Sulbactomax
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SULBACTOMAX (SULBACTOMAX)
Composition:
Active substances: ceftriaxone, sulbactam;
One 20 ml vial contains: ceftriaxone sodium equivalent to ceftriaxone 1000 mg, sulbactam sodium equivalent to sulbactam 500 mg;
One 10 ml vial contains: ceftriaxone sodium equivalent to ceftriaxone 500 mg, sulbactam sodium equivalent to sulbactam 250 mg.
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: white, pale yellow/creamy crystalline, slightly hygroscopic powder.
Pharmacotherapeutic group. Antibacterials for systemic use. Ceftriaxone, combinations. Third-generation cephalosporins. ATC code J01D D54.
Pharmacological Properties.
Pharmacodynamics.
Sulbactamax is a combination drug containing:
− ceftriaxone (a third-generation cephalosporin) with broad-spectrum activity against susceptible microorganisms during active multiplication by inhibiting the biosynthesis of the mukopeptide of the cell membrane;
− sulbactam — an irreversible inhibitor of most major beta-lactamases produced by penicillin-resistant microorganisms. It exerts significant antibacterial activity only against Neisseriaceae, Acinetobacter calcoaceticus, Bacteroides spp., Branhamella catarrhalis, and Pseudomonas cepacia. Sulbactam acts synergistically with penicillins and cephalosporins and also binds to certain penicillin-inactivating proteins, thereby increasing the susceptibility of some sensitive strains to the combination compared to monotherapy with a beta-lactam antibiotic.
Sulbactam is active against (including beta-lactamase-producing resistant strains):
− Gram-positive (aerobic): Staphylococcus aureus (methicillin-susceptible strains), coagulase-negative staphylococci, Streptococcus pyogenes (beta-hemolytic, group A), Streptococcus agalactiae (beta-hemolytic, group B), beta-hemolytic streptococci (other than groups A and B), Streptococcus viridans, Streptococcus pneumoniae. It should be noted that methicillin-resistant Staphylococcus spp., as well as Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes, are resistant to cephalosporins, including ceftriaxone;
− Gram-negative (aerobic): Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alcaligenes-like bacteria, Citrobacter diversus (including C. amalonaticus), Citrobacter freundii, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter spp. (others), Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis (formerly known as Branhamella catarrhalis), Moraxella osloensis, Moraxella spp. (others), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri, Proteus vulgaris, Pseudomonas fluorescens, Pseudomonas spp. (others), Providencia rettgeri, Providencia spp. (others), Salmonella typhi, Salmonella spp. (nontyphoidal), Serratia marcescens, Serratia spp. (others), Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (others).
Sulbactamax, like ceftriaxone, is used for the treatment of gonorrhea and syphilis, as Treponema pallidum is susceptible to ceftriaxone in vitro and in animal experiments, and clinical trials have shown that ceftriaxone is highly effective against primary and secondary syphilis;
− anaerobes: Bacteroides spp. (including some strains of B. fragilis), Clostridium spp. (except C. difficile), Fusobacterium spp. (except F. mortiferum and F. varium), Gaffkia anaerobica (formerly known as Peptococcus), Peptostreptococcus spp.
Note: Many beta-lactamase-producing strains of Bacteroides spp., including B. fragilis, as well as Clostridium difficile, are resistant to ceftriaxone.
Since the main active ingredient of the drug is ceftriaxone, susceptibility to Sulbactamax is determined by susceptibility to ceftriaxone, which can be assessed by the disk diffusion method
or by serial dilution methods on agar or in broth.
Pharmacokinetics.
The pharmacokinetics of ceftriaxone are nonlinear.
All major pharmacokinetic parameters, except for half-life (T1/2), are dose-dependent. Absorption: after intramuscular administration, maximum concentration is reached within 2–3 hours. The bioavailability of the drug after intramuscular administration is 100% (with respect to ceftriaxone).
After administration at a dose of 1–2 g, ceftriaxone penetrates well into tissues and body fluids. After intravenous administration, ceftriaxone rapidly penetrates into cerebrospinal fluid, where bactericidal concentrations against susceptible microorganisms are maintained for 24 hours.
