Medaxon powder for solution for injection 1 g bottle No. 10

Instructions Medaxon powder for solution for injection 1 g bottle No. 10

Composition

active ingredient: ceftriaxone;

1 vial contains ceftriaxone sodium equivalent to 1 g ceftriaxone.

Dosage form

Powder for solution for injection.

Main physicochemical properties: crystalline powder of almost white or yellowish color, slightly hygroscopic.

Pharmacotherapeutic group

Antibacterials for systemic use. Other beta-lactam antibiotics. Third generation cephalosporins. Ceftriaxone. ATX code J01D D04.

Pharmacological properties

Pharmacodynamics

Mechanism of action: Ceftriaxone inhibits bacterial cell wall synthesis after binding to penicillin-binding proteins, resulting in the cessation of cell wall (peptidoglycan) biosynthesis, which in turn leads to bacterial cell lysis and death.

Resistance. Bacterial resistance to ceftriaxone may develop by one or more of the following mechanisms: hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases; carbapenemases and Amp C enzymes, which may be induced or persistently inhibited in some aerobic Gram-negative bacteria; reduced affinity of penicillin-binding proteins for ceftriaxone; outer membrane impermeability in Gram-negative bacteria; bacterial efflux pumps.

Breakpoints for susceptibility testing. Breakpoints for minimum inhibitory concentration as defined by the European Committee for Antimicrobial Susceptibility Testing:

aSusceptibility is inferred based on susceptibility to cefoxitin.

b Susceptibility is inferred based on penicillin susceptibility.

c Isolates with MICs exceeding the susceptibility breakpoints are rare. If this occurs, retesting should be performed and, if confirmed, sent to a reference laboratory.

d The cut-off values refer to a daily intravenous dose of 1 g × 1 and a high dose of at least 2 g × 1.

Generally sensitive species

Gram-positive aerobes. Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Viridans group streptococci.

Gram-negative aerobes. Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.

Species that may acquire resistance

Gram-positive aerobes. Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.

Gram-negative aerobes. Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.

Anaerobes Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.

Resistant microorganisms

Gram-positive aerobes. Enterococcus spp., Listeria monocytogenes.

Gram-negative aerobes. Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.

Anaerobes. Clostridium difficile.

Others. Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.

£ All methicillin-resistant staphylococci are resistant to ceftriaxone.

+ Resistance rate > 50% in at least one region.

% Strains producing extended-spectrum beta-lactamase are always resistant.

Pharmacokinetics

Absorption.

Intramuscular administration. After intramuscular injection, the mean peak plasma levels of ceftriaxone are approximately half those observed after an equivalent intravenous dose. The maximum plasma concentration (Cmax) after a single intramuscular injection of 1 g of the drug is 81 mg/l and is reached 2-3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equal to that after an equivalent intravenous dose.

Intravenous administration. After intravenous bolus administration of ceftriaxone at doses of 500 mg and 1 g, the mean peak plasma levels of ceftriaxone are approximately 120 and 200 mg/l, respectively. After intravenous infusions of ceftriaxone at doses of 500 mg, 1 g and 2 g, the plasma levels of ceftriaxone are approximately 80, 150 and 250 mg/l, respectively.

Penetration into individual tissues. Ceftriaxone penetrates the meninges. Penetration is more pronounced in meningeal inflammation. The mean Cmax of ceftriaxone in the cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma compared to 2% in patients without meningeal inflammation. Cmax of ceftriaxone in the cerebrospinal fluid is reached approximately 4–6 hours after intravenous injection.

Protein binding. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is approximately 95% at plasma concentrations of less than 100 mg/L. Binding is saturable, with the extent of binding decreasing with increasing concentration (to 85% at plasma concentrations of 300 mg/L).

Metabolism: Ceftriaxone is not subject to systemic metabolism, but is converted to inactive metabolites by the 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 by glomerular filtration, 40–50% is excreted unchanged in the bile. The elimination half-life of ceftriaxone in adults is about 8 hours.

Patients with renal or hepatic impairment. In patients with renal or hepatic impairment, the pharmacokinetics of ceftriaxone are only slightly altered, with only a slight increase in half-life (less than 2-fold), even in patients with severe renal impairment. The relatively modest increase in half-life in renal impairment is due to a compensatory increase in extrarenal clearance resulting from reduced protein binding and a corresponding increase in extrarenal clearance of total ceftriaxone.

In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased due to a compensatory increase in renal clearance. This is also due to an increase in the free fraction of ceftriaxone in plasma, which contributes to a paradoxical increase in total clearance of the drug with an increase in the volume of distribution in parallel with this total clearance.

