Ceftraktam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFTRACTAM (CEFTRACTAM)

Composition:

Active substances: ceftriaxone, sulbactam;

1 vial contains ceftriaxone (as sterile sodium salt) 500 mg or 1000 mg and sulbactam (as sterile sodium salt) 250 mg or 500 mg, respectively.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder from white to light yellow, slightly hygroscopic.

Pharmacotherapeutic group. Antibacterials for systemic use. Other beta-lactam antibiotics. Third-generation cephalosporins. Ceftriaxone, combinations. ATC Code J01D D54.

Pharmacological Properties

Pharmacodynamics

Ceftactam is a combination drug containing:

• ceftriaxone (a third-generation cephalosporin) with a broad spectrum of activity against susceptible microorganisms during the active multiplication phase by inhibiting the biosynthesis of the muropeptide component of the cell membrane;
• sulbactam — an irreversible inhibitor of most major beta-lactamases produced by penicillin-resistant microorganisms. Sulbactam 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 proteins that inactivate penicillin, thereby increasing the susceptibility of some strains to the combination compared to monotherapy with a beta-lactam antibiotic.

Ceftactam is active against (including beta-lactamase-producing resistant strains):

• Gram-positive (aerobes): Staphylococcus aureus (methicillin-sensitive 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 (aerobes): 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).

Ceftactam, like ceftriaxone, is used for the treatment of gonorrhea and syphilis, since Treponema pallidum is sensitive 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., particularly B. fragilis, as well as Clostridium difficile, are resistant to ceftriaxone.

Since the main active ingredient of the drug is ceftriaxone, susceptibility to Ceftactam is determined by susceptibility to ceftriaxone, which can be assessed using the disk diffusion method or the serial dilution method on agar or broth.

Pharmacokinetics

The pharmacokinetics of ceftriaxone are nonlinear. All major pharmacokinetic parameters, except for the elimination 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% (based on ceftriaxone).

After administration at a dose of 1–2 g, ceftriaxone penetrates well into tissues and body fluids. Following 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 the lower albumin concentration in tissue fluid, the proportion 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 a dose of 50 mg/kg body weight, ceftriaxone concentrations in cerebrospinal fluid exceed the minimum inhibitory concentrations for the most common causative agents of meningitis by many times.

Ceftriaxone crosses the placental barrier and penetrates into breast milk in low 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 ranges from 10 to 22 mL/min, and renal clearance ranges from 5 to 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 twice as long. 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. 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.

Infectious-inflammatory diseases caused by microorganisms sensitive to the drug:

• 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 (including peritonitis, biliary tract and gastrointestinal tract infections);
• bacterial meningitis;
• gonorrhea;
• prevention of infections during surgical procedures.

When prescribing Ceftactam, official recommendations on antibiotic therapy and recommendations for prevention of antibiotic resistance should be followed.

Contraindications.

• Hypersensitivity to ceftriaxone, sulbactam, or to any cephalosporin antibiotic, to lidocaine (for intramuscular administration).
• History of severe hypersensitivity reactions (e.g., anaphylactic reactions) to any other type of beta-lactam antibacterial agents (penicillins, monobactams, carbapenems).
• Gastrointestinal disorders in medical history, particularly non-specific ulcerative colitis, enteritis, or antibiotic-associated colitis.
• Premature infants under 41 weeks of gestational age (gestational age + chronological age)*.
• Full-term newborns (up to 28 days of life):
  • with hyperbilirubinemia, jaundice, hypoalbuminemia, or acidosis (in these conditions, bilirubin binding to blood proteins is reduced)*;
  • who require (or are expected to require) intravenous administration of calcium-containing drugs or solutions due to the risk of formation of ceftriaxone-calcium precipitates in the lungs and kidneys (see sections "Special precautions" and "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/sulbactam, contraindications to lidocaine must be excluded if lidocaine is used as a solvent (see section "Special precautions", instructions for medical use of lidocaine, particularly contraindications).

