Promocef powder for solution for injection 1 g vial No. 1

Instructions for Promocef powder for solution for injection 1 g vial No. 1

Composition

active ingredient: ceftriaxone;

1 vial contains ceftriaxone (as ceftriaxone sodium) 1.0 g.

Dosage form

Powder for solution for injection.

Main physicochemical properties: almost white or yellowish crystalline powder.

Pharmacotherapeutic group

Antibacterials for systemic use. Other β-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. As a result, cell wall (peptidoglycan) biosynthesis is inhibited, which in turn leads to bacterial cell lysis and death.

Resistance: Bacterial resistance to ceftriaxone may develop through one or more of the following mechanisms:

Hydrolysis by β-lactamases, including extended-spectrum β-lactamases, carbapenemases, and Amp C enzymes, which can 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 pump.

Susceptibility breakpoints. Minimum inhibitory concentration breakpoints are defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a Susceptibility 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 observed, 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 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.

Innately 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 β-lactamase are always resistant.

Pharmacokinetics.

Absorption.

Intramuscular administration. After intramuscular injection, the mean peak plasma level of ceftriaxone is approximately half that observed after intravenous administration of an equivalent dose. The maximum plasma concentration 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 intravenous administration of an equivalent dose.

Intravenous administration. After intravenous bolus administration of ceftriaxone at a dose of 1 g, the mean peak plasma level of ceftriaxone is approximately 200 mg/l. After intravenous infusion of ceftriaxone at a dose of 1 g, the plasma level of ceftriaxone is approximately 150 mg/l.

Distribution: The volume of distribution of ceftriaxone is 7-12 L. Concentrations well in excess of the minimum inhibitory concentrations for most important pathogens are found in tissues including the lungs, heart, biliary tract, liver, tonsils, middle ear and nasal mucosa, bone, and spinal, pleural and

Penetration into individual tissues. Ceftriaxone penetrates the meninges. Penetration is more pronounced in cases of inflammation of the meninges. The average peak concentration 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 inflammation of the meninges. Peak concentrations of ceftriaxone in the cerebrospinal fluid are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is expected to be present in low concentrations in breast milk (see section "Use during pregnancy or lactation").

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. The total plasma clearance of ceftriaxone (bound and unbound) is 10-22 ml/min. Renal clearance is 5-12 ml/min. 50-60% of ceftriaxone is excreted unchanged by the kidneys, primarily by glomerular filtration, 40-50% is excreted unchanged in the bile. The 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 not significantly altered, with only a slight increase in half-life (less than 2-fold), even in patients with severe renal impairment.

The relatively moderate 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 an apparent paradoxical increase in total clearance of the drug with an increase in the volume of distribution parallel to this total clearance.

Elderly patients: In patients aged 75 years and older, the mean elimination half-life is usually 2-3 times higher than in younger adults.

Children. The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may 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, decreasing less than proportionally with dose. Non-linearity is observed as a result of saturation of plasma protein binding, so that total ceftriaxone is observed in plasma but not free (unbound) ceftriaxone.

Pharmacokinetic/pharmacodynamic relationship: As with other β-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

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.

Promocef® can be used for:

treatment of acute complications 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 from 15 days of age;

preoperative prevention of infections at the surgical site;

management of neutropenic patients who develop fever with suspected bacterial infection;

treatment of patients with bacteremia due to any of the above infections or if any of the above infections are suspected.

Promocef® should be prescribed together with other antibacterial drugs 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

Hypersensitivity to ceftriaxone or any other cephalosporin. History of severe hypersensitivity reactions (e.g. anaphylactic reactions) to any other type of β-lactam antibacterial agent (penicillins, monobactams and carbapenems).

Promocef® is contraindicated:

Premature newborns aged ≤41 weeks, taking into account the term of intrauterine development (gestational age + age after birth)*;

For full-term newborns (age ≤28 days):

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 preparations or infusions of calcium-containing solutions, as there is a risk of precipitation of the calcium salt of ceftriaxone (see sections "Special warnings and precautions for use" and "Adverse reactions").

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

Before intramuscular administration of ceftriaxone, it is necessary to exclude the presence of contraindications to the use of lidocaine, if it is used as a solvent (see the section "Special instructions for use", as well as the instructions for medical use of lidocaine).