Elderly patients: In patients aged 75 years and older, the mean elimination half-life is usually 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 continue to increase as a result of factors such as decreased glomerular filtration and impaired protein binding. The elimination half-life is shorter in children 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 nonlinear, and all major pharmacokinetic parameters, except for half-life, are dose-dependent, based on total drug concentration, and decrease less than proportionally with dose. Non-linearity is a result of saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone 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 over which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for the individual target species (i.e., %T > minimum inhibitory concentration).

Indication

Medaxon is used to treat 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. Medaxon can be used to treat: acute complications of chronic obstructive pulmonary disease in adults; disseminated Lyme disease (early (stage II) and late (stage III)) in adults and children, including newborns from 15 days of age; preoperative prophylaxis of infections at the surgical site; management of neutropenic patients who have developed fever and are suspected of having a bacterial infection; treatment of patients with bacteremia due to any of the above infections or if any of the above infections is suspected.

Medaxon should be administered together with other antibacterial agents if the possible range of bacterial pathogens does not fall within its spectrum of action (see section "Special instructions for use"). Official recommendations on the appropriate use of antibacterial agents should be taken into account.

Contraindication

Ceftriaxone is contraindicated in: preterm neonates ≤ 41 weeks of gestational age + postnatal age*; term neonates (≤ 28 days of age): with hyperbilirubinemia, jaundice, hypoalbuminemia or acidosis, as bilirubin binding is likely to be impaired in these conditions*; who require (or are expected to require) intravenous calcium or infusions of calcium-containing solutions, as there is a risk of precipitation of ceftriaxone calcium salt (see sections 4.4 and 4.8).

* In vitro studies have shown that ceftriaxone may displace bilirubin from its association with serum albumin, leading to a possible risk of bilirubin encephalopathy in such patients.

Before intramuscular administration of ceftriaxone, it is essential to exclude contraindications to the use of lidocaine when used as a diluent (see section "Special instructions for use"). See the instructions for medical use of lidocaine, especially contraindications. Ceftriaxone solutions containing lidocaine should never be administered intravenously.

Interaction with other medicinal products and other types of interactions

Ceftriaxone should not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for long-term infusion, such as parenteral nutrition solutions, using a Y-line. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that the system is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and neonatal cord blood plasma have shown that neonates are at increased risk of precipitation of ceftriaxone calcium.

Concomitant use of the drug with oral anticoagulants may increase the antivitamin K effect and the risk of bleeding. It is recommended to frequently check the international normalized ratio and adjust the dose of the antivitamin K agent appropriately both during and after ceftriaxone therapy (see section "Adverse reactions").

There is conflicting evidence regarding the potential for increased renal toxicity of aminoglycosides when used with cephalosporins. In such cases, careful monitoring of aminoglycoside levels (and renal function) should be undertaken in clinical practice.

In an in vitro study, antagonism was observed when chloramphenicol was used in combination with ceftriaxone. The clinical significance of this finding is unknown.

There have been no reported cases of interaction between ceftriaxone and oral calcium-containing drugs or between intramuscular ceftriaxone and calcium-containing drugs (intravenous or oral).

No renal dysfunction has been observed after concomitant use of high doses of ceftriaxone and potent diuretics (e.g. furosemide).

Concomitant use of probenecid does not reduce the excretion of ceftriaxone.

Application features

Hypersensitivity reactions. As with all beta-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section 4.8). In the event of a severe hypersensitivity reaction, ceftriaxone should be discontinued immediately and appropriate emergency measures should be taken. Before initiating treatment, it should be ascertained 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 non-severe hypersensitivity to other beta-lactam agents.

Cases of serious adverse reactions of the skin (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with ceftriaxone-containing medicinal products, which can be life-threatening or fatal; however, the frequency of these events is unknown (see section 4.8).
Jarisch-Herxheimer reaction (JHR).

Interaction with calcium-containing medicinal products. When ceftriaxone is used in patients of any age, the drug should not be mixed or administered simultaneously with any intravenous solutions containing calcium, even if different infusion systems are used or the drugs are administered at different infusion sites. However, in patients 28 days of age and older, ceftriaxone and calcium-containing solutions can be administered sequentially, one after the other, provided that the drugs are administered through different infusion systems at different body sites or that the infusion system is replaced or thoroughly flushed with saline between administrations to prevent the formation of a precipitate. For patients who require continuous infusions of calcium-containing solutions for total parenteral nutrition (TPN), healthcare professionals may prescribe alternative antibacterial agents that do not carry a similar risk of precipitate formation. If the use of ceftriaxone in patients requiring continuous nutrition is deemed necessary, PPH solutions and ceftriaxone may be administered simultaneously, albeit through different infusion systems and into different body sites. Alternatively, the PPH solutions may be suspended during the ceftriaxone infusion and the infusion systems flushed between the administrations of the solutions (see sections Contraindications, Adverse Reactions and Incompatibilities).

