In suspected ceftriaxone-associated encephalopathy (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 with the medicinal product 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 ceftriaxone use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryo/fetal, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the benefit outweighs the risk.
Lactation.
Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected 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/abandon 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 evidence of 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 affect the ability to drive or operate machinery (see section "Side effects"). Patients should exercise caution when driving or operating machinery.
Method of administration and dosage.
Dosage.
The dose of the drug depends on the severity, sensitivity, location, and type of infection, as well as the patient's age and liver and kidney function.
The doses listed below are generally recommended for these indications. In particularly severe cases, the highest dose within the recommended range should be used.
Table 1.
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 Alvococ can be administered.
Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Alvococ may be effective when administered intramuscularly at a dose of 1–2 g per day for 3 days.
Preoperative prophylaxis of surgical site infections.
A single dose of 2 g prior to surgery.
Gonorrhoea.
A single intramuscular dose of 500 mg.
Syphilis.
The generally recommended doses are 500 mg–1 g once daily, increased to 2 g once daily in cases of neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III)).
2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.
Children.
Neonates, infants, and children aged 15 days to 12 years (<50 kg).
Children with a body weight of 50 kg or more should receive the standard adult doses.
Table 2
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 50–80 mg/kg |
Once daily |
Intra-abdominal infections. |
| 50–100 mg/kg (maximum – 4 g) |
Once daily |
Complicated skin and soft tissue infections. |
| 80–100 mg/kg (maximum 4 g) |
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, 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 Alvoсoc at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or previous ineffective therapy, Alvoсoc may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.
Preoperative surgical site infection prophylaxis.
50–80 mg/kg as a single dose before surgery.
Syphilis.
The generally recommended doses are 75–100 mg/kg (maximum–4 g) once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III)).
50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be considered.
Neonates aged 0–14 days.
Alvoсoc is contraindicated in preterm neonates with a postmenstrual age of less than 41 weeks (gestational age + chronological age).
Table 3
| Ceftriaxone dose* |
Frequency of administration |
Indications |
| 20–50 mg/kg |
Once daily |
Intra-abdominal infections. Complicated skin and soft tissue infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia. Bone and joint infections. Management of febrile neutropenic patients with suspected bacterial infection |
| 50 mg/kg |
Once daily |
Bacterial meningitis. Bacterial endocarditis |
* In documented bacteremia, consideration should be given to using the highest dose within the recommended range.
The maximum daily dose of 50 mg/kg should not be exceeded.
Indications in neonates aged 0–14 days requiring special dosing regimens: Acute otitis media.
For initial treatment of acute otitis media, a single intramuscular injection of Alvoqok 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 subsides or after confirmation of eradication of 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 no need for dose adjustment in patients with mild to moderate hepatic impairment if renal function is normal. There are no study data in patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment.
In patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in preterminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.
Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not removed 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 renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended.
Administration method.
Intramuscular administration.
Alvoqok 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, the instructions for medical use of lidocaine should be consulted.
Intravenous administration.
Alvoqok can be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion to 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 administration is not feasible or less acceptable for the patient. Doses exceeding 2 g should be administered intravenously.
Ceftriaxone is contraindicated in neonates (≤ 28 days) 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 before surgery.
Reconstitution instructions
Freshly prepared solutions are recommended. For stability conditions of the prepared solution, see section "Storage conditions."
The ceftriaxone solution should not be mixed in the same syringe with any other drugs except 1% lidocaine hydrochloride solution (for intramuscular injections only).
The infusion system should be flushed after each administration.
For intramuscular injection, 1 g of Alvoqok should be dissolved in 3.5 mL of 1% lidocaine solution.
For intravenous injection, 1 g of Alvoqok should be dissolved in 10 mL of water for injections.
The displacement volume of 1 g of ceftriaxone is 0.71 mL in water for injections and in 1% lidocaine hydrochloride solution. After adding 10 mL of water for injections, the final concentration of the reconstituted solution is 93.37 mg/mL. After adding 3.5 mL of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 237.53 mg/mL.
Children.
