Alvobak
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALVOBAC (ALVOBAC)
Composition:
active substance: ceftriaxone;
1 vial contains ceftriaxone disodium hemiheptahydrate equivalent to ceftriaxone 1 g;
excipients: none.
Pharmaceutical form. Powder for solution for injection.
Main physico-chemical properties: crystalline powder of almost white or yellowish 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) ceases, leading to bacterial cell lysis and death. Resistance
Bacterial resistance to ceftriaxone may develop due to 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
The minimum inhibitory concentration (MIC) breakpoints 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 based on susceptibility to cefoxitin.
b. Susceptibility conclusion based on susceptibility to penicillin.
c. Rare isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints may occur; if observed, repeat testing should be performed, and upon confirmation, isolates should be referred 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.
Generally susceptible species
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.
Gram-negative aerobes
Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.
Species for which acquired resistance may be a problem
Gram-positive aerobes
Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.
Gram-negative aerobes
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.
Inherently resistant microorganisms
Gram-positive aerobes
Enterococcus spp., Listeria monocytogenes.
Gram-negative aerobes
Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.
Anaerobes
Clostridium difficile
Others:
Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
- Resistance frequency > 50% in at least one region.
% Strains producing extended-spectrum beta-lactamases are always resistant.
Pharmacokinetics
Absorption
Intramuscular administration
Following 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 1 g intramuscular dose 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 1 g ceftriaxone, the mean peak plasma concentration is approximately 200 mg/L. After intravenous infusion of 1 g ceftriaxone, plasma concentration is approximately 150 mg/L.
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) was observed with repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.
Penetration into specific tissues
Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak cerebrospinal fluid 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; the extent of binding decreases with increasing concentration (down 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 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 only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.
The moderately prolonged half-life in renal impairment is explained by compensatory increases in non-renal clearance due to reduced plasma protein binding, resulting in increased non-renal clearance of total 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 clearance of the drug, 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 plasma protein binding. In children, the elimination half-life is shorter than in neonates or adults.
Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.
Linearity / non-linearity
The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with dose. Non-linearity occurs due to saturation of plasma protein binding; thus, it is observed for total ceftriaxone in plasma, but not for free (unbound) ceftriaxone.
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.
Alvobak 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 or older;
- surgical prophylaxis of infection at the site of intervention;
- management of patients with neutropenia who develop fever suspected to be due to bacterial infection;
- treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of these infections is suspected.
Alvobak 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 Warnings and Precautions for Use").
Official recommendations on appropriate use of antibacterial agents should be taken into account.
Contraindications
Hypersensitivity to ceftriaxone or to any other cephalosporin. History of severe hypersensitivity reactions (e.g. anaphylactic reactions) to any other type of 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, since bilirubin binding is likely impaired in 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 Warnings and Precautions for Use" 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 such patients.
Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special Warnings and Precautions for Use"). Refer to the lidocaine product information, particularly contraindications.
Ceftriaxone solutions containing lidocaine must never be administered intravenously.
Interaction with Other Medicinal Products and Other Forms of Interaction
Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Alvobak 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 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 precipitate formation in newborns (see sections "Contraindications", "Special Warnings and Precautions for Use", "Dosage and Administration", "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 adjusted appropriately both during and after ceftriaxone therapy (see section "Adverse Reactions").
There are conflicting data regarding the potential for increased nephrotoxic effect 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 interaction has been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).
Patients receiving ceftriaxone may exhibit false-positive direct Coombs' test results.
Like other antibiotics, ceftriaxone may cause false-positive results in tests for galactosemia.
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 elimination.
Special Warnings and 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, ceftriaxone must be discontinued immediately and appropriate emergency measures should be initiated. Prior to initiating therapy, it is essential to determine whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or other types of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam drugs. Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)) have been reported, 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 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, 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 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 aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the drugs are administered through different infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with physiological saline 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 whose use is not associated with 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 Alvobac 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. Alvobac 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 Alvobac (see section "Side Effects"). Severe cases of hemolytic anemia, including fatal cases, have been reported during treatment with Alvobac in both adults and children.
If a patient develops anemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated anemia should be considered, and ceftriaxone therapy should be discontinued until the etiology is established.
Prolonged Treatment
During prolonged treatment, a complete blood count should be performed regularly.
Colitis / Overgrowth of Resistant Microorganisms
Cases of colitis and pseudomembranous colitis associated with antibacterial agents have been reported 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 initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic medicinal products should not be used.
As with other antibacterial agents, superinfections caused by microorganisms resistant to the drug may occur.
Severe Renal and Hepatic Impairment
In cases of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the medicinal product is recommended (see section "Dosage and Administration").
Effect on Serological Test Results
During treatment with Alvobac, the Coombs test may yield false-positive results. Alvobac 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 treatment with Alvobac, urine glucose levels should be determined using enzymatic assay methods (see section "Side Effects").
Antibacterial Spectrum
Ceftriaxone has a limited antibacterial spectrum 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 information must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Cholelithiasis
On ultrasound, shadows should prompt consideration of ceftriaxone calcium salt precipitation. Hyperechoic images, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency during ceftriaxone administration at 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 on discontinuation of the drug based on a benefit-risk assessment in the individual case (see section "Side Effects").
Cholestasis
Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving Alvobac (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 Alvobac administration cannot be excluded as an initiating or contributing factor in this condition.
Jarisch-Herxheimer Reaction (JHR)
In some patients with spirochetal infections, a Jarisch-Herxheimer reaction (JHR) may occur shortly after initiation of ceftriaxone therapy. JHR is generally a self-limiting condition or can be managed with symptomatic therapy. Antibiotic treatment should not be discontinued if JHR occurs.
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 in the individual case.