Children. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from its association with serum albumin. Medaxon is contraindicated in premature and full-term newborns at risk of bilirubin encephalopathy (see Contraindications).

Immune-mediated haemolytic anaemia. Cases of immune-mediated haemolytic anaemia have been reported in patients receiving cephalosporin antibacterial agents, including ceftriaxone (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment with ceftriaxone in both adults and children. If a patient develops anaemia while receiving ceftriaxone, the diagnosis of cephalosporin-associated anaemia should be considered and ceftriaxone should be discontinued until the etiology is established.

Long-term treatment. During long-term treatment, a complete blood count should be performed regularly.

Colitis/overgrowth of non-susceptible organisms. Antibacterial-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these events may range from mild to life-threatening. Therefore, it is important to consider the possibility of such a diagnosis in patients who develop diarrhoea during or after the use of ceftriaxone (see section 4.8). Ceftriaxone should be discontinued and appropriate anti-Clostridium difficile therapy should be considered. Medicinal products that inhibit peristalsis should not be used.

As with the use of other antibacterial agents, superinfections caused by microorganisms insensitive to the drug may occur.

Sodium: One gram of Medaxon contains 3.6 mmol sodium. This should be taken into consideration by patients on a controlled sodium diet.

Spectrum of antibacterial activity: Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as monotherapy in the treatment of certain types of infection unless the causative agent is already confirmed (see section 4.2). In polymicrobial infections where ceftriaxone-resistant organisms are suspected, the use of additional antibiotics should be considered.

Gallstone disease. In case of shadows on the sonogram, the possibility of ceftriaxone calcium salt precipitates should be considered. Shadows mistakenly considered as gallstones were observed on sonograms of the gallbladder, their frequency increased with the use of ceftriaxone at a dose of 1 g/day and above. Particular caution should be observed when using the drug in children. Such precipitates disappear after discontinuation of ceftriaxone therapy. In rare cases, the formation of ceftriaxone calcium salt precipitates was accompanied by symptoms. In the presence of symptoms, conservative non-surgical treatment is recommended, the doctor should decide to discontinue the drug, based on the results of the benefit-risk assessment of the specific case (see section "Adverse reactions").

Nephrolithiasis. Cases of kidney stones have been reported, which resolved after discontinuation of ceftriaxone (see section 4.8). In case of symptoms, an 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 the results of a benefit-risk assessment of the individual case.

Disposal of the medicinal product. Release of the medicinal product into the environment should be minimised. The medicinal product should not be released into wastewater or household waste. For disposal, use a so-called “waste collection system” if available.

Ability to influence reaction speed when driving vehicles or other mechanisms

During treatment with ceftriaxone, side effects such as dizziness may occur, which may affect the ability to drive or operate machinery (see section "Adverse reactions"). Patients should be careful when driving or operating other machinery.

Use during pregnancy or breastfeeding

Pregnancy.

Ceftriaxone crosses the placental barrier. There are limited data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/fetal, perinatal or postnatal development. Ceftriaxone should be used during pregnancy, particularly during the first trimester, only if the benefit outweighs the risk.

Breastfeeding period.

Ceftriaxone is excreted in breast milk in low concentrations, but no effects on the breastfed infant are expected at therapeutic doses. However, the risk of diarrhoea and fungal infections of the mucous membranes cannot be excluded. The possibility of sensitization should be considered. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility.

Reproductive studies have shown no evidence of adverse effects on male or female fertility.

Method of administration and doses

The dose of the drug depends on the severity, sensitivity, location and type of infection, as well as on the age and liver and kidney function of the patient. For the purpose of preoperative prophylaxis of infections, ceftriaxone should be administered 30–90 minutes before surgery. The generally recommended doses are given below. In particularly severe cases, the highest of the recommended doses should be used.

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

*In case of documented bacteremia, the highest recommended dose should be considered.

**When using doses exceeding 2 g per day, consideration should be given to

administration of the drug 2 times a day (with a 12-hour interval).

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

Acute otitis media. A single intramuscular dose of 1–2 g may be used. Some evidence suggests that in severe cases or when previous therapy has failed, ceftriaxone may be effective when administered intramuscularly at a dose of 1–2 g daily for 3 days.

Preoperative prophylaxis of surgical site infections: 2 g once before surgery.

Gonorrhea: Single dose of 500 mg intramuscularly.

Syphilis. The generally recommended doses are 500 mg to 1 g once daily, increasing to 2 g once daily for 10 to 14 days for neurosyphilis. Dosage recommendations for syphilis, including neurosyphilis, are based on limited data. National or local recommendations should also be taken into account.

Disseminated Lyme disease (early (stage II) and late (stage III)). 2 g once daily for 14–21 days. The recommended duration of treatment varies and national or local recommendations should be taken into account.

