Xonoctam^® (Powder) Instructions for Use

Marketing Authorization Holder

GFSC, LLC (Russia)

Manufactured By

Ruzpharma, LLC (Russia)

ATC Code

J01DD63 (Ceftriaxone and beta-lactamase inhibitor)

Active Substances

Sulbactam (Rec.INN registered by WHO)

Ceftriaxone (Rec.INN registered by WHO)

Dosage Form

Xonoctam®

Powder for solution for intravenous and intramuscular administration 1000 mg+500 mg

Dosage Form, Packaging, and Composition

Powder for solution for intravenous and intramuscular administration white or almost white in color.

Excipients: sodium – 132.19 mg.

1500 mg – vials (1) – cardboard packs.
1500 mg – vials (5, 10 or 50) – cardboard boxes (for hospitals).

Clinical-Pharmacological Group

Third generation cephalosporin with beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; third-generation cephalosporins

Pharmacological Action

Combined medicinal product, antibiotic.

Ceftriaxone is a semisynthetic broad-spectrum third-generation cephalosporin antibiotic. The bactericidal activity of ceftriaxone is due to the suppression of cell membrane synthesis.

Sulbactam is a derivative of the basic penicillin nucleus. It is an irreversible inhibitor of beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics; prevents the destruction of penicillins and cephalosporins by the action of beta-lactamases from resistant microorganisms, binds to penicillin-binding proteins, and exhibits synergy when used simultaneously with penicillins and cephalosporins.

Sulbactam does not possess clinically significant antibacterial activity (with the exception of Neisseriaceae and Acinetobacter spp.). It interacts with some penicillin-binding proteins, so this combination often has a more pronounced effect on susceptible strains than Ceftriaxone alone.

The Ceftriaxone+Sulbactam combination is active against all microorganisms susceptible to ceftriaxone and acts synergistically (reduces the MIC of the combination by up to 4 times compared to ceftriaxone).

The Ceftriaxone+Sulbactam combination exhibits activity against gram-negative aerobic microorganisms: Acinetobacter lwoffii, Acinetobacter anitratus*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus, Citrobacter freundii**, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp., Haemophilus duereyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxyloca, Klebsiella pneumoniae**, Moraxella catarrhalis, Moraxella osloensis, Moraxella spp., Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus vulgaris*, Proteus penneri*, Pseudomonas fluorences*, Pseudomonas spp. (clinical strains of Pseudomonas aeruginosa are resistant to ceftriaxone), Providencia spp., including Providencia rettgeri*, Salmonella spp. (non-typhoidal), Salmonella typhi, Serratia spp.*, including Serratia marcescens*, Shigella spp., Vibrio spp., Yersinia spp., including Yersinia enterocolitica; gram-positive aerobic microorganisms Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus spp. (coagulase-negative), Streptococcus pyogenes (beta-hemolytic streptococci group A), Streptococcus agalactia (beta-hemolytic streptococci group B), Streptococcus pneumoniae, Streptococcus spp. group Viridans; anaerobic microorganisms: Bacteroides spp., Clostridium spp. (except Clostridium difficile), Fusobacterium spp. (including Fusobacterium nucleatum), Peptococcus spp., Peptostreptococcus spp.

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

* some isolates of these species are resistant to ceftriaxone, mainly due to the production of chromosomally encoded beta-lactamases.

** some isolates of these species are resistant to ceftriaxone due to the production of a number of plasmid-mediated beta-lactamases.

Pharmacokinetics

The C_max of ceftriaxone after a single IM administration of a 1 g dose is approximately 81 mg/L, and is reached 2-3 hours after administration; the C_max of sulbactam is 6.24 mg/L, and is reached approximately 1 hour after administration.

The AUC for ceftriaxone after IM administration is the same as after IV administration of an equivalent dose, indicating 100% bioavailability after IM administration. The V_d of ceftriaxone is 7-12 L, that of sulbactam is 18-27.6 L. Ceftriaxone and Sulbactam are well distributed in various tissues and body fluids, including ascitic fluid, cerebrospinal fluid (in patients with meningeal inflammation), urine, saliva, tonsils, skin, fallopian tubes, ovaries, uterus, lungs, bones, bile, gallbladder, appendix. It crosses the placental barrier.