Solutions of ceftriaxone/sulbactam containing lidocaine must never be administered intravenously.

Interaction with other medicinal products and other types of interactions.

Calcium-containing products. Calcium-containing solutions such as Ringer's solution or Hartmann's solution must not be used to reconstitute the drug in vials or for further dilution of the reconstituted solution for intravenous administration due to the risk of formation of calcium-ceftriaxone precipitates.

Ceftriaxone-calcium precipitates may also form when ceftriaxone is mixed with calcium-containing solutions in the same infusion system. Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions, via a Y-site connector. However, except for 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 plasma and umbilical cord plasma from newborns have shown an increased risk of ceftriaxone-calcium precipitate formation in newborns (see sections "Dosage and administration", "Contraindications", "Special precautions", "Adverse reactions").

There are no reports of interaction between ceftriaxone and oral calcium-containing products, or between ceftriaxone administered intramuscularly and calcium-containing products administered intravenously or orally.

Non-steroidal anti-inflammatory drugs, antiplatelet agents, vitamin K antagonists (e.g., warfarin). Increased risk of bleeding. Enhanced effect of vitamin K antagonists. Frequent monitoring of the international normalized ratio (INR) is recommended, and dosage of vitamin K antagonists should be adjusted accordingly during and after ceftriaxone treatment (see section "Adverse reactions").

Aminoglycosides. Conflicting data exist regarding potential enhancement of aminoglycoside nephrotoxicity when used concomitantly with cephalosporins. In such cases, careful monitoring of aminoglycoside levels and renal function is required in clinical practice.

If combination therapy is necessary, the drugs should be administered separately at different sites and must not be mixed in the same syringe or in the same infusion solution due to physicochemical incompatibility.

Antibacterial bacteriostatic agents (chloramphenicol, tetracyclines). Possible reduction of the bactericidal effect of ceftriaxone.

In vitro studies combining chloramphenicol with ceftriaxone have shown antagonistic effects. The clinical significance of these findings is unknown.

Other beta-lactam antibiotics. Cross-allergic reactions may occur.

Loop diuretics. No renal function impairment has been observed when high doses of ceftriaxone are administered concomitantly with potent diuretics (e.g., furosemide).

Probenecid. Does not affect tubular secretion of ceftriaxone (in contrast to other cephalosporins).

Hormonal contraceptives. As with other antibiotics, the efficacy of hormonal contraceptives may be reduced; therefore, additional (non-hormonal) contraceptive methods are recommended during treatment and for 1 month after its completion.

Ethanol. No disulfiram-like effects have been observed. Ceftriaxone contains an N-methylthiotetrazole group, which could theoretically cause ethanol intolerance or bleeding, as seen with some other cephalosporins.

Like other antibiotics, ceftriaxone may reduce the therapeutic effect of the typhoid vaccine, but this effect applies only to the attenuated Ty21a strain.

Substances used in laboratory tests. False-positive urine glucose test results may occur when using Benedict's or Fehling's solution. Therefore, during ceftriaxone therapy, urine glucose levels should be determined using enzymatic methods.

False-positive Coombs' test results may occur in patients receiving ceftriaxone. As with other antibiotics, ceftriaxone may cause false-positive results in galactosemia testing.

Ceftactam solution is incompatible and must not be mixed in the same container or administered simultaneously with amsacrine, vancomycin, fluconazole, aminoglycosides.

Special precautions for use.

Hypersensitivity reactions.

As with other cephalosporins and beta-lactam antibiotics, there have been reports of severe acute hypersensitivity reactions (including anaphylactic shock), sometimes fatal, even in patients with no prior history of allergic reactions. Hypersensitivity reactions may also progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). If such reactions occur, the drug should be discontinued immediately and appropriate emergency measures should be initiated.

