Promocef®
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product PROMOCEF® (promocef®)
Composition:
Active substance: ceftriaxone;
1 vial contains ceftriaxone (as ceftriaxone sodium) 1.0 g.
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: crystalline powder of nearly white or yellowish color.
Pharmacotherapeutic group. Antibacterials for systemic use. Other β-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone. ATC code J01D D04.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action. Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. This leads to cessation of cell wall (peptidoglycan) biosynthesis, resulting in 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 may be inducible or stably derepressed in certain aerobic Gram-negative bacteria.
- Reduced affinity of penicillin-binding proteins for ceftriaxone.
- Decreased outer membrane permeability in Gram-negative bacteria.
- Bacterial efflux pumps.
Breakpoints for susceptibility testing. The minimal inhibitory concentration (MIC) breakpoints have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):
| Pathogen |
Dilution method (minimum inhibitory concentration, mg/l) |
|
| Susceptible |
Resistant |
|
| Enterobacteriaceae |
≤1 |
>2 |
| Staphylococcus spp. |
a |
a |
| Streptococcus spp. (groups A, B, C and G) |
b |
b |
| Streptococcus pneumoniae |
≤0.5c |
>2 |
| Viridans group Streptococci |
≤0.5 |
>0.5 |
| Haemophilus influenzae |
≤0.12c |
>0.12 |
| Moraxella catarrhalis |
≤1 |
>2 |
| Neisseria gonorrhoeae |
≤0.12 |
>0.12 |
| Neisseria meningitidis |
≤0.12 c |
>0.12 |
| Not species-related |
≤1d |
>2 |
a. Susceptibility conclusion was based on susceptibility to cefoxitin.
b. Susceptibility conclusion was based on susceptibility to penicillin.
c. Isolates with minimum inhibitory concentrations exceeding susceptibility breakpoints are rare; if observed, repeat testing should be performed, and if confirmed, isolates should be sent to a reference laboratory.
d. Breakpoints apply to a daily intravenous dose of 1 g × 1 and high dose of at least 2 g × 1.
Generally susceptible species
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible)£, Streptococcus pyogenes (group A), Streptococcus agalactiae (group B), Streptococcus pneumoniae, Streptococci of the Viridans group.
Gram-negative aerobes
Borrelia burgdorferi, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Providencia spp., Treponema pallidum.
Species for which acquired resistance may be a problem
Gram-positive aerobes
Staphylococcus epidermidis+, Staphylococcus haemolyticus+, Staphylococcus hominis+.
Gram-negative aerobes
Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli%, Klebsiella pneumoniae%, Klebsiella oxytoca%, Morganella morganii, Proteus vulgaris, Serratia marcescens.
Anaerobes
Bacteroides spp., Fusobacterium spp., Peptostreptococcus spp., Clostridium perfringens.
Initially resistant microorganisms
Gram-positive aerobes
Enterococcus spp., Listeria monocytogenes.
Gram-negative aerobes
Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia.
Anaerobes
Clostridium difficile.
Others:
Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Legionella spp., Ureaplasma urealyticum.
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
- Resistance frequency >50% in at least one region.
% Strains producing extended-spectrum β-lactamases are always resistant.
Pharmacokinetics
Absorption
Intramuscular administration. After intramuscular injection, the mean peak plasma concentration of ceftriaxone is approximately half of that observed after intravenous administration of an equivalent dose. The maximum plasma concentration following a single intramuscular dose of 1 g is 81 mg/L, achieved within 2–3 hours after administration. The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
Intravenous administration. After intravenous bolus injection of 1 g ceftriaxone, the mean peak plasma concentration is approximately 200 mg/L. After intravenous infusion of 1 g ceftriaxone, the plasma concentration is approximately 150 mg/L.
Distribution. The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are found in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, and nasal mucosa, as well as in bone, cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) is observed upon repeated dosing; steady state is generally achieved within 48–72 hours, depending on the route of administration.