Ceftriaxone solutions containing lidocaine should never be administered intravenously.

Interaction with other medicinal products and other types of interactions

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, should not be used for reconstitution of the drug in vials or for further dilution of the reconstituted solution for intravenous administration, as a precipitate may form. Precipitates of ceftriaxone calcium salt may also form when Promocef® is mixed with calcium-containing solutions in the same infusion system. Promocef® 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 other patients, except neonates, Promocef® 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 salt (see sections “Method of administration and dosage”, “Contraindications”, “Special precautions for use”, “Adverse reactions”).

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

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

In an in vitro study, antagonistic effects were observed when chloramphenicol was used in combination with Promocef®. The clinical significance of these findings 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).

False-positive Coombs test results are possible in patients using Promocef®.

Promocef®, like other antibiotics, may cause false-positive test results for galactosemia.

Similarly, when determining glucose in urine using non-enzymatic methods, the results may be false positive. For this reason, during the period of use of Promocef®, the level of glucose in urine should be determined using enzymatic methods.

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

Cases of serious skin adverse reactions (Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening) have been reported in association with ceftriaxone treatment, but the frequency of these events is unknown (see section "Adverse reactions"). Jarisch-Herxheimer reaction. Some patients with spirochetal infection may experience a Jarisch-Herxheimer reaction shortly after starting treatment with Promocef®. Symptomatic treatment may be required in the event of a Jarisch-Herxheimer reaction. Antibiotic treatment should not be discontinued if such a reaction occurs.

Encephalopathy: Encephalopathy has been reported with ceftriaxone (see section 4.8), particularly in elderly patients with severe renal impairment (see section 4.2) or central nervous system disorders. If ceftriaxone-related encephalopathy is suspected (e.g., decreased level of consciousness, altered mental status, myoclonus, convulsions), discontinuation of Promocef® should be considered.

Interaction with calcium-containing medicinal products. In premature and full-term infants less than 1 month of age, cases of ceftriaxone calcium precipitates in the lungs and kidneys with fatal outcomes have been observed. In at least one of these patients, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. According to the available scientific data, there are no confirmed cases of intravascular precipitates, except in neonates who were administered ceftriaxone and calcium-containing solutions or any other calcium-containing drugs. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium precipitates compared to patients of other age groups.

When ceftriaxone is used in patients of any age, it 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 may 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: The safety and efficacy of ceftriaxone in neonates, infants, and children have been established at the doses described in the Dosage and Administration section. Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from its binding to serum albumin.

Promocef® is contraindicated in premature and full-term newborns at risk of developing bilirubin encephalopathy (see section "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 anemia while taking ceftriaxone, the diagnosis of cephalosporin-associated anemia should be considered and ceftriaxone should be discontinued until the etiology is determined.

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

Colitis/overgrowth of nonsusceptible organisms: Cases of colitis and pseudomembranous colitis associated with the use of antibacterial agents have been reported in the setting of

use of almost all antibacterial agents, including ceftriaxone. The severity of these diseases can range from mild to life-threatening. Therefore, it is important to consider the possibility of this diagnosis in patients who develop diarrhea during or after the use of ceftriaxone (see section "Adverse reactions"). Ceftriaxone therapy should be discontinued and appropriate anti-Clostridium difficile therapy should be considered. Medicinal products that inhibit peristalsis should not be used.

Severe renal and hepatic impairment: In case of severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended (see section "Method of administration and dosage").

Patients with severe renal impairment may experience disturbances of consciousness (loss of consciousness, decreased level of consciousness), convulsions or involuntary movements (choreoathetosis, myoclonus), etc. The condition of such patients should be carefully monitored, and appropriate measures should be taken if any disturbances occur, such as discontinuation of the drug.

Effect on serological tests. When using the drug, the Coombs test may give false-positive results. Ceftriaxone may also cause false-positive results in tests for galactosemia (see section "Adverse reactions").

Non-enzymatic methods may give false positive results when measuring glucose in urine. During treatment with ceftriaxone, urine glucose levels should be measured using enzymatic methods (see section 4.8).

Sodium: Each gram of the drug contains 3.6 mmol of sodium. This should be taken into account when prescribing the drug to 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, additional antibiotics should be considered.