Before initiating therapy, it is essential to determine whether the patient has a history of 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 agents. The risk of anaphylactic reactions is increased in patients with a history of anaphylaxis or hypersensitivity reactions to various allergens. Use with caution in patients with a predisposition to allergic diathesis.

Severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been reported during ceftriaxone use; these may be life-threatening or fatal; however, the frequency of these events is unknown (see section "Adverse reactions").

Jarisch-Herxheimer reaction.

In some patients with infections caused by spirochetes, a Jarisch-Herxheimer reaction may occur shortly after initiation of ceftriaxone therapy. The Jarisch-Herxheimer reaction is usually self-limiting or may require symptomatic treatment. If this reaction occurs, antibiotic therapy should not be discontinued.

Prothrombin time.

Ceftriaxone may prolong prothrombin time. Therefore, prothrombin time should be monitored in patients with impaired vitamin K synthesis or deficiency (e.g., due to chronic liver disease, advanced age, or malnutrition), as well as in patients who have received prolonged anticoagulant therapy prior to administration of Ceftactam. Vitamin K (10 mg/week) should be administered if prolonged prothrombin time is observed at the beginning or during treatment.

Colitis/overgrowth of non-susceptible microorganisms.

Cases of antibiotic-associated colitis/pseudomembranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone/sulbactam. The severity of symptoms may range from mild to fatal colitis. Antibacterial agents suppress normal intestinal flora, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of C. difficile-associated diarrhea. Hyperproducing toxin strains of C. difficile are associated with increased morbidity and mortality, as such infections may be resistant to antibacterial therapy and may require colectomy. Therefore, it is important to consider this diagnosis in all patients who develop diarrhea during or after antibiotic use (see section "Adverse reactions"). A detailed medical history should be obtained, as C. difficile-associated diarrhea may occur up to two months after completion of antibacterial therapy. Consideration should be given to discontinuing ceftriaxone/sulbactam therapy and initiating specific treatment against C. difficile. Depending on clinical indications, appropriate fluid and electrolyte replacement, protein supplementation, antibiotic therapy effective against C. difficile, and surgical evaluation should be provided. Antiperistaltic agents should not be used.

As with other antibacterial agents, superinfection caused by microorganisms not susceptible to the drug may occur.

With prolonged antibiotic use, difficulty in controlling non-susceptible microorganisms may arise. Therefore, careful monitoring of patients is required. Appropriate measures should be taken if superinfection occurs.

Cholelithiasis.

Following administration of the drug, usually at doses exceeding standard recommended doses, ultrasound examination of the gallbladder may reveal shadows that may be mistaken for gallstones. These are precipitates of ceftriaxone calcium salt, which disappear after discontinuation or cessation of ceftriaxone therapy. Rarely, formation of ceftriaxone calcium salt precipitates has been associated with symptoms. In symptomatic cases, conservative non-surgical treatment is recommended. The physician should consider discontinuing the drug, weighing the benefit-risk ratio in each individual case (see section "Adverse reactions").

Biliary stasis.

Cases of pancreatitis, possibly due to biliary tract obstruction, have been reported during ceftriaxone use. Most patients had risk factors for cholestasis and biliary sludge, such as prior extensive therapy, severe illness, or total parenteral nutrition. Formation of precipitates in the biliary tract due to ceftriaxone/sulbactam use cannot be excluded as a trigger or cofactor for this complication.

Nephrolithiasis.

Cases of kidney stone formation have been reported, which resolved after discontinuation of ceftriaxone (see section "Adverse reactions"). Ultrasound examination should be performed if symptoms occur. The decision to use the drug in patients with a history of kidney stones or hypercalciuria should be made by the physician, weighing the benefit-risk ratio in each individual case.

Children.

The safety and efficacy of ceftriaxone/sulbactam in neonates, infants, and children have been established for the doses described in the section "Administration and dosage". Ceftriaxone, a component of the drug, may displace bilirubin from its binding to serum albumin.

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 "Administration and dosage").

In patients with impaired renal function but normal hepatic function, the dose of Ceftactam 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 Ceftactam is not required.