Penetration into specific tissues. Ceftriaxone penetrates into the meninges. Penetration is enhanced during meningitis. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis is up to 25% of that in plasma, compared to 2% in patients without meningitis. Peak cerebrospinal fluid concentrations are reached approximately 4–6 hours after intravenous injection. Ceftriaxone crosses the placental barrier, and its presence in low concentrations in breast milk is expected (see section "Use during pregnancy or breastfeeding").
Protein binding. Ceftriaxone reversibly binds to albumin. Plasma protein binding is approximately 95% at plasma concentrations below 100 mg/L. Binding is saturable, and the degree of binding decreases with increasing concentration (to 85% at a plasma concentration of 300 mg/L).
Metabolism. Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.
Elimination. Total plasma clearance of ceftriaxone (bound and unbound) is 10–22 mL/min. Renal clearance is 5–12 mL/min. 50–60% of ceftriaxone is excreted unchanged by the kidneys, primarily via glomerular filtration, and 40–50% is excreted unchanged in bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours.
Patients with renal or hepatic impairment. In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only minimally altered, with only a slight increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.
The moderately prolonged elimination half-life in renal impairment is explained by compensatory increase in extrarenal clearance due to reduced protein binding and the consequent increase in total ceftriaxone extrarenal clearance.
In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increase in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, leading to a seemingly paradoxical increase in total drug clearance, paralleled by an increase in volume of distribution.
Elderly patients. In patients aged 75 years and older, the mean elimination half-life is typically 2–3 times longer than in younger adults.
Children. The elimination half-life of ceftriaxone is prolonged in neonates up to 14 days of age. Free ceftriaxone levels may further increase due to factors such as reduced glomerular filtration and impaired protein binding. In older children, the elimination half-life is shorter than in neonates or adults. Plasma clearance and volume of distribution of total ceftriaxone are higher in neonates, infants, and children than in adults.
Linearity/non-linearity. The pharmacokinetics of ceftriaxone are non-linear, and all major pharmacokinetic parameters, except elimination half-life, are dose-dependent based on total drug concentration, decreasing less than proportionally with increasing dose. Non-linearity is observed due to saturation of plasma protein binding; thus, it is evident for total ceftriaxone in plasma but not for the free (unbound) fraction.
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 during which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., %T > minimum inhibitory concentration).
Clinical characteristics.
Indications.
Treatment of the following infections in adults and children, including full-term newborns (from birth):
- bacterial meningitis;
- community-acquired pneumonia;
- hospital-acquired pneumonia;
- acute otitis media;
- intra-abdominal infections;
- complicated urinary tract infections (including pyelonephritis);
- bone and joint infections;
- complicated skin and soft tissue infections;
- gonorrhea;
- syphilis;
- bacterial endocarditis.
Promotsef® 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 site infections;
- management of patients with neutropenia who develop fever suspected to be due to bacterial infection;
- treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections are suspected.
Promotsef® should be administered in combination with other antibacterial agents if the potential range of bacterial pathogens is not covered by its spectrum of activity (see section "Special 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 β-lactam antibacterial agents (penicillins, monobactams, and carbapenems).
Promotsef® is contraindicated:
In preterm newborns aged ≤41 weeks postmenstrual age (gestational age + postnatal age)*;
In full-term newborns (aged ≤28 days):
- with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis, as bilirubin binding is likely impaired under these conditions*;
- who require (or are expected to require) intravenous administration of calcium-containing drugs or infusions of calcium-containing solutions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions for use" and "Adverse reactions").
* In vitro studies have shown that ceftriaxone may displace bilirubin from albumin binding in blood serum, leading to a risk of bilirubin encephalopathy in such patients.
Before intramuscular administration of ceftriaxone, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions for use" and the instructions for medical use of lidocaine).
Solutions of ceftriaxone containing lidocaine must never be administered intravenously.
Interaction with other medicinal products and other forms of interaction.
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of the drug 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 Promotsef® is mixed with calcium-containing solutions in the same infusion system. Promotsef® must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site connector. However, in patients other than newborns, Promotsef® 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 newborn umbilical cord blood have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitate formation (see sections "Dosage and administration", "Contraindications", "Special precautions for use", "Adverse reactions").