Newborns, infants and children aged 15 days to 12 years (<50 kg)

Children weighing < 50 kg should receive the usual adult doses.

* In case of documented bacteremia, the use of

the highest recommended dose.

** In case of doses exceeding 2 g per day, consideration should be given to

administration of the drug twice a day (with a 12-hour interval).

Indications in neonates, infants and children under 12 years of age (<50 kg) requiring special dosing regimens

Preoperative prophylaxis of surgical site infections: 50–80 mg/kg once before surgery.

Syphilis: The generally recommended dose for children is 75–100 mg/kg (maximum 4 g) once daily for 10–14 days. Dosage recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local recommendations should also be taken into account.

Disseminated Lyme disease (early (stage II) and late (stage III)): 50–80 mg/kg once daily for 14–21 days. The recommended duration of treatment varies and national or local recommendations should be taken into account.

Acute otitis media: A single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used for the initial treatment of acute otitis media. Some evidence suggests that in cases of severe illness or failure of previous therapy, ceftriaxone may be effective when administered intramuscularly at a dose of 50 mg/kg daily for 3 days.

Newborns aged 0–14 days

Ceftriaxone is contraindicated for use in premature infants under 41 weeks of gestational age (gestational age + postnatal age).

*In cases of documented bacteremia, the highest recommended dose should be considered.

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: A single intramuscular injection of ceftriaxone at a dose of 50 mg/kg may be used for the initial treatment of acute otitis media.

Preoperative prophylaxis of surgical site infections: 20–50 mg/kg once before surgery.

Syphilis: The generally recommended dose is 50 mg/kg once daily for 10-14 days. Dosage recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local recommendations should also be taken into account.

Duration of treatment. The duration of treatment depends on the course of the disease. Given the general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after the disappearance of fever or confirmation of eradication of the bacterial infection.

Method of administration

Intramuscular administration: Ceftriaxone can be administered by deep intramuscular injection. Intramuscular injection should be given into the center of a relatively large muscle. It is recommended that no more than 1 g be administered at a single site.

If lidocaine is used as a diluent, the resulting solution should never be administered intravenously (see Contraindications). For detailed information, it is recommended to consult the instructions for medical use of lidocaine.

The use of lidocaine requires a preliminary test to determine individual sensitivity to this drug.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, should not be used to dissolve ceftriaxone in vials or to further dilute 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 line. Therefore, ceftriaxone should not be mixed or administered simultaneously with calcium-containing solutions.

Elderly patients: provided that renal and hepatic function are satisfactory, dose adjustment is not required in elderly patients.

Patients with hepatic impairment: Available data suggest that no dose adjustment is necessary for patients with mild or moderate hepatic impairment, provided that renal function is not impaired. There are no data in patients with severe hepatic impairment (see section 5.2).

Patients with renal insufficiency: there is no need to reduce the dose of ceftriaxone if renal function is not impaired. Only in the case of pre-terminal renal insufficiency (creatinine clearance less than 10 ml/min) the daily dose of ceftriaxone should not exceed 2 g. Patients on dialysis do not need additional administration of the drug after dialysis. Ceftriaxone is not removed 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 impairment: in cases of concomitant severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended.

Children

The drug should be administered to children according to the dosage specified in the section "Method of administration and doses".

Overdose

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

Adverse reactions

The most common adverse reactions observed with ceftriaxone are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

Infections and infestations: fungal infections of the genitals, pseudomembranous colitis, superinfections.

From the blood and lymphatic system: eosinophilia, leukopenia, thrombocytopenia, granulocytopenia, anemia, coagulation disorders, hemolytic anemia, agranulocytosis.

On the part of the immune system: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions, Jarisch-Herxheimer reaction (see section "Special warnings and precautions for use").

From the nervous system: headache, dizziness, convulsions.

From the organs of hearing and balance: vertigo.

Respiratory, thoracic and mediastinal disorders: bronchospasm.

Gastrointestinal: diarrhea, loose stools, nausea, vomiting, pancreatitis, stomatitis, glossitis.

On the part of the hepatobiliary system: increased levels of liver enzymes, precipitates in the gallbladder, kernicterus.

Skin and subcutaneous tissue disorders: rash; pruritus, urticaria, 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").

From the kidneys and urinary system: hematuria, glycosuria, oliguria, formation of precipitates in the kidneys (reversible).

General disorders and administration site conditions: phlebitis, injection site pain, fever, edema, chills.

Laboratory test results: increased blood creatinine levels, false-positive Coombs test results, false-positive galactosemia test results, false-positive non-enzymatic glucose test results.

Infections and infestations: cases of diarrhea after the use of ceftriaxone m