Lavakson

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAVAXON (LavaxonE)

Composition:

Active substance: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to ceftriaxone 1.0 g or 2.0 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder from white to yellow-orange in color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone.

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Ceftriaxone is a parenteral third-generation cephalosporin antibiotic with prolonged action.

Mechanism of action.

The bactericidal activity of ceftriaxone is due to inhibition of cell wall synthesis. Ceftriaxone is active in vitro against a broad spectrum of Gram-negative and Gram-positive microorganisms. Ceftriaxone is highly stable against most beta-lactamases (both penicillinases and cephalosporinases) produced by Gram-positive and Gram-negative bacteria. Ceftriaxone is generally active in vitro and in clinical infections against the following microorganisms (see section "Indications"):

Gram-positive aerobes.

Staphylococcus aureus (methicillin-susceptible), coagulase-negative staphylococci, Streptococcus pyogenes (beta-hemolytic, group A), Streptococcus agalactiae (beta-hemolytic, group B), beta-hemolytic streptococci (groups neither A nor B), Streptococcus viridans, Streptococcus pneumoniae.

Note. Methicillin-resistant Staphylococcus spp. are resistant to cephalosporins, including ceftriaxone. Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes are also resistant to ceftriaxone.

Gram-negative aerobes.

Acinetobacter lwoffi, Acinetobacter anitratus (mainly A. baumannii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alkali-like bacteria, Borrelia burgdorferi, Burkholderia cepacia, Capnocytophaga spp., Citrobacter diversus (including C. amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes *, Enterobacter cloacae *, Enterobacter spp. (others)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri *, Proteus vulgaris, Pseudomonas fluorescens **, Pseudomonas spp. (others)*, Providencia rettgeri, Providencia spp. (others), Salmonella typhi, Salmonella spp. (group enteritidis), Serratia marcescens, Serratia spp. (others), Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others).

* Some isolates of these species are resistant to ceftriaxone, mainly due to chromosomally mediated beta-lactamase production;

** some isolates of Klebsiella pneumoniae are resistant to ceftriaxone due to production of several plasmid-mediated beta-lactamases.

Note. Many strains of the above-mentioned microorganisms exhibiting multiple resistance to antibiotics such as aminopenicillins and ureidopenicillins, first- and second-generation cephalosporins, and aminoglycosides, remain susceptible to ceftriaxone. Treponema pallidum is susceptible to ceftriaxone in vitro and in animal studies. Clinical trials have shown that ceftriaxone is effective in the treatment of primary and secondary syphilis. With rare exceptions, clinical isolates of P. aeruginosa are resistant to ceftriaxone.

Anaerobes.

Bacteroides spp. (bile-sensitive)*, Clostridium spp. (except C. perfringens group), Fusobacterium nucleatum, Fusobacterium spp. (others), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococci.

* Some isolates of Bacteroides spp. are resistant to ceftriaxone.

Note. Many strains of Bacteroides spp., particularly those producing beta-lactamases (e.g., B. fragilis), are resistant to ceftriaxone. Clostridium difficile is resistant.

Susceptibility to ceftriaxone can be determined by the disk diffusion method or by agar or broth dilution methods using standardized procedures similar to those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). For ceftriaxone, the NCCLS has established the following criteria for interpretation of susceptibility testing results:

To determine microbial sensitivity, ceftriaxone-impregnated disks should be used, since in vitro studies have shown that ceftriaxone is active against certain strains resistant when tested with disks intended for the entire cephalosporin group.

Instead of NCCLS standards for determining microbial susceptibility, other well-standardized guidelines such as DIN and ICS may also be used, allowing adequate assessment of the sensitivity level.

Pharmacokinetics.

The pharmacokinetics of ceftriaxone are nonlinear. All major pharmacokinetic parameters based on total drug concentrations (free and protein-bound ceftriaxone), with the exception of elimination half-life, are dose-dependent.

Absorption.

Maximum plasma concentration after intramuscular administration of 1 g of the drug is 81 mg/L, reached within 2–3 hours after administration. Single intravenous infusions of 1 g and 2 g result in concentrations of 168.1 ± 28.2 mg/L and 256.9 ± 16.8 mg/L, respectively, within 30 minutes. The area under the plasma concentration-time curve (AUC) after intravenous administration is equivalent to that after intramuscular administration. This indicates that the bioavailability of ceftriaxone after intramuscular injection is 100%.

Distribution.

The volume of distribution of ceftriaxone ranges from 7 to 12 L. After intravenous administration, ceftriaxone rapidly penetrates into interstitial fluid, where bactericidal concentrations against susceptible microorganisms are maintained for 24 hours.