Concomitant use of the drug with oral anticoagulants may enhance the effect of vitamin K antagonists and increase the risk of bleeding. Frequent monitoring of the international normalized ratio (INR) is recommended, and the dose of vitamin K antagonist should be adjusted appropriately during and after Promotsef® therapy (see section "Adverse reactions").
There are conflicting data regarding the potential for increased nephrotoxic effect of aminoglycosides when used concomitantly with cephalosporins. In such cases, careful adherence to clinical practice recommendations for monitoring aminoglycoside levels (and renal function) is advised.
In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with Promotsef®. 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).
False-positive Coombs test results may occur in patients receiving Promotsef®.
Like other antibiotics, Promotsef® may cause false-positive results in galactosemia testing.
Similarly, false-positive results may occur when urine glucose is tested using non-enzymatic methods. Therefore, during Promotsef® therapy, urine glucose levels should be determined using enzymatic methods.
No renal function impairment has been observed after concomitant administration of high doses of ceftriaxone and potent diuretics (e.g., furosemide).
Concomitant administration of probenecid does not reduce ceftriaxone excretion.
Special precautions for use.
Hypersensitivity reactions. As with all β-lactam antibiotics, serious hypersensitivity reactions, sometimes fatal, have been reported (see section "Side effects"). Hypersensitivity reactions may also progress to Kounis syndrome, a severe allergic reaction that may lead to myocardial infarction (see section "Side effects"). In the case of severe hypersensitivity reactions, Promotsef® should 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 β-lactam agents. Promotsef® should be used with caution in patients with a history of mild hypersensitivity to other β-lactam drugs.
Cases of severe skin adverse reactions (Stevens-Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported with ceftriaxone treatment, which may be life-threatening; however, the frequency of these events is unknown (see section "Side effects").
Jarisch-Herxheimer reaction. Some patients with spirochetal infections may experience a Jarisch-Herxheimer reaction shortly after initiation of Promotsef® therapy. Symptomatic treatment may be required if a Jarisch-Herxheimer reaction occurs. Antibiotic therapy should not be discontinued if this reaction occurs.
Encephalopathy. Encephalopathy has been reported with ceftriaxone use (see section "Side effects"), 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 Promotsef® should be considered.
Interaction with calcium-containing drugs. In preterm and term neonates under 1 month of age, cases of precipitation of calcium-ceftriaxone salt 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 available scientific data, confirmed cases of intravascular precipitation have only been reported in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing medications. In vitro studies have shown that neonates are at increased risk of calcium-ceftriaxone salt precipitation compared to patients in other age groups.
Ceftriaxone must not be mixed or co-administered with any intravenous solutions containing calcium, regardless of the patient's age, even when using different infusion systems or administering through different infusion sites. However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, provided they are given through separate infusion systems into different body sites, or the infusion system is replaced or thoroughly flushed with saline solution between administrations to prevent precipitation. For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), healthcare providers may consider alternative antibacterial agents not associated with such precipitation risk. If ceftriaxone use in patients requiring continuous TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through separate infusion systems and at different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion lines should be flushed between administrations (see sections "Contraindications", "Side effects", and "Incompatibilities").
Children. The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the "Dosage and administration" section. Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its binding to serum albumin.
Promotsef® is contraindicated in preterm and term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").
Immune-mediated hemolytic anemia. Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibiotics, including ceftriaxone (see section "Side effects"). Severe cases of hemolytic anemia, including fatal outcomes, have been reported during ceftriaxone treatment in both adults and children.
If anemia develops during ceftriaxone therapy, hemolytic anemia associated with cephalosporin use should be considered, and ceftriaxone should be discontinued until the etiology is determined.
Prolonged therapy. Complete blood counts should be monitored regularly during prolonged treatment.
Colitis/overgrowth of non-susceptible microorganisms. Cases of colitis and pseudomembranous colitis associated with antibiotic use have been reported with nearly all antibacterial agents, including ceftriaxone. The severity of these conditions may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after ceftriaxone therapy (see section "Side effects"). Discontinuation of ceftriaxone therapy and initiation of appropriate treatment for Clostridium difficile should be considered. Antiperistaltic agents should not be used.