Ceftriaxone reversibly binds to albumin. Due to lower albumin concentrations in tissue fluid, the fraction of free ceftriaxone is higher in tissue fluid than in blood plasma. Maximum concentration (Cmax) in cerebrospinal fluid is reached approximately 4 hours after intravenous administration and averages 18 mg/L. In bacterial meningitis, the average concentration of ceftriaxone in cerebrospinal fluid is 17% of the plasma concentration; in aseptic meningitis, it is approximately 4%. In adult patients with meningitis, 2–24 hours after administration of a 50 mg/kg dose, ceftriaxone concentrations in cerebrospinal fluid are many times higher than the minimum inhibitory concentrations for the most common meningitis pathogens.
Ceftriaxone crosses the placental barrier and penetrates into breast milk in small concentrations.
Ceftriaxone does not undergo systemic metabolism but is converted into inactive metabolites by intestinal flora.
50–60% of ceftriaxone is excreted unchanged in urine, and 40–50% is excreted unchanged in bile. The elimination half-life of ceftriaxone in adults is approximately 8 hours. Total plasma clearance is 10–22 mL/min, and renal clearance is 5–12 mL/min. In newborns, approximately 70% of the dose is excreted by the kidneys. In infants during the first 8 days of life, as well as in elderly individuals (aged 75 years and older), the elimination half-life is on average 2 times longer. In patients with impaired renal or hepatic function, the pharmacokinetics of the drug are only slightly altered, with only a minor increase in elimination half-life observed. In cases of impaired renal function alone, the proportion of ceftriaxone excreted in bile increases; in cases of impaired hepatic function alone, the proportion excreted by the kidneys increases.
Clinical characteristics.
Indications.
‒ Lower respiratory tract infections;
‒ acute bacterial otitis media;
‒ skin and soft tissue infections;
‒ kidney and urinary tract infections;
‒ bone and joint infections;
‒ septicemia;
‒ intra-abdominal infections (peritonitis, biliary tract and gastrointestinal tract infections);
‒ meningitis;
‒ gonorrhea;
‒ surgical infection prophylaxis.
Contraindications.
Hypersensitivity to ceftriaxone or any other cephalosporin. History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, and carbapenems); renal and/or hepatic impairment; gastrointestinal disorders in medical history, particularly ulcerative colitis, enteritis, or antibiotic-associated colitis.
Ceftriaxone 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 salt (see sections «Special precautions», «Adverse reactions»).
* In vitro studies have shown that ceftriaxone may displace bilirubin from its binding to serum albumin, potentially increasing the 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»). Refer to the lidocaine medical instructions, particularly contraindications.
Ceftriaxone solutions containing lidocaine must never be administered intravenously.
Interaction with other medicinal products and other types of interactions.
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to dissolve ceftriaxone in vials or to dilute reconstituted solution for intravenous administration due to the likelihood of ceftriaxone-calcium salt precipitation. Precipitation of ceftriaxone-calcium salts may also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous infusion system. Ceftriaxone must not be administered intravenously simultaneously with calcium-containing solutions, including calcium-containing parenteral nutrition solutions, via a Y-site connector. However, in patients other than newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, one after another, provided the infusion line is thoroughly flushed with a compatible fluid between infusions. In vitro studies using adult and neonatal umbilical plasma have shown that newborns are at increased risk of ceftriaxone-calcium salt precipitation (see sections «Dosage and administration», «Contraindications», «Special precautions», «Adverse reactions», «Incompatibilities»).
Concomitant use of ceftriaxone with oral anticoagulants may enhance the anti-vitamin K effect 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 «Adverse reactions»).
Conflicting data exist regarding the potential for increased nephrotoxicity 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.
Ceftriaxone must not be mixed with amikacin, vancomycin, fluconazole, or aminoglycosides.
No renal function impairment has been observed when high doses of ceftriaxone are used concomitantly with potent diuretics such as furosemide.
No disulfiram-like (antabuse-like) effects have been observed after alcohol consumption immediately following ceftriaxone administration.
Ceftriaxone contains an N-methylthiotetrazole side chain, which may cause ethanol intolerance and bleeding tendencies, as seen with some other cephalosporins.