In cases of concomitant severe hepatic and renal pathology, serum ceftriaxone concentrations should be monitored regularly. In patients undergoing hemodialysis, the dose of the drug does not need to be adjusted after the procedure.

Caution is advised when administering ceftriaxone to patients with renal impairment who are also receiving aminoglycosides and diuretics.

Interaction with calcium-containing products.

Cases of ceftriaxone calcium salt precipitates in the lungs and kidneys with fatal outcomes have been described in premature and full-term infants up to 1 month of age. At least one of these patients received ceftriaxone and calcium at different times and through different intravenous infusion systems. According to available scientific data, confirmed cases of intravascular precipitates have been reported only in neonates who received ceftriaxone and calcium-containing solutions or other calcium-containing products. In vitro studies have shown that neonates have an increased risk of ceftriaxone calcium salt precipitate formation compared to patients in other age groups.

Ceftriaxone should not be mixed or administered simultaneously with any calcium-containing intravenous solutions in patients of any age, even when using different infusion systems or administering the drugs into different infusion sites.

However, in children aged 28 days and older, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that the drugs are administered through different infusion systems into different body sites or the infusion system is replaced or thoroughly flushed with saline between administrations to prevent precipitate formation. In patients requiring continuous infusion of calcium-containing solutions for total parenteral nutrition (TPN), the physician may consider alternative antibacterial therapy not associated with a similar risk of precipitate formation. If ceftriaxone use in patients requiring TPN is deemed necessary, TPN solutions and ceftriaxone may be administered simultaneously, but through different infusion systems and into different body sites. Alternatively, TPN infusion may be paused during ceftriaxone infusion, and infusion lines should be flushed between administrations (see sections "Contraindications", "Adverse reactions", and "Incompatibility").

Immune-mediated hemolytic anemia.

Cases of immune-mediated hemolytic anemia have been reported in patients receiving cephalosporins, including ceftriaxone (see section "Adverse reactions"). Severe cases of hemolytic anemia (including fatal cases) have been reported during ceftriaxone treatment in both adults and children. If anemia develops during treatment with the drug, this diagnosis should be considered, and the antibiotic should be discontinued until the etiology of anemia is determined.

Long-term therapy.

During prolonged treatment with the drug, a complete blood count should be monitored regularly.

Sodium.

Ceftriaxone sodium salt and sulbactam sodium salt contain sodium, which should be taken into account in patients on a sodium-restricted diet.

Effect on serological test results.

During ceftriaxone/sulbactam use, the Coombs test may yield false-positive results. Ceftriaxone may also cause false-positive results in galactosemia testing and in non-enzymatic methods for glucose detection in urine. Therefore, during treatment with the drug, urine glucose levels should be determined using enzymatic analysis methods (see section "Adverse reactions").

Use of lidocaine.

If lidocaine solution is used as a solvent, the drug may be administered only intramuscularly. Prior to administration, contraindications, warnings, and other relevant information provided in the lidocaine product instructions must be considered (see section "Contraindications"). Lidocaine solution must never be administered intravenously.

Encephalopathy.

Cases of encephalopathy have been reported during ceftriaxone use (see section "Adverse reactions"), particularly in elderly patients with severe renal impairment (see section "Administration and dosage") 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.

Disposal of medicinal product.

Environmental contamination with the medicinal product should be minimized. The drug should not be disposed of via wastewater systems 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.

Use during pregnancy or breastfeeding.

Pregnancy.

Ceftriaxone and sulbactam cross the placental barrier. Data on use in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryo/fetal, peri- or postnatal development. The drug may be used during pregnancy, particularly in the first trimester, only if the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding.