As with other antibacterial agents, superinfections caused by organisms not susceptible to ceftriaxone may occur.
Severe renal and hepatic impairment. In cases of severe renal and hepatic impairment, careful clinical monitoring of the drug's safety and efficacy is recommended (see section "Dosage and administration").
Patients with severe renal dysfunction may develop disturbances of consciousness (loss of consciousness, decreased level of consciousness), seizures, or involuntary movements (choreoathetosis, myoclonus), etc. Such patients should be closely monitored, and appropriate measures, including discontinuation of the drug, should be taken if any disturbances occur.
Effect on serological test results. The Coombs test may yield false-positive results during ceftriaxone therapy. Ceftriaxone may also cause false-positive results in galactosemia testing (see section "Side effects").
False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During ceftriaxone therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Side effects").
Sodium content. 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 sodium-controlled diet.
Antibacterial spectrum. Ceftriaxone has a limited antibacterial spectrum and may be inappropriate for use as monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections where resistant organisms are suspected, additional antibiotics should be considered.
Use of lidocaine. If lidocaine solution is used as a solvent, ceftriaxone may only be administered intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Gallstone disease. When shadows are observed on ultrasound, precipitation of calcium-ceftriaxone salt should be considered. Hypoechoic images, 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 required when administering the drug to children. Such precipitates resolve after discontinuation of ceftriaxone therapy. In rare cases, calcium-ceftriaxone salt precipitation has been associated with symptoms. If symptoms occur, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment in the individual case (see section "Side effects").
Biliary stasis. Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported in patients receiving ceftriaxone (see section "Side effects"). Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior prolonged therapy, severe illness, and total parenteral nutrition. Precipitation in the biliary tract due to ceftriaxone administration cannot be ruled out as an initiating or contributing factor.
Nephrolithiasis. Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Side effects"). If symptoms occur, ultrasound examination should be performed. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician based on a benefit-risk assessment in the individual case.
Disposal of medicinal product. Environmental contamination with the medicinal product should be minimized. The drug should not be allowed to enter sewage systems or household waste. Unused medicinal product after treatment completion or expiry should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal.
Use during pregnancy or breastfeeding.
Pregnancy. Ceftriaxone crosses the placental barrier. Data on ceftriaxone use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonic/fetal, peri- or postnatal development. Ceftriaxone may be used during pregnancy, particularly in the first trimester, only if the potential benefit outweighs the potential risk.
Breastfeeding. Ceftriaxone is excreted in breast milk in low concentrations, and no effects on breastfed infants are expected with therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. The possibility of sensitization should be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abandon ceftriaxone therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
Fertility. Reproductive function studies have not shown evidence of adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery.
Appropriate studies have not been conducted. Due to the possibility of side effects such as dizziness, ceftriaxone may affect the ability to drive vehicles or operate complex machinery.
Dosage and Administration.
Dosage. The dose of the drug depends on the severity, sensitivity, localization, and type of infection, as well as on the patient's age and liver and kidney function.
The following recommended doses are provided for these indications. In particularly severe cases, the highest dose within the recommended range should be used.
Adults and children aged 12 years and older (≥50 kg).
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 1-2 g |
Once daily |
Community-acquired pneumonia. Acute exacerbation of chronic obstructive pulmonary disease. Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis) |
| 2 g |
Once daily |
Hospital-acquired pneumonia. Complicated skin and soft tissue infections. Bone and joint infections |
| 2-4 g |
Once daily |
Management of febrile neutropenic patients suspected of bacterial infection. Bacterial endocarditis. Bacterial meningitis |
* In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.
** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.
Indications in adults and children aged 12 years and older (≥50 kg) requiring special dosing regimens.
Acute otitis media. A single intramuscular dose of 1–2 g of Promotsef® may be administered. Some data suggest that Promotsef® may be effective when given intramuscularly at a dose of 1–2 g daily for 3 days in patients with severe condition or in whom prior therapy has failed.
Prophylaxis of surgical site infections. Single dose of 2 g administered preoperatively.