Use of lidocaine. If lidocaine solution is used as a diluent, ceftriaxone can only be administered intramuscularly. Before administering the drug, it is necessary to take into account the contraindications to the use of lidocaine, precautions and other relevant information given in the instructions for medical use of lidocaine (see section "Contraindications"). Lidocaine solution should never be administered intravenously.

Gallstone disease. In the event of shadows on the sonogram, the possibility of ceftriaxone calcium precipitates should be considered. Shadows mistaken for gallstones have been observed on sonograms of the gallbladder, and their frequency increased with ceftriaxone doses of 1 g/day and above. Particular caution should be exercised when using the drug in children. Such precipitates disappear after cessation of ceftriaxone therapy. In rare cases, the formation of ceftriaxone calcium precipitates has been accompanied by symptoms. In the presence of symptoms, conservative non-surgical treatment is recommended, and the physician should decide to discontinue the drug based on the results of the benefit-risk assessment in a specific case (see section "Adverse reactions").

Bile stasis: Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients receiving ceftriaxone (see section 4.8). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as previous prolonged therapy, severe illness and total parenteral nutrition. It cannot be excluded that the formation of biliary precipitates due to the use of the drug may be an initiating or additional factor in the development of this disorder.

Nephrolithiasis. Cases of kidney stones have been reported, which resolved after discontinuation of ceftriaxone (see section 4.8). If symptoms are present, an ultrasound examination should be performed. Decision on use of the drug

Patients with a history of kidney stones or hypercalciuria should be treated by a doctor based on the results of a benefit-risk assessment in a specific case.

Disposal of the medicinal product. Release of the medicinal product into the external environment should be minimized. The medicinal product should not be disposed of via sewage system or household waste. Unused medicinal product after the end of treatment or the expiry date should be returned in the original packaging to the supplier (doctor 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 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.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

No relevant studies have been conducted. Due to the possibility of side effects such as dizziness, ceftriaxone may affect the ability to drive or operate machinery.

Method of administration and doses

Dosage. The dose of the drug depends on the severity, sensitivity, location and type of infection, as well as the age and liver and kidney function of the patient.

The doses given below are generally recommended for these indications. In particularly severe cases, the highest dose in the recommended range should be used.

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

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

** In case of doses exceeding 2 g per day, twice daily administration (12 hours apart) should be considered.

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 of Promocef® may be used. Some evidence suggests that, in cases where the patient's condition is severe or previous therapy has been ineffective, Promocef® may be effective when administered intramuscularly at a dose of 1-2 g per day 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 dose is 500 mg-1 g once daily, increasing to 2 g once daily for neurosyphilis for 10-14 days. 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 also be taken into account.

Children

Neonates, infants and children aged 15 days to 12 years (<50 kg). Children weighing 50 kg or more should receive the usual adult doses.

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

** In case of doses exceeding 2 g per day, twice daily administration (12 hours apart) should be considered.

Indications in neonates, infants and children aged 15 days to 12 years (<50 kg) requiring special dosing regimens:

Acute otitis media. A single intramuscular injection of Promocef® at a dose of 50 mg/kg may be used for the initial treatment of acute otitis media. Some data suggest that in cases where the child's condition is severe or previous therapy has been ineffective, Promocef® 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 once before surgery.

Syphilis: The generally recommended dose 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.

Neonates 0-14 days of age. Promocef® is contraindicated for use in premature neonates under 41 weeks (gestational age + calendar age).

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

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. A single intramuscular injection of Promocef® 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.

Elderly patients: No dose adjustment is required in elderly patients provided that renal and hepatic function is satisfactory.

Patients with hepatic insufficiency

Available data suggest that there is no need to adjust the dose in patients with mild or moderate hepatic impairment, unless renal function is impaired.

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

Patients with renal insufficiency. There is no need to reduce the dose of ceftriaxone in patients with impaired renal function, unless liver function is impaired. Only in the case of pre-terminal renal insufficiency (creatinine clearance less than 10 ml/min) should the daily dose of ceftriaxone not exceed 2 g.

Patients on dialysis do not require additional post-dialysis dosing. Ceftriaxone is not removed from the body by peritoneal dialysis or hemodialysis. Close clinical monitoring of safety and efficacy 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.

Method of administration

Intramuscular administration. Promocef® can be administered by deep intramuscular injection. Intramuscular injection should be given in the center of a relatively large muscle.