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. 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 medicinal products should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be performed via a dedicated "waste collection system" if available.
Important Information on Excipients
Sodium
One gram of Alvobac contains 2.28 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.
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 potential benefit outweighs the potential risk.
Breastfeeding Period
Ceftriaxone passes into breast milk in low concentrations, but 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/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 revealed any adverse effects on male or female fertility.
Ability to Affect Reaction Speed When Driving or Operating Machinery
During ceftriaxone therapy, adverse reactions such as dizziness may occur, which could impair the ability to drive or operate machinery (see section "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 on the patient's age and liver and kidney function.
The dosages listed below are generally recommended for these indications. In particularly severe cases, the highest dose within the recommended range should be used.
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. Acute exacerbation of chronic obstructive pulmonary disease. Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis) |
| 2 g |
Once daily |
Hospital-acquired pneumonia. Complicated skin and soft tissue infections. Bone and joint infections |
| 2–4 g |
Once daily |
Management of febrile neutropenic patients with suspected 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 daily 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 Alvobac medicinal product may be administered.
Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Alvobac may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.
Preoperative prophylaxis of surgical site infections
A single dose of 2 g administered preoperatively.
Gonorrhoea
A single intramuscular dose of 500 mg.
Syphilis
The generally recommended doses are 500 mg – 1 g once daily, increasing the dose to 2 g once daily in cases of neurosyphilis, for 10–14 days. 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 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* |
Dosing frequency** |
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 newborns, infants, and children aged 15 days to 12 years (< 50 kg) requiring special dosing regimens:
Acute otitis media
For initial treatment of acute otitis media, a single intramuscular injection of Alvobak at a dose of 50 mg/kg may be administered. Some data suggest that in cases of severe illness or previous ineffective therapy, Alvobak may be effective when given 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 may vary; national or local guidelines should also be considered.
Newborns aged 0–14 days
Alvobak is contraindicated in preterm newborns under 41 weeks of gestational age (gestational age + postnatal age).
Table 3
| Ceftriaxone dose* |
Frequency of administration |
Indications |
| 20–50 mg/kg |
Once daily |
Intra-abdominal infections. |
| 50 mg/kg |
Once daily |
Bacterial meningitis. |
* 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 should 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 Alvobac at a dose of 50 mg/kg may be administered.
Preoperative prophylaxis of surgical site infections
20–50 mg/kg as a single dose before surgery.
Syphilis
The generally recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered. Duration of treatment
The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after fever subsides or after confirmation of eradication of bacterial infection.
Geriatric patients
In patients with normal renal and hepatic function, dose adjustment in elderly patients is not required.
Patients with hepatic impairment
Available data indicate that dose adjustment is not necessary in patients with mild to moderate hepatic impairment 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 hepatic function is normal. Only in pre-terminal stages of 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 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 renal and hepatic dysfunction, careful clinical monitoring of the safety and efficacy of the drug is recommended.
Administration method
Intramuscular administration
The medicinal product Alvobac 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 package leaflet for lidocaine should be consulted. Prior to lidocaine use, a sensitivity test should be performed to determine individual susceptibility to this medicinal product.
Intravenous administration
The medicinal product Alvobac 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 warnings and precautions for use"). Intramuscular administration should be considered when intravenous administration is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously. Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including intravenous 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 dissolve ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of ceftriaxone calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special warnings and precautions for use", and "Incompatibilities").
For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes prior to surgery.
Children
The drug should be administered to children according to the dosing instructions specified in the section "Administration and dosage".
Overdose
In case of overdose, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse Reactions
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.
Events are classified by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); frequency not known (cannot be estimated from available data).
Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous 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.
Immune system disorders: frequency not knowna – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactionsb, Jarisch-Herxheimer reaction (JHR)b.
Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not knowna – seizures.
Cardiac disorders: frequency not knowna – Kounis syndrome.
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 – elevated liver enzymes; frequency not knowna – biliary precipitatesb, nuclear jaundice, hepatitis1, cholestatic hepatitis1,2.
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)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 methods for glucose testingb.
a Based on post-marketing reports. Since information on these reactions is voluntarily reported from a population of uncertain size, reliable estimation of frequency is not possible, and thus frequency is categorized as "not known".
b See section "Special warnings and precautions for use".
1 Usually reversible upon discontinuation of ceftriaxone.
2 See section "Special warnings and precautions for use".
Infections and infestations
Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special warnings and 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 elimination half-life of ceftriaxone compared to adults (see sections "Pharmacodynamics", "Contraindications", "Special warnings and precautions for use").
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 g, and who also had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those with dehydration. Precipitates may be symptomatic or asymptomatic and may lead to renal failure and anuria; they typically resolve after discontinuation of ceftriaxone (see section "Special warnings and precautions for use").
Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence of precipitate formation with intravenous administration, exceeding 30% in some studies. The incidence 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 warnings and precautions for use").
Reporting of 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 and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Reconstituted solution should be stored for no more than 6 hours at temperatures not exceeding 25 °C, or for no more than 24 hours at 2–8 °C.
Storage conditions
No special storage conditions required. Store in a place inaccessible to children.
Incompatibilities
Ceftriaxone must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution.
Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides. It should not be mixed with solvents other than those specified in the section "Dosage and administration".
Packaging
1 g of powder in a glass vial; 1 or 10 vials per cardboard box.
Prescription status. Prescription only.
Manufacturer
ACS DOBFAR S.P.A.
Manufacturer's address and location of operations
NUCLEO INDUSTRIALE S. ATTO (LOC. S. NICOLÒ A TORDINO), 64100 TERAMO (TE), ITALY or VIA ALESSANDRO FLEMING, 2, VERONA (VR), 37135, ITALY.