In vitro studies have shown antagonistic effects when chloramphenicol is used in combination with ceftriaxone. The clinical significance of these findings is unknown.
There are no reports of interaction between ceftriaxone and orally ingested calcium-containing products, or between intramuscular ceftriaxone and calcium-containing products (administered intravenously or orally).
In patients receiving ceftriaxone, false-positive results in the Coombs test may occur.
Like other antibiotics, ceftriaxone may cause false-positive results in galactosemia testing.
Similarly, false-positive results may occur when glucose in urine is tested by non-enzymatic methods. Therefore, during ceftriaxone therapy, glucose in urine should be tested using enzymatic methods.
Bacteriostatic agents may interfere with the bactericidal action of cephalosporins.
Ceftriaxone may reduce the efficacy of hormonal oral contraceptives. Therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after completion of therapy.
Probenecid does not affect the elimination of ceftriaxone.
Special precautions for use.
Hypersensitivity reactions.
As with all beta-lactam antibiotics, serious hypersensitivity reactions, occasionally leading to fatal outcomes, have been reported (see section "Adverse reactions"). Hypersensitivity reactions may also progress to Kounis syndrome — a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). In case of severe hypersensitivity reactions, ceftriaxone therapy should be immediately discontinued and appropriate emergency measures initiated. Prior to initiating treatment, it is essential to determine whether the patient has previously experienced severe hypersensitivity reactions to ceftriaxone, other cephalosporins, or any other type of beta-lactam agents. Ceftriaxone should be administered with caution in patients with a history of mild hypersensitivity to other beta-lactam medicinal products.
The risk of anaphylactic reactions is increased in patients with a history of anaphylaxis or those suffering from hypersensitivity reactions to various allergens; therefore, ceftriaxone should be used cautiously in patients with a predisposition to allergic diathesis.
Severe skin adverse reactions have been reported [Stevens–Johnson syndrome or Lyell’s syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)], associated with ceftriaxone therapy, which may be life-threatening or fatal, although the frequency of these events is unknown (see section "Adverse reactions").
Encephalopathy.
Cases of encephalopathy have been reported during ceftriaxone therapy (see section "Adverse reactions"), 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 ceftriaxone should be considered.
Jarisch–Herxheimer reaction.
In some patients with spirochetal infections, a Jarisch–Herxheimer reaction may occur immediately after initiation of ceftriaxone therapy. This reaction is typically self-limiting or can be managed with symptomatic treatment. Antibiotic therapy need not be discontinued upon occurrence of this reaction.
The drug may prolong prothrombin time. Therefore, prothrombin time should be monitored in suspected vitamin K deficiency.
Colitis/overgrowth of non-susceptible microorganisms.
Diarrhea associated with Clostridium difficile , ranging from mild to fatal colitis, may occur during treatment with nearly all antibacterial agents, including ceftriaxone and sulbactam. Antibacterial agents alter the normal gut flora, leading to overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of Clostridium difficile-associated diarrhea. Hyperproducing toxin strains of Clostridium difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. Clostridium difficile-associated diarrhea should be considered in all patients receiving antibiotics. A detailed medical history is essential, as Clostridium difficile-associated diarrhea may occur up to two months after completion of antibacterial therapy. Discontinuation of ceftriaxone and initiation of appropriate therapy against Clostridium difficile should be considered. Antiperistaltic agents should not be used.
As with other antibacterial agents, superinfections caused by microorganisms not susceptible to the drug may occur.
Appropriate fluid and electrolyte management, protein supplementation, antibiotic therapy effective against Clostridium difficile , and surgical evaluation should be considered based on clinical indications.
Prolonged use of ceftriaxone may lead to difficulties in controlling non-susceptible microorganisms. Therefore, careful monitoring of patients is required. Appropriate measures should be taken if superinfection occurs.
Antibacterial spectrum.
Ceftriaxone has a limited antibacterial spectrum and may be inappropriate as monotherapy for certain types of infections, except when the causative pathogen has already been confirmed (see section "Dosage and administration"). In polymicrobial infections involving organisms resistant to ceftriaxone, additional antibiotics should be considered.