Plasma protein binding: Ceftriaxone – 70-90%, Sulbactam – 38%. Ceftriaxone does not undergo systemic metabolism; it is converted into inactive metabolites by the action of intestinal microflora.

The T_1/2 of sulbactam is on average about 1 hour, that of ceftriaxone is about 8 hours. The plasma clearance of ceftriaxone is 10-20 ml/min, renal clearance is 5-12 ml/min.

Approximately 84% of the sulbactam dose and 50-60% of the ceftriaxone dose are excreted by the kidneys unchanged; the remainder of ceftriaxone is excreted in bile through the intestines.

No significant changes in the pharmacokinetic parameters of both components of this combination were noted upon repeated administration. No accumulation was observed upon administration.

Penetration into cerebrospinal fluid: In newborns and children with meningeal inflammation, Ceftriaxone penetrates into the CSF, and in the case of bacterial meningitis, an average of 17% of the plasma ceftriaxone concentration diffuses into the cerebrospinal fluid, which is approximately 4 times more than in aseptic meningitis. Twenty-four hours after IV administration of ceftriaxone at a dose of 50-100 mg/kg body weight, concentrations in the cerebrospinal fluid exceed 1.4 mg/L. In adult patients with meningitis, 2-24 hours after administration of a dose of 50 mg/kg body weight, ceftriaxone concentrations in the cerebrospinal fluid are many times higher than the minimum inhibitory concentrations for the most common causative agents of meningitis.

Indications

Infectious and inflammatory diseases caused by pathogens susceptible to the combination of ceftriaxone with sulbactam: kidney and urinary tract infections; infections of the abdominal organs (peritonitis, infections of the biliary tract and gastrointestinal tract); lower respiratory tract infections (including pneumonia); ENT infections (including acute otitis media); bacterial meningitis; septicemia: bone and joint infections; skin and soft tissue infections (including wound infections); Lyme disease; genital infections, including uncomplicated gonorrhea; infectious diseases in patients with reduced immunity; prevention of postoperative infections.

ICD codes

Dosage Regimen

It is administered parenterally: IM or IV. The dose, method, regimen and duration of therapy are established individually, depending on the indications, clinical situation and age.

For adults and children over 12 years of age, the standard dose is 1-2 g of ceftriaxone (0.5-1 g of sulbactam) once a day or divided into 2 administrations (every 12 hours).

In severe cases or in infections caused by pathogens with only moderate susceptibility to ceftriaxone, the daily dose can be increased to 4 g. The maximum daily dose of sulbactam is 4 g.

For children under 12 years of age, the dose and regimen are established depending on the indications and body weight.

Adverse Reactions

Allergic reactions: fever or chills, anaphylactic or anaphylactoid reactions (e.g., bronchospasm), rash, itching, allergic dermatitis, urticaria, edema, exudative multiforme erythema, Stevens-Johnson syndrome, Lyell’s syndrome, allergic pneumonitis, serum sickness.

Nervous system disorders: headache, dizziness, seizures, vertigo.

Digestive system disorders: abdominal pain, diarrhea, nausea, vomiting, taste disturbance, dyspepsia, flatulence, stomatitis, glossitis, pancreatitis, pseudomembranous colitis.

Liver and biliary tract disorders: cholelithiasis, gallbladder “sludge phenomenon”, jaundice.

Hematopoietic system disorders: anemia (including hemolytic), leukopenia, lymphopenia, leukocytosis, lymphocytosis, monocytosis, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, granulocytopenia, basophilia, increased (decreased) prothrombin time, increased thromboplastin time, agranulocytosis.

Urinary system disorders: genital mycosis, oliguria, vaginitis, nephrolithiasis.

Local reactions: with IV administration – phlebitis, pain, induration along the vein; with IM administration – pain, sensation of warmth, tightness or induration at the injection site.

Laboratory parameters: increased activity of hepatic transaminases and ALP, hyperbilirubinemia, hypercreatininemia, increased urea concentration, presence of sediment in urine, glucosuria, hematuria.