Ceftriaxone passes into breast milk in low concentrations, and no effects on breastfed infants are expected when the drug is used at therapeutic doses. However, the risk of diarrhea and fungal mucosal infections cannot be excluded. Sensitization should also be considered. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from 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 evidence of adverse effects on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

No specific studies with ceftriaxone/sulbactam have been conducted. Due to the possibility of adverse reactions such as dizziness, the drug may affect the ability to drive or operate machinery. Patients should exercise caution when driving or operating machinery.

Administration and Dosage

Administer intravenously or intramuscularly. Prior to initiating therapy, hypersensitivity to the antibiotic and to lidocaine (in case of intramuscular administration) must be ruled out by performing a skin test.

Daily dose for adults and children aged 12 years and older: 1.5–3 g of Ceftraktam (1–2 g calculated as ceftriaxone) once daily (every 24 hours). In severe cases or for infections caused by pathogens with reduced susceptibility to ceftriaxone, the daily dose of Ceftraktam may be increased up to 6 g (4 g ceftriaxone).

Newborns, infants, and children under 12 years of age.

Recommended once-daily doses are listed below.

• For newborns (up to 14 days of age): 20–50 mg/kg body weight (based on ceftriaxone) administered once daily over at least 60 minutes to prevent displacement of bilirubin from albumin binding and reduce the potential risk of bilirubin encephalopathy. The daily dose should not exceed 50 mg/kg body weight (based on ceftriaxone).

Ceftriaxone is contraindicated in neonates aged ≤ 28 days who require (or are expected to require) intravenous calcium-containing solutions, including continuous intravenous infusions containing calcium such as parenteral nutrition, due to the risk of precipitation of calcium-ceftriaxone salts (see section "Contraindications").

• For newborns aged 15 days and older, and children under 12 years of age: 20–80 mg/kg body weight (based on ceftriaxone) once daily.

Children weighing over 50 kg should receive adult doses.

Intravenous doses of 50 mg/kg body weight (based on ceftriaxone) or higher should be administered slowly over 30–60 minutes by drip infusion.

The total daily dose in children should not exceed 2 g (calculated as ceftriaxone).

For elderly patients, dosage should be the same as for adults, provided hepatic and renal function are satisfactory.

Duration of treatment with Ceftraktam depends on the course of the disease. Treatment should continue (as with any antibiotic therapy) for at least 48–72 hours after normalization of body temperature and confirmation of pathogen eradication by bacteriological testing.

Combination therapy. Synergistic effects have been reported with concomitant use of ceftriaxone and aminoglycosides against many Gram-negative microorganisms; therefore, they may be used in severe, life-threatening infections caused by Pseudomonas aeruginosa. However, it should be noted that increased 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.

Dosing in special situations

In bacterial meningitis in infants and children aged 15 days to 12 years, treatment should be initiated at a dose of 100 mg/kg body weight (but not exceeding 4 g based on ceftriaxone) once daily. After pathogen identification and susceptibility testing, the dose may be adjusted downward accordingly.

Optimal outcomes were achieved with the following treatment durations:

Neisseria meningitidis Haemophilus influenzae Streptococcus pneumoniae Enterobacteriaceae

4 days 6 days 7 days 10-14 days

For the treatment of gonorrhea (caused by penicillinase-producing or non-penicillinase-producing strains), a single intramuscular dose of 250 mg is recommended (based on ceftriaxone).

For prophylaxis of postoperative complications, a single dose of 1.5–3 g of Ceftactam (1–2 g of ceftriaxone) should be administered 30–90 minutes before the start of surgery, depending on the degree of infection risk. During surgery on the colon and rectum, a 5-nitroimidazole agent (e.g., ornidazole) should be administered simultaneously (but separately).

In patients with impaired renal function and normal liver function, there is no need to reduce the dose. Only in cases of preterminal renal failure (creatinine clearance less than 10 ml/min), the daily dose of Ceftactam must not exceed 3 g (2 g of ceftriaxone).

Patients undergoing hemodialysis do not require additional drug administration after dialysis. Serum ceftriaxone concentration should be monitored for possible dose adjustment, as elimination may be reduced in these patients.

