Cef 1000 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEF 1000 mg (CEF 1000 mg)

Composition:

Active substance: ceftriaxone;

One vial contains ceftriaxone sodium equivalent to 1000 mg of anhydrous ceftriaxone.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

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

ATC code J01D D04.

Pharmacological properties.

Pharmacodynamics.

Ceftriaxone is a third-generation cephalosporin antibiotic.

Mechanism of action

Ceftriaxone inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. As a result, biosynthesis of the cell wall (peptidoglycan) ceases, leading to bacterial cell lysis and death.

Resistance

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

• hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases, carbapenemases, and Amp C enzymes, which may be inducible or stably derepressed in certain aerobic Gram-negative bacteria;
• reduced affinity of penicillin-binding proteins for ceftriaxone;
• decreased outer membrane permeability in Gram-negative bacteria;
• bacterial efflux pumps.

Breakpoints for susceptibility testing

The minimum inhibitory concentration (MIC) breakpoints have been defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

a. The conclusion on susceptibility was based on susceptibility to cefoxitin;

b. The conclusion on susceptibility was based on susceptibility to penicillin;

c. Isolates with minimum inhibitory concentrations exceeding the susceptibility breakpoints are rarely observed. If such isolates are detected, repeat testing should be performed, and if confirmed, they should be sent to a reference laboratory;

d. The breakpoints apply to a daily intravenous dose of 1 g × 1 and high doses of at least 2 g × 1.

Ceftriaxone is active against the following microorganisms (susceptible species):

Gram-positive aerobes:

Staphylococcus aureus (methicillin-susceptible)*;

Staphylococcus coagulase-negative (methicillin-susceptible)*;

* All methicillin-resistant staphylococci are resistant to ceftriaxone.

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

The following microorganisms are moderately susceptible to ceftriaxone (species that may develop resistance):

Gram-positive aerobes:

Staphylococcus epidermidis**

Staphylococcus haemolyticus**

Staphylococcus hominis**

** Resistance frequency > 50% in at least one region.

Gram-negative aerobes:

Citrobacter freundii

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli***

Klebsiella pneumoniae ***

Klebsiella oxytoca ***

Morganella morganii

Proteus vulgaris

Serratia marcescens

*** Strains producing extended-spectrum beta-lactamases are always resistant.

Anaerobes:

Bacteroides spp.

Fusobacterium spp.

Peptostreptococcus spp.

Clostridium perfringens

The following microorganisms are resistant to ceftriaxone:

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

Pharmacokinetics.

Absorption.

Intramuscular administration.

The maximum plasma concentration after a single intramuscular dose of 1 g of ceftriaxone is 81 mg/L and is reached 2–3 hours after administration. The area under the plasma concentration-time curve after intravenous administration is equivalent to that after intramuscular administration.

Intravenous administration.

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

Distribution.

The volume of distribution of ceftriaxone is 7–12 L. Concentrations substantially exceeding the minimum inhibitory concentrations for most clinically relevant pathogens are achieved in tissues, including lungs, heart, biliary tract, liver, tonsils, middle ear, nasal mucosa, bones, as well as cerebrospinal, pleural, and synovial fluids, and prostatic secretion. An 8–15% increase in mean peak plasma concentration (Cmax) was observed with repeated dosing; steady state was generally achieved within 48–72 hours, depending on the route of administration.

Penetration into specific tissues.

Ceftriaxone penetrates into the meninges. Penetration is enhanced during inflammation of the meninges. The mean peak concentration of ceftriaxone in cerebrospinal fluid in patients with bacterial meningitis reaches up to 25% of that in plasma, compared to 2% in patients without meningeal inflammation. Peak concentrations in cerebrospinal fluid are achieved 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 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 as concentration increases (to 85% at a plasma concentration of 300 mg/L).

Biotransformation.

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.

Pharmacokinetics in special clinical situations.

Patients with renal or hepatic impairment.

In patients with impaired renal or hepatic function, the pharmacokinetics of ceftriaxone are only slightly altered, with a minor increase in elimination half-life (less than two-fold), even in patients with severe renal impairment.

The relatively moderate increase in half-life observed in renal impairment is explained by compensatory increases in extrarenal clearance due to reduced protein binding and a corresponding increase in total ceftriaxone clearance.