Gonorrhea. Single intramuscular dose of 500 mg.
Syphilis. The generally recommended doses are 500 mg–1 g once daily, increasing the dose to 2 g once daily in neurosyphilis, administered for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be taken into account.
Disseminated Lyme borreliosis (early (Stage II) and late (Stage III)). 2 g once daily for 14–21 days. The recommended duration of treatment may vary; national or local guidelines should also be considered.
Children
Neonates, infants, and children aged 15 days to 12 years (<50 kg). For children with body weight of 50 kg or more, the usual adult doses should be used.
| Ceftriaxone dose* |
Frequency of administration** |
Indications |
| 50-80 mg/kg |
Once daily |
Intra-abdominal infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia |
| 50-100 mg/kg (maximum – 4 g) |
Once daily |
Complicated skin and soft tissue infections. Bone and joint infections. Management of febrile neutropenic patients with suspected bacterial infection |
| 80-100 mg/kg (maximum 4 g) |
Once daily |
Bacterial meningitis |
| 100 mg/kg (maximum 4 g) |
Once daily |
Bacterial endocarditis |
* In documented cases of bacteremia, consideration should be given to using the highest dose within the recommended range.
** When doses exceeding 2 g per day are used, administration of the drug twice daily (with a 12-hour interval) should be considered.
Indications in newborns, infants, and children aged 15 days to 12 years (<50 kg) requiring special dosing regimens:
Acute otitis media. For initial treatment of acute otitis media, a single intramuscular injection of Promotsef® at a dose of 50 mg/kg may be used. Some data suggest that in cases of severe illness or after ineffective prior therapy, Promotsef® 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 generally recommended dosage 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 may vary; national or local guidelines should also be considered.
Newborns aged 0–14 days. Promotsef® is contraindicated in preterm newborns under 41 weeks of gestational age (gestational age + postnatal age).
| Ceftriaxone dose* |
Frequency of administration |
Indications |
| 20-50 mg/kg |
Once daily |
Intra-abdominal infections. Complicated skin and soft tissue infections. Complicated urinary tract infections (including pyelonephritis). Community-acquired pneumonia. Hospital-acquired pneumonia. Bone and joint infections. Management of febrile neutropenic patients suspected of bacterial infection |
| 50 mg/kg |
Once daily |
Bacterial meningitis. Bacterial endocarditis |
* 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 Promotsef® at a dose of 50 mg/kg may be used.
Preoperative prophylaxis of surgical site infections. 20–50 mg/kg as a single dose before surgery.
Syphilis. The generally recommended dose is 50 mg/kg once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.
Duration of treatment. The duration of treatment depends on the course of the disease. In accordance with general recommendations for antibiotic therapy, ceftriaxone should be continued for 48–72 hours after fever subsides or after confirmation of eradication of bacterial infection.
Geriatric patients. In the presence of 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 available for patients with severe hepatic impairment (see section "Pharmacokinetics").
Patients with renal impairment. Dose reduction of ceftriaxone is not necessary in patients with impaired renal function, provided hepatic function is normal. However, in patients with pre-terminal renal failure (creatinine clearance less than 10 mL/min), the daily dose of ceftriaxone must not exceed 2 g.
Patients undergoing dialysis do not require additional doses of the drug after dialysis. Ceftriaxone is not eliminated from the body by peritoneal dialysis or hemodialysis. Careful clinical monitoring of the safety and efficacy of the drug is recommended.
Patients with severe hepatic and renal impairment. In cases of concomitant severe renal and hepatic impairment, careful clinical monitoring of the safety and efficacy of the drug is recommended.
Administration method
Intramuscular administration. The medicinal product Promotsef® can be administered by deep intramuscular injection. Intramuscular injections should be given into the center of a relatively large 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"). For detailed information, it is recommended to consult the lidocaine product information leaflet.
Prior to using lidocaine, a sensitivity test should be performed to determine individual hypersensitivity to this medicinal product.