After administration at doses of 1–2 g, ceftriaxone penetrates well into tissues and body fluids. For over 24 hours, its concentrations exceed the minimum inhibitory concentrations for most pathogens by more than 60-fold in over 60 different tissues and fluids (including lungs, heart, biliary tract, liver, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretions).

Ceftriaxone reversibly binds to albumin, with the extent of binding decreasing as concentration increases—for example, from 95% at plasma concentrations below 100 mg/L to 85% at 300 mg/L. Due to lower albumin concentrations in tissue fluid, the proportion of free (unbound) ceftriaxone is higher in tissue fluid than in plasma.

Ceftriaxone crosses the inflamed meninges in children, including newborns. Maximum concentration in cerebrospinal fluid (CSF) is reached approximately 4 hours after intravenous administration and averages 18 mg/L at doses of 50–100 mg/kg. In bacterial meningitis, the average CSF concentration of ceftriaxone is 17% of the plasma concentration; in aseptic meningitis, it is 4%. Twenty-four hours after intravenous administration of Lavaxon at 50–100 mg/kg, ceftriaxone concentrations in CSF exceed 1.4 mg/L. In adults with meningitis, administration of a 50 mg/kg dose results in CSF concentrations that exceed the minimum inhibitory concentrations for the most common meningitis pathogens by several-fold within 2–24 hours.

Ceftriaxone crosses the placental barrier and passes into breast milk in small concentrations (3–4% of maternal plasma concentration at 4–6 hours post-dose).

Metabolism.

Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.

Elimination.

Total plasma clearance of ceftriaxone is 10–22 mL/min. Renal clearance is 5–12 mL/min. Approximately 50–60% of ceftriaxone is excreted unchanged by the kidneys and 40–50% unchanged via bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours.

Pharmacokinetics in special populations.

In neonates, approximately 70% of the dose is excreted renally. In children during the first 8 days of life and in patients aged 75 years and older, the elimination half-life is on average 2–3 times longer than in younger adults.

In patients with mild to moderate renal or hepatic impairment, the pharmacokinetics of ceftriaxone are only minimally altered, with only a slight increase in plasma elimination half-life. When only renal function is impaired, biliary excretion increases; when only hepatic function is impaired, renal excretion increases.

Clinical characteristics.

Indications.

Lavaxon is indicated for the treatment of the following infections in adults and children, including full-term newborns (from birth):

• bacterial meningitis;
• community-acquired pneumonia;
• hospital-acquired pneumonia;
• acute otitis media;
• intra-abdominal infections;
• complicated urinary tract infections (including pyelonephritis);
• bone and joint infections;
• complicated skin and soft tissue infections;
• gonorrhea;
• syphilis;
• bacterial endocarditis.

The drug 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 suggestive of 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.

The drug should be administered in combination with other antibacterial agents when the potential range of bacterial pathogens falls outside its spectrum of activity (see section "Special precautions for use").

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

Contraindications.

Hypersensitivity to ceftriaxone or to any other cephalosporin. 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 neonates 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 salts (see sections "Special 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-induced encephalopathy in these patients.

Prior to intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use"). Refer to the lidocaine prescribing information, particularly contraindications.

Solutions of ceftriaxone 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 Lavaxon in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-type connector. However, in patients other than neonates, 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 plasma from adult and neonatal umbilical cord blood have shown that neonates are at increased risk of ceftriaxone-calcium salt precipitate formation (see sections "Contraindications", "Special precautions for use", "Method of administration and dosage", and "Adverse reactions").

Concomitant use of the drug with oral anticoagulants may enhance the anti-vitamin K effect 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 nephrotoxicity of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.

In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.

No interactions have been reported between ceftriaxone and orally administered calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (for intravenous or oral administration).

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, false-positive results may occur when urine glucose is tested by non-enzymatic methods. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

No renal function impairment has been observed following concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).

Concomitant administration of probenecid does not reduce ceftriaxone excretion.

Special precautions for use.

Hypersensitivity reactions.

As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Kounis syndrome—a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, administration of 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 used with caution in patients with a history of mild hypersensitivity to other beta-lactam agents.

Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS syndrome]) associated with ceftriaxone therapy have been reported. These reactions may be life-threatening or fatal; however, the frequency of such events is unknown (see section "Adverse reactions").

Jarisch-Herxheimer reaction.

In some patients with spirochetal infections, a Jarisch-Herxheimer reaction may occur immediately after initiation of ceftriaxone therapy. This reaction is typically self-limiting or may be managed with symptomatic treatment. Antibiotic therapy need not be discontinued upon occurrence of this reaction.

Interaction with calcium-containing medicinal products.