The drug should be used in children according to the dosing instructions specified in the section "Administration and dosage."
Overdose.
In case of overdose, hemodialysis or peritoneal dialysis does not reduce excessive plasma concentrations of the drug. In overdose, nausea, vomiting, and diarrhea may occur. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse Reactions
The adverse reactions most commonly observed during ceftriaxone administration include eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes. The frequency of adverse reactions to ceftriaxone was determined based on clinical trial data.
Reactions are classified by frequency as follows:
- very common (≥ 1/10);
- common (≥ 1/100 to < 1/10);
- uncommon (≥ 1/1000 to < 1/100);
- rare (≥ 1/10,000 to < 1/1000);
- frequency not known (cannot be estimated from available data).
Infections and infestations:
uncommon – genital fungal infections;
rare – pseudomembranous colitis^b;
frequency not known^a – superinfections^b.
Blood and lymphatic system disorders:
common – eosinophilia, leukopenia, thrombocytopenia;
uncommon – granulocytopenia, anemia, coagulation disorders;
frequency not known^a – hemolytic anemia^b, agranulocytosis.
Immune system disorders:
frequency not known^a – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions^b, Jarisch-Herxheimer reaction^b (see section "Special precautions").
Nervous system disorders:
uncommon – headache, dizziness;
rare – encephalopathy;
frequency not known^a – seizures.
Cardiac disorders:
frequency not known^a – Kounis syndrome.
Ear and labyrinth disorders:
frequency not known^a – vertigo.
Respiratory, thoracic and mediastinal disorders:
rare – bronchospasm.
Gastrointestinal disorders:
common – diarrhea^b, loose stools;
uncommon – nausea, vomiting;
frequency not known^a – pancreatitis^b, stomatitis, glossitis.
Hepatobiliary disorders:
common – elevated liver enzymes;
frequency not known^a – biliary precipitates^b, nuclear jaundice, hepatitis^1, cholestatic hepatitis^1,^b.
Skin and subcutaneous tissue disorders:
common – rash;
uncommon – pruritus;
rare – urticaria;
frequency not known^a – Stevens-Johnson syndrome^b, toxic epidermal necrolysis^b, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS)^b (see section "Special precautions").
Renal and urinary disorders:
rare – hematuria, glucosuria;
frequency not known^a – oliguria, renal precipitates (reversible).
General disorders and administration site conditions:
uncommon – phlebitis, injection site pain, fever;
rare – swelling, chills.
Investigations:
uncommon – increased blood creatinine levels;
frequency not known^a – false-positive Coombs test^b, false-positive galactosemia test^b, false-positive non-enzymatic glucose tests^b.
^a Based on post-marketing reports. Since information on these reactions is voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency; hence, frequency is categorized as "not known".
^b See section "Special precautions"
^1 Usually reversible upon discontinuation of ceftriaxone
Infections and infestations.
Cases of diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be provided (see section "Special precautions").
Ceftriaxone calcium salt precipitates.
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 products. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Pharmacodynamics", "Contraindications", "Special precautions").
Cases of renal precipitates 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 g, and who 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, may lead to renal failure and anuria, and typically resolve after discontinuation of ceftriaxone (see section "Special precautions").
Cases of biliary precipitates of ceftriaxone calcium 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 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").
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after drug 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 reporting system.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
The reconstituted solution should be stored protected from light for up to 6 hours at room temperature or for up to 24 hours at 2–8 °C.
Incompatibilities.
Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.
Solutions containing ceftriaxone should not be mixed with other medicinal products or added to them, 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 co-administered with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications", "Special precautions", "Dosage and administration", and "Adverse reactions").
For combination with other antibiotics, separate syringes or infusion solutions should be used.
Packaging.
1 g of powder in a glass vial stoppered with a rubber plug and sealed with an aluminum crimp cap equipped with a flip-off cap providing tamper-evidence. One vial per cardboard pack.
Prescription status. Prescription only.
Manufacturer.
Laboratorio Reig Quesada, S.A.
Manufacturer's address and location of operations.
Calle Gerona, 111, Polígono Industrial, Toledo, 45007 (Toledo), Spain.