In patients with hepatic impairment, the elimination half-life of ceftriaxone does not increase due to compensatory increases in renal clearance. This also results from an increased free fraction of ceftriaxone in plasma, leading to a paradoxical increase in total drug clearance, with volume of distribution increasing in parallel with total clearance.

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. All major pharmacokinetic parameters, except elimination half-life, are dose-dependent. Non-linearity occurs due to saturation of plasma protein binding, and thus this phenomenon is observed for total ceftriaxone in plasma, but not for the free (unbound) fraction.

Pharmacokinetic/pharmacodynamic relationship.

As with other beta-lactams, the pharmacokinetic/pharmacodynamic index that best correlates with in vivo efficacy is the percentage of the dosing interval during which the unbound concentration remains above the minimum inhibitory concentration of ceftriaxone for specific target organisms (i.e., %T > minimum inhibitory concentration).

Clinical characteristics.

Indications.

The medicinal product is used for the treatment of the following infections in adults and children, including full-term newborns (from the first days of life):

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

The medicinal product 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 site infection prophylaxis;
• management of neutropenic patients with fever suspected of bacterial infection;
• treatment of patients with bacteremia arising from any of the above-mentioned infections or when any of the above-mentioned infections is suspected.

The medicinal product 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.

Ceftriaxone is contraindicated:

• In patients with hypersensitivity to ceftriaxone or any other cephalosporin. In patients with a history of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems).
• 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 products or infusions, due to the risk of precipitation of ceftriaxone-calcium salts (see sections "Special precautions for use" and "Side effects").

* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, thus posing 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"). The package leaflet for lidocaine should be consulted, particularly the "Contraindications" section. Solutions of ceftriaxone containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other forms of interaction.

Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute the medicinal product "CEF 1000 mg" in vials or for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Precipitates of ceftriaxone-calcium salts may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous solutions containing calcium, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site administration system. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided that the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and newborn umbilical plasma have shown an increased risk of ceftriaxone-calcium salt precipitation in newborns (see sections "Method and dose of administration", "Contraindications", "Special precautions for use", "Side effects", "Incompatibilities").

Concomitant use of the medicinal product 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 appropriately adjusted both during and after ceftriaxone therapy (see section "Side effects").

There are conflicting data regarding the potential for increased nephrotoxic effects of aminoglycosides when used concomitantly with cephalosporins. In such cases, clinical guidelines for monitoring aminoglycoside levels (and renal function) should be strictly followed.

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

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

False-positive results in the Coombs test may occur in patients receiving ceftriaxone.

Ceftriaxone, like other antibiotics, may cause false-positive results in tests for galactosemia.

Likewise, false-positive results may occur when glucose in urine is tested by non-enzymatic methods. For this reason, enzymatic methods should be used to determine glucose levels in urine during ceftriaxone therapy.

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 other cephalosporins, anaphylactic reactions, including fatal outcomes, have been reported with ceftriaxone, even in patients without prior history of hypersensitivity. Before 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. Ceftriaxone should be used with caution in patients with a history of mild hypersensitivity to other β-lactam medicinal products. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate emergency measures should be initiated.

Cases of severe cutaneous adverse reactions, such as Stevens-Johnson syndrome or Lyell's syndrome (toxic epidermal necrolysis), have been reported. A life-threatening drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with ceftriaxone use, which may be fatal, has also been reported. However, the frequency of such adverse reactions is unknown (see section Adverse reactions).

Interaction with calcium-containing medicinal products.

Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, even when administered through different infusion systems. In term newborns up to 1 month of age and preterm infants, precipitates of ceftriaxone calcium salt in the lungs and kidneys have been observed, leading to fatal outcomes when ceftriaxone and calcium-containing products were administered concomitantly. In at least one of these cases, ceftriaxone and calcium were administered at different times and through different intravenous infusion systems. No confirmed cases of intravascular precipitate formation have been reported in patients other than newborns receiving ceftriaxone and calcium-containing solutions or other calcium-containing medicinal products. In vitro studies have demonstrated that newborns have an increased risk of ceftriaxone calcium salt precipitate formation compared to patients in other age groups.