The daily dose of Ceftactam in patients undergoing hemodialysis must not exceed 3 g (2 g of ceftriaxone).

In patients with impaired liver function and normal renal function, there is no need to reduce the dose.

In cases of concomitant severe renal and hepatic insufficiency, plasma ceftriaxone concentrations should be regularly monitored and the dose adjusted as necessary, since drug elimination may be reduced in such patients.

Preparation of solutions

Solutions should be prepared immediately before use. After adding the solvent, visual inspection for complete dissolution is required. Freshly prepared solutions retain their physical and chemical stability for 6 hours at room temperature (or for 24 hours at 5 °C). Depending on concentration and storage duration, the color of solutions may vary from pale yellow to amber. This property of the active substance does not affect the efficacy or tolerability of the drug.

For intramuscular injection, the contents of the vial should be dissolved in 5 ml of sterile water for injections or in 3.5 ml of 1 % lidocaine solution. The solution should be injected deeply into a relatively large muscle mass, with no more than 1 g (calculated as ceftriaxone) administered into one buttock.

Solutions containing lidocaine must not be administered intravenously! (see section "Contraindications"). For detailed information, refer to the lidocaine instructions for medical use.

Prior to lidocaine use, a sensitivity test should be performed to determine individual sensitivity to this medicinal product.

For intravenous injections, the contents of the vial should be dissolved in 10 ml of water for injections and administered slowly (over 2–4 minutes).

Intravenous infusion should last at least 30 minutes. To prepare the solution, the contents of the vial should be dissolved in 40 ml of one of the following infusion solutions that do not contain calcium ions:

• 5 % glucose solution;
• 0.9 % sodium chloride solution;
• 0.45 % sodium chloride solution;
• 5 % glucose solution + 0.225 % sodium chloride solution;
• 5 % glucose solution + 0.9 % sodium chloride solution;
• water for injections.

Solvents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used for reconstitution of Ceftactam in vials or for dilution of the reconstituted solution for intravenous administration, as precipitation of ceftriaxone-calcium may occur. Formation of ceftriaxone-calcium precipitates may also occur when Ceftactam is mixed with calcium-containing solutions in the same infusion system. Therefore, Ceftactam must not be administered intravenously simultaneously with calcium-containing solutions, including calcium-containing solutions for prolonged infusions such as parenteral nutrition solutions. However, except in neonates, Ceftactam and calcium-containing solutions may be administered sequentially if the infusion system is thoroughly flushed with a compatible solution between infusions (see "Interaction with other medicinal products and other types of interactions").

Children.

The drug is used in pediatric practice.

In neonates aged ≤ 28 days, the drug is contraindicated 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 the lungs and kidneys leading to fatal outcomes have been reported in neonates and premature infants following concomitant administration of ceftriaxone and calcium-containing drugs. 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 systems.

Overdose.

Symptoms. Information on overdose cases is limited. In case of overdose, the manifestations of adverse reactions may be intensified.

Treatment. Symptomatic therapy should be administered. Hemodialysis and peritoneal dialysis are ineffective. There is no specific antidote.

Adverse reactions.

Infections and infestations: possible development of superinfection (secondary fungal infections, including candidomycosis, genital mycosis, and infections caused by resistant microorganisms).

Gastrointestinal tract: diarrhoea, nausea, vomiting, flatulence, stomatitis, glossitis, dysgeusia, gastrointestinal bleeding; pancreatitis (possibly due to obstruction of biliary passages by precipitates of calcium salt of ceftriaxone), pseudomembranous enterocolitis.

Hepatobiliary system: pseudocholelithiasis of the gallbladder, precipitation of calcium salts of ceftriaxone in the gallbladder with corresponding symptoms in children, reversible cholelithiasis in children; increased activity of liver transaminases and alkaline phosphatase in blood plasma, hyperbilirubinemia, hepatitis¹, cholestatic hepatitis^1,2, nuclear jaundice.