Gallstone disease.
On ultrasound, shadows may indicate precipitation of ceftriaxone calcium salt. Hypoechoic images, mistakenly interpreted as gallstones, have been observed in the gallbladder on 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, precipitation of ceftriaxone calcium salt has been associated with clinical symptoms. In symptomatic cases, conservative non-surgical treatment is recommended, and the physician should decide whether to discontinue the drug based on a benefit-risk assessment for the individual case (see section "Adverse reactions").
Biliary stasis.
Isolated cases of pancreatitis, possibly due to obstruction of biliary tracts, have been reported in patients receiving ceftriaxone. Most of these patients had risk factors for cholestasis and biliary sludge formation, such as prior extensive therapy, severe illness, or total parenteral nutrition. Precipitation in the biliary tract due to Sulbactomax administration cannot be excluded as an initiating or contributing factor in the development of this condition.
Nephrolithiasis.
Cases of renal stone formation, which resolved after discontinuation of ceftriaxone, have been reported (see section "Adverse reactions"). Ultrasound examination should be performed if symptoms occur. The decision to administer the drug to patients with a history of nephrolithiasis or hypercalciuria should be made by the physician based on a benefit-risk assessment for the individual case.
Children.
Ceftriaxone, a component of the drug, may displace bilirubin from its binding to serum albumin. Therefore, ceftriaxone is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section "Contraindications").
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").
In patients with impaired renal function but normal hepatic function, the dose of Sulbactomax does not need to be reduced. In renal impairment (creatinine clearance below 10 mL/min), the daily dose of ceftriaxone should not exceed 2 g.
In patients with impaired hepatic function but preserved renal function, dose adjustment of Sulbactomax is not required.
In cases of concomitant severe hepatic and renal disease, serum concentrations of ceftriaxone should be monitored regularly. In patients undergoing hemodialysis, the dose of the drug does not need to be adjusted after the procedure.
Caution should be exercised when administering ceftriaxone to patients with renal impairment who are concurrently receiving aminoglycosides and diuretics.
Interaction with calcium-containing medicinal products.
In premature and full-term infants under 1 month of age, cases of ceftriaxone calcium salt precipitation in the lungs and kidneys with fatal outcomes have been reported. In at least one of these patients, ceftriaxone and calcium were administered at different times and via 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 medicinal products. In vitro studies have shown that neonates are at increased risk of ceftriaxone calcium 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 age, 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, provided the drugs are administered through different 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 professionals may consider alternative antibacterial agents not associated with this precipitation risk. If ceftriaxone use is deemed necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be temporarily interrupted during ceftriaxone infusion, and infusion systems flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibilities").
Immune-mediated hemolytic anemia.
Cases of immune-mediated hemolytic anemia have been observed in patients receiving cephalosporin-class antibacterial agents, including ceftriaxone (see section "Adverse reactions"). Cases of severe hemolytic anemia, including fatal cases, have been reported in both adult and pediatric patients.
If a patient develops anemia during ceftriaxone therapy, a diagnosis of cephalosporin-associated hemolytic anemia should be considered, and ceftriaxone should be discontinued until the etiology is established.
Long-term therapy.
During prolonged treatment, regular monitoring of blood parameters is recommended.
Sodium.
Ceftriaxone sodium and sulbactam sodium contain sodium, which should be considered in patients on a sodium-restricted diet.
Effect on serological test results.
The Coombs test may yield false-positive results during Sulbactomax therapy. Ceftriaxone may also cause false-positive results in galactosemia testing (see section "Adverse reactions").
False-positive results may occur when testing for glucose in urine using non-enzymatic methods. During Sulbactomax therapy, urine glucose levels should be determined using enzymatic assay methods (see section "Adverse reactions").
Use of lidocaine.
When lidocaine solution is used as a solvent, ceftriaxone may be administered only intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product information must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.
Disposal of the medicinal product.
Environmental contamination by the medicinal product should be minimized. The drug must not be disposed of via wastewater or household waste. Any unused medicinal product after completion of treatment or expiry should be returned in its original packaging to the supplier (physician or pharmacist) for proper disposal. A "waste collection system" should be used for disposal if available.