Intravenous administration. The medicinal product Promotsef® can be administered by intravenous infusion lasting at least 30 minutes (the preferred route) or by slow intravenous injection over more than 5 minutes. Intermittent intravenous administration should be performed over 5 minutes, preferably into large veins. Intravenous doses of 50 mg/kg or higher should be administered by infusion 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 precautions"). Intramuscular administration should be considered only when intravenous administration is not feasible or less suitable for the patient. Doses exceeding 2 g should be administered intravenously.
Ceftriaxone is contraindicated in neonates (≤28 days) who require or are expected to require treatment with calcium-containing intravenous solutions, including infusion solutions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium salts of ceftriaxone (see section "Contraindications").
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitation of calcium salts of ceftriaxone may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Therefore, ceftriaxone must not be mixed or co-administered with calcium-containing solutions (see sections "Contraindications", "Special precautions", and "Incompatibilities").
For preoperative prophylaxis of surgical site infections, ceftriaxone should be administered 30–90 minutes prior to surgery.
Children.
The product should be administered to children according to the dosing instructions specified in the section "Administration and dosage".
Overdose.
In case of overdose, hemodialysis or peritoneal dialysis will not reduce excessive plasma concentrations of the drug. Symptoms of overdose may include nausea, vomiting, and diarrhea. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse reactions.
The most commonly observed adverse reactions during ceftriaxone use are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.
Events are classified by frequency as follows: very common, common, uncommon, rare, frequency not known (cannot be estimated from available data).
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.
Immune system disorders: frequency not known: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity, Jarisch-Herxheimer reaction (see section "Special precautions").
Cardiac disorders: frequency not known: Kounis syndrome.
Nervous system disorders: uncommon: headache, dizziness; frequency not known: seizures; rare: encephalopathy.
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: elevated liver enzymes; frequency not known: biliary precipitates, kernicterus, hepatitis, cholestatic hepatitis (usually reversible upon discontinuation of ceftriaxone).
Skin and subcutaneous tissue disorders: common: rash; uncommon: pruritus; rare: urticaria; frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions"), erythema multiforme, acute generalized exanthematous pustulosis.
Renal and urinary disorders: rare: hematuria, glucosuria; frequency not known: oliguria, renal precipitates (reversible).
General disorders and administration site conditions: uncommon: phlebitis, injection site pain, malaise; rare: edema, chills.
Investigations: uncommon: increased blood creatinine levels; frequency not known: false-positive Coombs test, false-positive galactosemia test, false-positive results in 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 precautions").
Ceftriaxone calcium salt precipitates. Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and full-term neonates (age <28 days) who received intravenous ceftriaxone and calcium-containing solutions. Post-mortem examinations revealed ceftriaxone calcium salt precipitates in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications", "Special precautions").
Cases of renal precipitates have been reported, primarily in children aged 3 years and older, who received high daily doses (e.g., ≥80 mg/kg/day) or total doses exceeding 10 grams, and who also had additional risk factors (e.g., limited fluid intake or bed rest). The risk of precipitate formation increases in immobilized patients and 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 precautions").
Cases of ceftriaxone calcium salt precipitates in the gallbladder have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable rates of precipitate formation—over 30% in some studies. The incidence 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 typically resolve after discontinuation of ceftriaxone (see section "Special precautions").
Shelf life. 3 years.
Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.
Incompatibilities.
Promotsef® must not be mixed with calcium-containing solutions such as Ringer's solution or Hartmann's solution.
Promotsef® is incompatible with amsacrine, vancomycin, fluconazole, and aminoglycosides.
The product should not be mixed with any other solvents except those specified in the section "Dosage and administration".
Packaging. 1 g of powder in a vial; 1 or 5 vials per carton; or 1 or 5 vials in a blister, 1 blister per carton.
Prescription status. Prescription only.
Manufacturer. Private Joint Stock Company "Lekhim-Kharkiv". LLC "Lekhim-Obukhiv".
Bulk production by manufacturer: Qilu Pharmaceutical Co., Ltd., China.
Manufacturer's address and location of operations:
Ukraine, 61115, Kharkiv region, Kharkiv, Severin Pototsky Street, 36.
Ukraine, 08700, Kyiv region, Obukhiv, Kyivska Street, 126 A.