When administering ceftriaxone to patients of any age, the medicinal product must not be mixed or administered simultaneously with any intravenous solutions containing calcium, even when using different infusion systems or administering the drugs into different infusion sites.

However, in patients aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided the drugs are administered through different infusion systems into different body sites, the infusion system is replaced, or the system is thoroughly flushed with physiological saline solution between administrations to prevent precipitate formation.

For patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider prescribing alternative antibacterial agents not associated with this precipitate risk. If ceftriaxone use is deemed necessary in patients requiring continuous TPN, TPN infusion must be suspended during ceftriaxone infusion, and infusion systems must be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").

Children.

The safety and efficacy of ceftriaxone in neonates, infants, and children have been established for the doses described in the section "Dosage and administration". Studies have shown that ceftriaxone, like some other cephalosporins, may displace bilirubin from its albumin complex in serum. Therefore, the use of "CEF 1000 mg" is contraindicated in preterm and full-term newborns with hyperbilirubinemia (see sections "Contraindications" and "Children").

Immune-mediated (autoimmune) hemolytic anemia.

Immune-mediated hemolytic anemia has been observed in patients receiving cephalosporins, including ceftriaxone. Cases of severe hemolytic anemia, including fatal outcomes, have been reported in adults and children.

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

Complete blood counts should be monitored regularly during prolonged treatment.

Prolonged therapy.

During prolonged therapy, complete blood counts should be performed regularly.

Colitis / overgrowth of resistant microorganisms.

Ceftriaxone should be used with caution in patients with a history of gastrointestinal disorders, particularly colitis. Diarrhea associated with Clostridium difficile, ranging from mild to severe colitis with fatal outcomes, may occur during treatment with nearly all antibacterial agents, including ceftriaxone. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Strains of Clostridium difficile that overproduce toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. Clostridium difficile-associated diarrhea must be considered in all patients during or after antibiotic therapy. A detailed medical history should be obtained, as Clostridium difficile-associated diarrhea may occur up to two months after discontinuation of antibacterial agents.

If Clostridium difficile-associated diarrhea is suspected or confirmed, antibiotic therapy not effective against Clostridium difficile should be discontinued. Appropriate fluid and electrolyte replacement, protein supplementation, and antibiotic therapy effective against Clostridium difficile should be initiated as clinically indicated, and surgical intervention may be required in severe cases.

Cases of pseudomembranous colitis associated with cephalosporin antibiotics have been reported. If pseudomembranous colitis is suspected (diarrhea occurring after antibiotic administration), the drug should be discontinued and appropriate measures taken.

Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfections may develop. Use of "CEF 1000 mg", like other broad-spectrum antibiotics, may alter the normal colonic flora and promote overgrowth of Candida species.

With prolonged use of ceftriaxone, uncontrolled growth of drug-resistant microorganisms may occur. Therefore, patients must be closely monitored, and appropriate measures should be taken promptly if superinfection is suspected.

Severe renal and hepatic impairment.

Careful clinical monitoring of the safety and efficacy of the medicinal product is recommended in cases of severe renal and hepatic impairment (see section "Dosage and administration").

"CEF 1000 mg" should be used with caution in patients with renal impairment who are concurrently receiving aminoglycosides and diuretics.

Effect on serological test results.

Occasionally, false-positive Coombs' test results may occur in patients treated with the drug.

As with other antibiotics, the drug may cause false-positive results in galactosemia testing.

False-positive results may also occur when testing for glucose in urine using non-enzymatic methods; therefore, glucosuria during ceftriaxone therapy should be assessed only by enzymatic methods.

The presence of ceftriaxone may interfere with blood glucose measurements using certain blood glucose monitoring systems. Refer to the instructions for each system to confirm its suitability for use during ceftriaxone therapy. Alternative measurement methods should be used if necessary.

Sodium content.

1 g of sodium ceftriaxone contains approximately 3.6 mmol of sodium. This should be considered for patients on a sodium-restricted diet.

Antibacterial spectrum.

Although ceftriaxone has a broad antibacterial spectrum, it may be unsuitable for monotherapy in certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections involving microorganisms resistant to ceftriaxone, additional antibiotics should be considered.

Use of lidocaine.