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, perinatal, 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. Sensitization is possible. 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 revealed any adverse effects on male or female fertility.
Ability to affect reaction speed when driving or operating machinery.
No specific studies have been conducted. Due to the possibility of adverse reactions such as dizziness, Sulbactomax may affect the ability to drive or operate machinery. Patients should exercise caution when driving or operating machinery.
Method of Administration and Dosage
Administer intravenously or intramuscularly. Prior to administration, perform skin sensitivity tests for the antibiotic and lidocaine.
Adults and children aged 12 years and older: 1–2 g (calculated as ceftriaxone) once daily (every 24 hours). In severe cases or infections caused by pathogens with reduced sensitivity to ceftriaxone, the daily dose may be increased up to 4 g (calculated as ceftriaxone).
Newborns, infants, and children under 12 years of age.
Recommended doses for once-daily administration are provided below.
Newborns (up to 14 days of age). Doses are expressed in terms of ceftriaxone: 20–50 mg/kg body weight once daily. The daily dose should not exceed 50 mg/kg body weight. No differences in dosing are required between full-term and preterm infants.
Ceftriaxone is contraindicated in newborns aged ≤ 28 days when treatment with intravenous solutions containing calcium is necessary (or anticipated), including continuous intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of precipitation of ceftriaxone-calcium salts (see section "Contraindications").
Newborns aged 15 days and older, and children under 12 years of age. Doses are expressed in terms of ceftriaxone: 20–80 mg/kg body weight once daily. Children with body weight exceeding 50 kg should receive adult doses.
The total daily dose for children should not exceed 2 g (calculated as ceftriaxone).
Intravenous doses exceeding 50 mg/kg (calculated as ceftriaxone) should be administered by slow infusion (over 30–60 minutes).
Elderly patients. Dose adjustment is not required in elderly patients.
Duration of treatment depends on the course of the disease. After normalization of body temperature and laboratory results confirming absence of the pathogen, the drug should be continued for at least an additional 48–72 hours.
Combination therapy.
Given the synergistic effect observed when ceftriaxone and aminoglycosides are used together against many Gram-negative microorganisms, they may be used concomitantly in severe, life-threatening infections caused by Pseudomonas aeruginosa. However, enhanced efficacy of such combinations is not always predictable. Due to physical incompatibility between ceftriaxone and aminoglycosides, they should be administered separately at their recommended doses.
Dosage in special situations.
Meningitis
For bacterial meningitis in infants and children aged 15 days to 12 years, treatment should begin with a dose of 100 mg/kg (but not exceeding 4 g calculated as ceftriaxone) once daily. Once the causative organism is identified and its sensitivity determined, the dose may be reduced accordingly. Optimal treatment durations achieving best outcomes were:
Neisseria meningitidis – 4 days
Streptococcus pneumoniae – 7 days
Haemophilus influenzae – 6 days
Sensitive Enterobacteriaceae – 10–14 days
Neuroborreliosis (Lyme disease): adults and children – 50 mg/kg (maximum daily dose 2 g) once daily for 14 days.
Gonorrhea caused by penicillinase-producing or non-penicillinase-producing strains: single intramuscular dose of 250 mg.
Prophylaxis of postoperative infections. Doses are expressed in terms of ceftriaxone. Depending on the risk level of infection, administer a single dose of 1–2 g (calculated as ceftriaxone) 30–90 minutes before surgery. For procedures on the colon and rectum, simultaneously (but separately) administer a 5-nitroimidazole agent (e.g., ornidazole).
Renal impairment. Dose reduction is not required if liver function remains normal. Only in pre-terminal renal failure with creatinine clearance below 10 mL/min should the daily dose not exceed 2 g (calculated as ceftriaxone).
For patients undergoing dialysis, no additional dose is required after dialysis; however, serum ceftriaxone concentration should be monitored (and dose adjusted if necessary), as elimination may be reduced in such patients.
The daily dose of Sulbactomax in patients undergoing dialysis should not exceed 2 g.
Hepatic impairment. Dose reduction is not required if renal function remains normal.