Fatal precipitations of ceftriaxone-calcium salt in the lungs and kidneys have been reported in premature and full-term neonates up to 1 month of age. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to available scientific data, there have been no confirmed cases of intravascular precipitation 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 higher risk of ceftriaxone-calcium salt precipitation compared to patients in other age groups.

Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of patient age, even when using different infusion systems or administering through different infusion sites. However, in patients aged 28 days or older, ceftriaxone and calcium-containing solutions may be administered sequentially if administered through separate infusion systems at different body sites, or if 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 alternative antibacterial agents that do not carry a similar precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, provided they are given through separate infusion systems at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems should be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").

Children.

The safety and efficacy of Lavaxon in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like certain other cephalosporins, may displace bilirubin from its binding to serum albumin.

Lavaxon is contraindicated in premature 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 Lavaxon (see section "Adverse reactions"). Severe cases of hemolytic anemia, including fatal cases, have been reported during Lavaxon treatment in both adults and children.

If anemia develops during ceftriaxone therapy, cephalosporin-associated anemia should be considered, and ceftriaxone should be discontinued until the etiology is determined.

Prolonged therapy.

During prolonged treatment, a complete blood count should be monitored 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 "Adverse reactions"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic agents 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 drug is recommended (see section "Dosage and administration").

Effect on serological test results.

When using Lavaxon, the Coombs test may yield false-positive results. Lavaxon may also cause false-positive results in galactosemia testing (see section "Adverse reactions").

False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Lavaxon therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Adverse reactions").

Sodium.

One gram of Lavaxon contains 3.6 mmol of sodium. This should be taken into account for patients on a sodium-controlled diet.

Spectrum of antibacterial activity.

Ceftriaxone has a limited spectrum of antibacterial activity and may be inappropriate for use as monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant organisms are suspected, consideration should be given to the use of additional antibiotics.

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 considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis.

In the presence of shadows on ultrasound, the possibility of ceftriaxone-calcium salt precipitation should be considered. Shadows, mistakenly interpreted as gallstones, have been observed on gallbladder ultrasound, with increased frequency at ceftriaxone doses of 1 g/day or higher. Particular caution is advised when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. Rarely, ceftriaxone-calcium precipitates have 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 "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving Lavaxon (see section "Adverse reactions"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, or total parenteral nutrition. The formation of precipitates in the biliary tract due to Lavaxon administration cannot be ruled out as an initiating or contributing factor in this condition.

Nephrolithiasis.

Cases of kidney stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). 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 therapy (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Dosage and administration") or central nervous system disorders. If ceftriaxone-associated encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, seizures), discontinuation of ceftriaxone should be considered.

Disposal of medicinal product.

Environmental contamination with the medicinal product should be minimized. Care should be taken to prevent the medicinal product from entering sewage systems or household waste. Any unused medicinal product after completion of treatment or after expiry should be returned in the original packaging to the supplier (physician or pharmacist) for proper disposal.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Data on the use of ceftriaxone in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, perinatal, or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.

Breastfeeding period.

Ceftriaxone is excreted in 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 also 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 mother.

Fertility.

Reproductive function studies revealed no evidence of adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

Appropriate studies have not been conducted. Due to the possible occurrence of adverse reactions such as dizziness, Lavaxon may affect the ability to drive vehicles or operate complex machinery.

Method of administration and dosage.

Dosage

The dose of the medicinal product depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and liver and kidney function.

The recommended doses for specific indications are listed below. In particularly severe cases, the highest dose within the recommended range should be used.

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

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

** When doses exceeding 2 g per day are used, consideration should be given to administering the drug twice daily (with a 12-hour interval).

Indications in adults and children aged 12 years and older (≥ 50 kg) requiring special dosing regimens.

Acute otitis media

A single intramuscular dose of 1–2 g of ceftriaxone may be used.

Some data suggest that in cases of severe illness or when prior therapy has been ineffective, Lavakson may be effective when administered intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative surgical site infection prophylaxis

Single dose of 2 g prior to surgery.

Gonorrhea

Single dose of 500 mg administered intramuscularly.

Syphilis

Recommended dose is 0.5–1 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

Children aged 15 days to 12 years (<50 kg)

Children with body weight ≥ 50 kg should receive the standard adult doses.

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

** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.

Indications in 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 Lavaxon at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or after ineffective prior therapy, Lavaxon may be effective when administered intramuscularly at a dose of 50 mg/kg per day for 3 days.

Preoperative prophylaxis of surgical site infections

50–80 mg/kg as a single dose before surgery.

Syphilis

The recommended dose 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.

Newborns aged 0–14 days

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

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

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

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

Acute otitis media

For initial treatment of acute otitis media, a single intramuscular injection of Lavaxon 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 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 defervescence or 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 no need for dose adjustment in patients with mild to moderate hepatic impairment, provided renal function is normal.