When lidocaine solution is used as a solvent, ceftriaxone may be administered intramuscularly only. Before administration, contraindications, warnings, and other relevant information in the lidocaine injection solution instructions must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Cholelithiasis (gallstone disease).

After administration of ceftriaxone at doses exceeding the usual recommended doses, ultrasound examination of the gallbladder may reveal shadows caused by precipitates of ceftriaxone calcium salt, which may be misdiagnosed as concrements (gallstones).

Ceftriaxone calcium salt precipitates rarely cause clinical symptoms and usually resolve after discontinuation or completion of therapy. If clinical symptoms related to the gallbladder occur, the decision to continue treatment should be made by the physician, weighing the benefits and risks for each individual patient. Conservative management is recommended.

Particular caution should be exercised when administering the drug to children.

Biliary stasis.

Isolated cases of pancreatitis, possibly due to obstruction of the biliary tract, have been reported in patients receiving ceftriaxone. Most of these patients had pre-existing risk factors for biliary stasis, such as prior treatment, severe illness, prolonged bed rest, or total parenteral nutrition. The formation of precipitates in the biliary tract due to ceftriaxone use cannot be excluded as an initiating or contributing factor. Therefore, the drug should be used with special caution in patients with risk factors for biliary obstruction. If symptoms of obstruction occur, the drug should be discontinued and appropriate measures taken.

Nephrolithiasis (kidney stones).

Cases of renal precipitation of ceftriaxone calcium salt have been reported, which resolved after discontinuation of ceftriaxone (see section "Adverse reactions"). Ultrasound examination should be performed if symptoms occur. The decision to administer the drug to patients with a history of kidney stones or hypercalciuria should be made by the physician, weighing the benefits and risks for each individual patient.

Jarisch-Herxheimer reaction (JHR).

The Jarisch-Herxheimer reaction may occur immediately after initiation of ceftriaxone therapy in patients infected with Treponema pallidum (spirochete). Symptoms usually resolve spontaneously but may require symptomatic treatment. Antibiotic therapy should not be discontinued due to this reaction.

Disposal of unused or expired medicinal product: Environmental contamination should be minimized. The medicinal product should not be disposed of via household sewage or as household waste. "Take-back" systems (if available) are recommended for disposal.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone crosses the placental barrier. Limited data are available on the use of ceftriaxone in pregnant women. Animal reproductive studies did not reveal embryotoxic, fetotoxic, teratogenic effects or other adverse effects of ceftriaxone, including on postnatal development of offspring. During pregnancy, particularly in the first trimester, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

Ceftriaxone passes into breast milk in small concentrations, and significant adverse effects on infants are not expected with therapeutic doses. However, the risk of diarrhea and fungal mucosal infections in infants cannot be excluded. The risk of sensitization should also be considered. If treatment with the drug is prescribed for a breastfeeding mother, the possibility of discontinuing breastfeeding should be considered. The decision to discontinue breastfeeding or to refrain from using the drug should be made by the physician, taking into account the benefits of breastfeeding for the child and the therapeutic benefit for the mother.

Reproductive function (fertility).

Animal studies on reproductive function did not reveal any adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

Given that adverse reactions (e.g., dizziness) may occur during treatment, patients should exercise caution when driving or operating machinery during therapy.

Method of administration and dosage.

Dosage.

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

The dosages listed in the tables below are generally accepted for the specified indications. In particularly severe cases, the maximum doses within the recommended range should be used.

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

*In cases of confirmed bacteremia, the highest doses of the recommended range should be used.

**If the dose of the drug exceeds 2 g per day, the drug can be administered twice daily with an interval of 12 hours.

Adults and children aged 12 years and older (≥ 50 kg) who require special dosing regimens.

Acute otitis media: administer intramuscularly at a dose of 1–2 g once daily.

In severe patient condition or in case of ineffectiveness of previous therapy, "CEF 1000 mg" can be administered intramuscularly at a dose of 1–2 g per day for 3 days.

Preoperative prophylaxis: administer 2 g of the drug as a single dose.

Gonorrhea: it is recommended to administer 0.5 g intramuscularly as a single dose (calculated as ceftriaxone).