Severe renal or hepatic insufficiency
Plasma ceftriaxone concentrations should be monitored regularly, and dosage adjusted as necessary, since elimination may be reduced in such patients.
Reconstitution and administration method. General rule: the solution should be used immediately after preparation. The solution remains physically and chemically stable for 6 hours at room temperature or for 24 hours at 5°C. Depending on concentration and storage duration, the solution color may vary from pale yellow to amber. Color change does not affect drug efficacy or tolerability.
For intramuscular injections: reconstitute the vial contents with 3.5 mL of 1% lidocaine solution or 5 mL of water for injections; administer into the center of the gluteal 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, refer to the lidocaine product information leaflet.
Prior to using lidocaine as a solvent, a sensitivity test for individual lidocaine hypersensitivity must be performed.
For intravenous injections: reconstitute the vial contents with 10 mL of water for injections; administer intravenously slowly (over 2–4 minutes).
Intravenous infusion should last no less than 30 minutes. To prepare the infusion solution, reconstitute the vial contents in 40 mL of one of the following infusion solutions that do not contain calcium ions:
− 5% glucose solution
− 0.9% sodium chloride solution
− 5% glucose + 0.225% sodium chloride solution
− 5% glucose + 0.9% sodium chloride solution
− water for injections
Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute Sulbactomax in vials or to dilute 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 Sulbactomax is mixed with calcium-containing solutions in the same intravenous infusion system. Sulbactomax must not be administered intravenously simultaneously with calcium-containing solutions, including continuous infusions containing calcium, such as parenteral nutrition. However, except in newborns, ceftriaxone and calcium-containing solutions may be administered sequentially, provided the infusion system is thoroughly flushed with a compatible solution between infusions (see "Interaction with other medicinal products and other forms of interaction").
Children.
The drug is used in pediatric practice.
It is contraindicated in newborns aged ≤ 28 days when treatment with intravenous calcium-containing solutions is necessary (or anticipated), including intravenous infusions containing calcium, such as parenteral nutrition, due to the risk of ceftriaxone-calcium salt precipitation (see "Method of Administration and Dosage").
Cases of precipitation in lungs and kidneys leading to fatal outcomes have been reported in newborns and preterm infants following concomitant administration of ceftriaxone and calcium-containing products. In some of these cases, the same intravenous infusion system was used for both ceftriaxone and calcium-containing solutions, and precipitates were observed in some infusion lines.
Overdose.
Symptoms: limited information is available on overdose cases. Overdose may lead to an intensification of adverse reactions. Nausea, vomiting, and diarrhea may occur.
Treatment: hemodialysis or peritoneal dialysis are ineffective. There is no specific antidote. Treatment of overdose is symptomatic.
Adverse Reactions
Infections and infestations: candidiasis, genital fungal infections, secondary fungal infections and infections caused by resistant microorganisms, pseudomembranous colitis, superinfections.
Blood and lymphatic system disorders: eosinophilia, neutropenia, leukopenia, leukocytosis, lymphopenia, granulocytopenia, anemia including hemolytic anemia, thrombocytopenia, thrombocytosis, basophilia, increased/decreased prothrombin time, coagulation disorders, hypoprothrombinemia, agranulocytosis. During prolonged treatment, regular monitoring of blood parameters is recommended.
Gastrointestinal disorders: diarrhoea, loose stools, nausea, vomiting, flatulence, stomatitis, taste disturbances, glossitis; pancreatitis possibly developed due to biliary tract obstruction. Precipitates formed by ceftriaxone in the biliary tract may contribute to the development of pancreatitis; pseudomembranous enterocolitis has been reported.
Hepatobiliary disorders: pseudocholelithiasis of the gallbladder, precipitates of calcium ceftriaxone salt in the gallbladder with corresponding symptoms in children, reversible cholelithiasis in children, increased activity of liver transaminases and alkaline phosphatase, hyperbilirubinemia, nuclear jaundice; frequency unknown – hepatitis1, cholestatic hepatitis1,2.