Blood and lymphatic system disorders: eosinophilia, leukopenia, leukocytosis, neutropenia, lymphopenia, thrombocytopenia, thrombocytosis, granulocytopenia, basophilia, anaemia, including haemolytic anaemia, prolonged/shortened prothrombin time, coagulopathies, epistaxis, hypoprothrombinemia, agranulocytosis. Blood picture should be monitored regularly during prolonged therapy.

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

Nervous system disorders: headache, dizziness, tremor, seizures, encephalopathy.

Ear and labyrinth disorders: vertigo.

Renal and urinary system disorders: increased blood urea and creatinine levels, cylindruria, glucosuria, haematuria, oliguria, interstitial nephritis.

Skin and subcutaneous tissue disorders: skin rashes, allergic dermatitis, pruritus, urticaria, oedema, including angioneurotic oedema, exanthema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), acute generalized exanthematous pustulosis.

Cardiovascular disorders: increased/decreased blood pressure, palpitations, Kounis syndrome.

Respiratory disorders: dyspnoea, bronchospasm.

General disorders and administration site conditions: chills, fever, weakness; with intravenous administration – phlebitis, pain, induration along the vein. With intramuscular administration – pain at the injection site. Intramuscular injection without using lidocaine is painful.

Effects on laboratory test results: false-positive Coombs test, galactosemia test, and non-enzymatic methods for glucose in urine may occur. During treatment with Ceftactam, glucosuria should be determined only by enzymatic methods if necessary.

Cases of diarrhoea following ceftriaxone/sulbactam administration may be associated with overgrowth of Clostridium difficile. Management should include administration of adequate fluid and electrolytes (see section "Special precautions").

¹Usually reversible upon discontinuation of ceftriaxone
²See section "Special precautions"

Calcium salt precipitates of ceftriaxone.

Rare cases of severe adverse reactions, sometimes fatal, have been reported in premature and full-term neonates (age < 28 days) who received intravenous ceftriaxone and calcium-containing products. Post-mortem examinations revealed calcium salt precipitates of ceftriaxone in lungs and kidneys. The high risk of precipitate formation in neonates is due to their small blood volume and longer elimination half-life of ceftriaxone compared to adults (see sections "Contraindications" and "Special precautions").

Cases of precipitate formation in kidneys have been reported, predominantly in children aged 3 years and older, who received high daily doses (≥ 80 mg/kg/day) or cumulative doses exceeding 10 g, and who had additional risk factors (limited fluid intake, dehydration, immobility, bed rest). Precipitate formation may be symptomatic or asymptomatic and may lead to renal failure, which usually resolves after discontinuation of ceftriaxone.

Cases of precipitation of calcium salt of ceftriaxone in the gallbladder have been reported, mainly in patients receiving doses higher than the standard recommended dose. In prospective studies of ceftriaxone in children, the incidence of precipitate formation after intravenous administration varied, in some studies exceeding 30%. The incidence appears to be lower when the drug is administered slowly (over 20–30 minutes). Precipitate formation is usually asymptomatic, but in rare cases clinical symptoms such as pain, nausea, and vomiting may occur. 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 original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

Do not mix in the same syringe or intravenous infusion system with other medicinal products except those specified in the section "Dosage and administration".

Pharmaceutically incompatible with other antimicrobial agents. Do not mix the drug solution in the same container with other antibiotics or with calcium-containing solutions (such as Hartmann's and Ringer's solutions, or total parenteral nutrition solutions) due to the risk of precipitate formation (see sections "Dosage and administration", "Special precautions", and "Adverse reactions").

Incompatible with amsacrine, vancomycin, fluconazole, labetalol, aminoglycosides, and other antibiotics.

Packaging. Powder for solution for injection, 500 mg/250 mg or 1000 mg/500 mg in a vial; 1 vial; 1 vial in a pack; 5 vials in a cassette, 1 cassette in a tray.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical and Pharmaceutical Plant".

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.