Syphilis: the usual dose is 0.5 g–1 g once daily. For the treatment of neurosyphilis, the dose is increased to 2 g once daily for 10–14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on limited data. National or local guidelines should also be considered.

Disseminated Lyme borreliosis at early (stage II) and late (stage III) stages: the drug is administered at a dose of 2 g once daily for 14–21 days. The recommended duration of treatment varies; national or local guidelines should also be considered.

Children.

Neonates, infants, and children from 15 days to 12 years of age (< 50 kg).

For children with body weight of 50 kg and above, adult doses should be used.

*In cases of confirmed bacteremia, the highest doses of the recommended range should be used.

**If the dose of the drug exceeds 2 g per day, the drug can be administered twice daily with an interval of 12 hours.

Indications in newborns, infants, and children from 15 days to 12 years (< 50 kg) requiring special dosing

Acute otitis media: administer 50 mg/kg body weight as a single intramuscular dose. Data on efficacy of "CEF 1000 mg" in severe cases or in the absence of response to prior therapy when administered intramuscularly at a dose of 50 mg/kg daily for 3 days are limited.

Preoperative prophylaxis: administer 50 – 80 mg/kg body weight as a single dose.

Syphilis: the commonly used dose is 75 – 100 mg/kg (maximum 4 g) once daily for 10 – 14 days. Dosing recommendations for syphilis, including neurosyphilis, are based on very limited data. National or local guidelines should also be considered.

Disseminated Lyme borreliosis [early (stage II) and late (stage III)]: the drug is administered at a dose of 50 – 80 mg/kg body weight once daily for 14 – 21 days. The recommended duration of treatment may vary; national or local guidelines should also be taken into account.

Newborns aged 0 – 14 days.

"Cef 1000 mg" is contraindicated in preterm infants less than 41 weeks of age, calculated from gestational age plus postnatal age.

*In cases of confirmed bacteremia, the highest doses within the recommended range should be used.

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

Indications in neonates 0–14 days requiring special dosing.

Acute otitis media: at the beginning of treatment, the drug is administered as a single intramuscular injection at a dose of 50 mg/kg body weight.

Preoperative prophylaxis: the drug is administered as a single dose of 20–50 mg/kg body weight.

Syphilis: the usual dose is 50 mg/kg body weight 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 therapy.

The duration of therapy depends on the therapeutic response achieved. Antibiotic therapy should generally continue for at least 48–72 hours after the disappearance of signs and symptoms of infection or laboratory confirmation of the absence of infection.

Geriatric patients.

Dose adjustment is not required in elderly patients provided that renal and hepatic functions are satisfactory.

Patients with hepatic impairment.

Dose reduction is not necessary in patients with mild to moderate hepatic impairment if renal function remains normal. There are no data available on use in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment.

Dose reduction is not required in patients with renal impairment if hepatic function remains normal. In patients with end-stage renal disease (creatinine clearance < 10 mL/min), the daily dose should not exceed 2 g. For patients undergoing hemodialysis, no additional dose of the drug is required after dialysis. Continuous clinical monitoring of safety and efficacy is recommended.

Patients with severe hepatic and renal impairment.

In patients with severe hepatic and renal impairment, continuous clinical monitoring of safety and efficacy of the drug is recommended.

Administration methods.

Intramuscular injections.

"Cef 1000 mg" can be administered by deep intramuscular injection. Lidocaine solution is used as the solvent. To prepare the solution for intramuscular injection, the contents of the vial are dissolved in 3.5 mL of 1% lidocaine hydrochloride solution. The injection should be administered deeply into the upper outer quadrant of the gluteus maximus muscle, with no more than 1 g injected into a single gluteal site. Doses exceeding 1 g should be divided and administered at different sites. Before administration, contraindications, warnings, and other relevant information regarding lidocaine hydrochloride use must be carefully considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Intravenous injections.