Skin and subcutaneous tissue disorders: skin rashes; allergic dermatitis; pruritus; urticaria; edema including angioneurotic edema; acute generalized exanthematous pustulosis, exanthema; exudative multiform erythema; Stevens-Johnson syndrome; toxic epidermal necrolysis (Lyell’s syndrome); drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Renal and urinary disorders: increased blood urea and creatinine concentrations, oliguria, hematuria, glucosuria; cylindruria, interstitial nephritis, renal precipitates (reversible).
Nervous system disorders: headache and dizziness, tremor, seizures; rarely – encephalopathy.
Cardiac disorders: increased or decreased blood pressure, palpitations, Kounis syndrome (frequency unknown).
Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.
Immune system disorders: anaphylactic or anaphylactoid reactions, anaphylactic shock, hypersensitivity, Jarisch-Herxheimer reaction.
Ear and labyrinth disorders: vertigo.
General disorders: malaise, chills, serum sickness, edema, epistaxis, weakness.
Local reactions: following intravenous administration – phlebitis, pain, induration along the vein; following intramuscular administration – pain at injection site. Intramuscular injection without lidocaine is painful.
Effects on laboratory test results.
Increased blood creatinine levels. In isolated cases, false-positive results in the Coombs test may occur during treatment. As with other antibiotics, the drug may cause false-positive results in galactosemia testing. False-positive results may also occur in urine glucose testing; therefore, during treatment with Sulbactomax, glucosuria should be assessed only by enzymatic methods if necessary.
Cases of diarrhoea following ceftriaxone administration may be associated with Clostridium difficile. Adequate fluid and electrolyte replacement should be administered (see section "Special precautions").
Precipitates of calcium ceftriaxone salt.
Rare cases of severe adverse reactions, sometimes fatal, have been reported in premature and full-term neonates (aged < 28 days) who received intravenous ceftriaxone and calcium-containing products. Post-mortem examinations revealed precipitates of calcium ceftriaxone salt in the lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer ceftriaxone half-life compared to adults (see sections "Contraindications", "Special precautions").
Cases of renal precipitate formation have been reported, primarily in children aged 3 years and older, who received high daily doses (≥ 80 mg/kg/day) or cumulative doses exceeding 10 g, as well as those with additional risk factors (limited fluid intake, bed rest). The risk of precipitate formation increases in immobilized or dehydrated patients. Renal precipitates may be asymptomatic or clinically evident and may lead to renal failure, which resolves after discontinuation of ceftriaxone therapy.
Cases of calcium ceftriaxone salt precipitates in the gallbladder have been reported, predominantly in patients receiving doses higher than the standard recommended dose. In children, prospective studies have shown variable incidence of precipitate formation after intravenous administration – in some studies exceeding 30%. 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 usually resolve after discontinuation of ceftriaxone (see section "Special precautions").
1Usually reversible upon discontinuation of ceftriaxone.
2See section "Special precautions".
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging, out of reach of children.
Incompatibilities.
The product must never be added to infusion solutions containing calcium, such as Hartmann’s or Ringer’s solutions, including complete parenteral nutrition solutions (see sections "Administration and dosage", "Special precautions", and "Adverse reactions") due to the risk of precipitate formation! Calcium-containing solutions should also not be administered within 48 hours after the last dose of ceftriaxone. The product is incompatible with mitoxantrone, vancomycin, fluconazole, aminoglycosides, and other antibiotics.
Packaging.
1 vial of 10 or 20 ml per cardboard box.
Prescription category. Prescription only.
Manufacturer.
Venus Remedies Limited.
Manufacturer’s address.
Hill Top Industrial Estate, Jarmajri, ERIPR Phase-I (Ext.), Batoli Kalan, Baddi, District Solan, Himachal Pradesh 173205, India.
or*
Manufacturer.
Swiss Paracelsus Ltd.
Manufacturer’s address.
Block II, Plot No. 402, 412-414, Kerala Industrial Area, GIDC, near Bavla, Ahmedabad, Gujarat, 382 220, India.
Marketing Authorisation Holder:
Mili Healthcare Limited.
Address of Marketing Authorisation Holder:
2nd Floor, Office Suite, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.
*The package insert includes the manufacturer responsible for the batch release and supply.