Other: increased sweating, “flushing”, nosebleed, palpitations, formation of precipitates in the lungs.

Contraindications

Hypersensitivity to sulbactam and ceftriaxone, as well as to other cephalosporins, penicillins, beta-lactam antibiotics; hyperbilirubinemia or jaundice in full-term newborns; premature newborns who have not reached the “postmenstrual” age of 41 weeks (taking into account the period of intrauterine development and age); full-term newborns who require IV administration of calcium-containing solutions; acidosis, hypoalbuminemia in full-term newborns.

With caution

In ulcerative colitis, in impaired liver and kidney function, in enteritis and colitis associated with the use of antibacterial drugs.

Use in Pregnancy and Lactation

Use during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus (Ceftriaxone and Sulbactam cross the placental barrier).

If it is necessary to use during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

It should be used with caution in patients with severe liver dysfunction. There is no need to adjust the dose if kidney function remains normal.

In case of combined renal and hepatic impairment, the plasma concentration of ceftriaxone should be regularly determined and its dose adjusted if necessary.

Use in Renal Impairment

It should be used with caution in patients with severe renal dysfunction. There is no need to adjust the dose if liver function remains normal.

In case of combined renal and hepatic impairment, the plasma concentration of ceftriaxone should be regularly determined and its dose adjusted if necessary.

Pediatric Use

Contraindicated for use in hyperbilirubinemia or jaundice in full-term newborns; in premature newborns who have not reached the “postmenstrual” age of 41 weeks (taking into account the period of intrauterine development and age); in full-term newborns who require IV administration of calcium-containing solutions.

Geriatric Use

In elderly patients, this combination is used in the usual adult doses, without age-related adjustments.

Special Precautions

Cases of serious hypersensitivity reactions have been described in patients receiving beta-lactam antibiotics such as cephalosporins. If they occur, the product should be discontinued and adequate therapy prescribed.

When used concomitantly with aminoglycosides, renal function should be monitored.

During long-term treatment, it is necessary to regularly monitor the peripheral blood picture, indicators of the functional state of the liver and kidneys.

During treatment with ceftriaxone, false-positive results of the Coombs test, the test for galactosemia, and when determining glucose in urine may be noted (glucosuria is recommended to be determined only by the enzymatic method).

When using ceftriaxone (like other antibiotics), the development of superinfection is possible, which requires its discontinuation and the appointment of appropriate treatment. Ceftriaxone can displace bilirubin from its binding with serum albumin. As with the use of other cephalosporins, the development of autoimmune hemolytic anemia is possible. Cases of severe hemolytic anemia in adults and children, including fatal outcomes, have been reported. In case of anemia, ceftriaxone therapy must be discontinued.

Influence on the ability to drive vehicles and mechanisms

Considering the profile of adverse reactions, during treatment with the Ceftriaxone+Sulbactam combination, caution must be exercised when driving vehicles, operating machinery, and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

Bacteriostatic antibiotics reduce the bactericidal effect of ceftriaxone/sulbactam.

Antagonism with chloramphenicol in vitro.

With simultaneous use of large doses of ceftriaxone and “loop” diuretics (for example, furosemide), no impairment of renal function was observed. There is no indication that Ceftriaxone increases the nephrotoxicity of aminoglycosides.

Probenecid does not affect the elimination of ceftriaxone.

Ceftriaxone and aminoglycosides have synergism against many gram-negative bacteria. Although the increased efficacy of such combinations is not always predictable, it should be considered in severe, life-threatening infections, such as those caused by Pseudomonas aeruginosa.

Ceftriaxone reduces the effectiveness of oral contraceptives, so it is recommended to use additional non-hormonal contraceptive means.

Formation of calcium salts precipitates of ceftriaxone may occur when mixing this combination and calcium-containing solutions when using a single venous access.

The Ceftriaxone+Sulbactam combination should not be mixed or administered simultaneously with other antimicrobial drugs.

The Ceftriaxone+Sulbactam combination is pharmaceutically incompatible with solutions containing calcium ions (including Hartmann’s and Ringer’s solutions) – precipitation may form; with amsacrine, vancomycin, fluconazole and aminoglycosides.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.