"Cef 1000 mg" can be administered by intravenous infusion over at least 30 minutes (preferred) or by slow intravenous injection over at least 5 minutes into large veins. Intravenous doses of 50 mg/kg body weight or higher in neonates and children under 12 years of age should be administered by infusion. In neonates, the intravenous dose should be infused over 60 minutes to minimize displacement of bilirubin from its albumin-serum complex by ceftriaxone, thereby reducing the potential risk of bilirubin encephalopathy. The intramuscular route should be used only when the intravenous route 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 intravenous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute "Cef 1000 mg" in vials or for further dilution of the reconstituted solution for intravenous administration, due to the risk of precipitation of ceftriaxone-calcium salts. Precipitation of ceftriaxone-calcium salts may also occur when "Cef 1000 mg" is mixed with calcium-containing solutions in the same intravenous infusion system. "Cef 1000 mg" must not be co-administered intravenously with calcium-containing solutions, including prolonged infusions containing calcium such as parenteral nutrition via a Y-site connector (see "Administration and dosage").

For preoperative prophylaxis, "Cef 1000 mg" should be administered 30–90 minutes prior to surgical intervention.

Children.

The drug should be administered to children according to the dosing instructions specified in the section "Administration and dosage."

Overdose.

Symptoms: nausea, vomiting, and diarrhea may occur.

Treatment: symptomatic treatment; hemodialysis or peritoneal dialysis is ineffective. There is no specific antidote.

Adverse Reactions

The most commonly observed adverse reactions during ceftriaxone administration are eosinophilia, leukopenia, thrombocytopenia, diarrhea, rash, and elevated liver enzymes.

Infections and infestations: genital fungal infections; pseudomembranous colitis; superinfections.

Blood and lymphatic system disorders: eosinophilia, leukopenia, thrombocytopenia; granulocytopenia, anemia, coagulation disorders; hemolytic anemia, agranulocytosis.

Immune system disorders: anaphylactic shock, anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions, Jarisch-Herxheimer reaction (JHR).

Nervous system disorders: headache, dizziness; seizures.

Ear and labyrinth disorders: vertigo.

Respiratory, thoracic and mediastinal disorders: bronchospasm.

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

Hepatobiliary disorders: elevated liver enzymes; gallbladder precipitates, nuclear jaundice.

Skin and subcutaneous tissue disorders: rash; pruritus; urticaria; Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Renal and urinary disorders: hematuria, glucosuria; oliguria, renal precipitates (reversible).

General disorders and administration site conditions: phlebitis, injection site pain, malaise; swelling, chills.

Investigations: increased blood creatinine levels; false-positive Coombs test results, false-positive galactosemia test results, false-positive non-enzymatic glucose determination tests.

Characteristics of specific adverse reactions.

Infections and infestations.

Cases of diarrhea following ceftriaxone administration may be associated with Clostridium difficile. Appropriate fluid and electrolyte replacement should be administered (see section "Special precautions").

Precipitates of ceftriaxone calcium salt.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in preterm and term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing solutions. Precipitates of ceftriaxone calcium salt were found in the lungs and kidneys at autopsy. 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", and "Pharmacodynamics").

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 or dehydrated patients. 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 gallbladder precipitates of ceftriaxone calcium salt have been reported, primarily in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence rates of precipitate formation with intravenous administration—over 30% in some studies. The incidence of precipitate formation is lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases may present with clinical symptoms such as pain, nausea, and vomiting. Symptomatic treatment is recommended in such cases. Precipitates usually resolve after discontinuation of ceftriaxone (see section "Special precautions").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution should be used immediately. Any unused prepared solution should be discarded.

Incompatibilities.

Do not add "CEF 1000 mg" to infusion solutions containing calcium, such as Ringer's solution or Hartmann's solution. These solutions should also not be used for further dilution of the reconstituted solution for intravenous administration, as precipitation may occur. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions, including parenteral nutrition.

Ceftriaxone is incompatible and should not be mixed with amsacrine, vancomycin, fluconazole, or aminoglycosides.

Do not mix with solvents other than those specified in the section "Administration and dosage".

Packaging.

1000 mg of powder in a glass vial, 1 vial in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Nitin Lifesciences Ltd. / Nitin Lifesciences Ltd.

Manufacturer's address and location of operations.

Village-Rampur Road, Paonta Sahib, District Sirmour, Himachal Pradesh, India

Marketing authorization holder.

Ochoa Impex / Ochoa Impex.

Address of the marketing authorization holder.

E-360, Greater Kailash part-II, New Delhi-110048, India.