There are no study data in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment

For patients with impaired renal function, there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in pre-terminal renal failure (creatinine clearance less than 10 mL/min) should the daily dose of ceftriaxone not exceed 2 g.

If the patient is undergoing dialysis, there is no need for additional drug administration after dialysis. Ceftriaxone is not eliminated 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.

Route of administration

Intramuscular administration

Ceftriaxone may be administered by deep intramuscular injection. The injection should be given into the center of the gluteal muscle. It is recommended not to inject more than 1 g at a single site.

If lidocaine is used as a solvent, the resulting solution must never be administered intravenously (see section "Contraindications"). It is recommended to refer to the lidocaine package insert.

Intravenous administration

Ceftriaxone may 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 in neonates and children under 12 years of age. In neonates, intravenous doses should be administered over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see sections "Contraindications" and "Special warnings and precautions for use"). 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) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to 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 before surgery.

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, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. In case of overdose, nausea, vomiting, and diarrhea may occur. There is no specific antidote. Treatment of overdose is symptomatic.

Adverse reactions.

The most commonly observed adverse reactions during ceftriaxone use are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzyme levels.

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, < 1/10)
uncommon (≥ 1/1000, < 1/100)
rare (≥ 1/10000, < 1/1000)
frequency not known (cannot be estimated from available data; based on post-marketing reports; because reports of these reactions were voluntary and the population size is unknown, reliable frequency estimation is not possible, therefore they are categorized as reactions with unknown frequency).

Infections and infestations: uncommon – genital fungal infections; rare – pseudomembranous colitis; frequency not known – superinfections.

Blood and lymphatic system disorders: common – eosinophilia, leukopenia, thrombocytopenia; uncommon – granulocytopenia, anemia, coagulation disorders; frequency not known – hemolytic anemia, agranulocytosis.

Cardiac disorders: frequency not known – Kounis syndrome.

Immune system disorders: frequency not known – anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity, Jarisch-Herxheimer reaction (see section "Special warnings and precautions for use").

Nervous system disorders: uncommon – headache, dizziness; rare – encephalopathy; frequency not known – seizures.

Ear and labyrinth disorders: frequency not known – vertigo.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – loose stools, diarrhea; uncommon – nausea, vomiting; frequency not known – pancreatitis, stomatitis, glossitis.

Hepatobiliary disorders: common – increased liver enzyme levels; frequency not known – biliary sludge, kernicterus, hepatitis\1, cholestatic hepatitis\1,2

\1 Usually reversible upon discontinuation of ceftriaxone.

\2 See section "Special warnings and precautions for use".

Skin and subcutaneous tissue disorders: common – rash; uncommon – pruritus; rare – urticaria; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special warnings and precautions for use").

Renal and urinary disorders: rare – hematuria, glucosuria; frequency not known – oliguria, formation of precipitates in the kidneys (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 – false-positive Coombs test results, false-positive galactosemia test results, false-positive results with non-enzymatic glucose tests.

Infections and infestations.

Diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate 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 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 half-life compared to adults (see sections "Contraindications" and "Special warnings and precautions for use").

Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams, and who had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients or those with dehydration. Precipitates may be symptomatic or asymptomatic, may lead to renal failure and anuria, and resolve after discontinuation of ceftriaxone (see section "Special warnings and precautions for use").

Cases of ceftriaxone calcium salt precipitate formation in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation with intravenous administration: in some studies exceeding 30%. The rate of precipitate formation appears 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 warnings and precautions for use").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

The reconstituted solution should be stored for no more than 6 hours at room temperature and no more than 24 hours at 2–8 °C.

Incompatibilities.

According to published data, ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.

Lavaxon must not be mixed with certain calcium-containing diluents, such as Ringer's solution or Hartmann's solution, due to the potential for precipitate formation.

Solutions containing ceftriaxone should not be mixed or combined with other drugs except those specified in the section "Dosage and administration".

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition solutions (see sections "Contraindications", "Dosage and administration", "Special warnings and precautions for use", and "Adverse reactions").

When prescribing Lavaxon in combination with another antibiotic, the drugs should be administered using separate syringes or in separate infusion solutions.

Packaging.

1.0 g or 2.0 g of the drug in a glass vial, stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap providing first-opening control.

1 vial or 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Astral steritech Private Limited
Astral steritech Private Limited

Manufacturer's address and place of business.

911, G.I.D.C., Makarpura, Vadodara, Gujarat, 390 010, India
911, Gidc, Makarpura, Vadodara, Gujarat 390 010, India (IND)

Marketing authorization holder.

M.Biotech Ltd
M.Biotech Ltd

Address of the marketing authorization holder.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom