Cefotaxime combi

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOTAXIME COMBI (CEFOTAXIME COMBI)

Composition:

Active substance: cefotaxime;

1 vial contains cefotaxime (as cefotaxime sodium) 0.5 g or 1 g.

1 set for preparation of solution for intramuscular injections contains:

1 vial: cefotaxime (as cefotaxime sodium) – 1.0 g.

1 ampoule of 5 ml solvent: lidocaine, injection solution, 10 mg/ml.

1 set for preparation of solution for intravenous injections contains:

1 vial: cefotaxime (as cefotaxime sodium) – 0.5 or 1.0 g.

1 ampoule of 5 ml or 10 ml solvent: water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical characteristics: white or slightly yellowish powder.

Solvent: lidocaine, injection solution, 10 mg/ml, 5 ml in ampoule.

Main physico-chemical characteristics: clear colorless or slightly colored liquid.

or

Solvent: water for injections, solvent for parenteral administration, 5 ml or 10 ml in ampoule.

Main physico-chemical characteristics: clear colorless liquid.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Beta-lactam antibiotics. Third-generation cephalosporins. Cefotaxime.

ATC code J01D D01.

Pharmacological Properties.

Pharmacodynamics.

Cefotaxime is a semi-synthetic third-generation cephalosporin antibiotic intended for parenteral administration. It exerts a bactericidal effect and has a broad spectrum of activity.

The following organisms have demonstrated in vitro susceptibility to cefotaxime.

Gram-positive: staphylococci, including coagulase-positive, coagulase-negative, and penicillinase-producing strains; β-hemolytic and other streptococci, such as Streptococcus mitis (viridans) (most enterococcal strains, e.g., Streptococcus faecalis, are relatively resistant), Streptococcus (Diplococcus) pneumoniae, Clostridium spp.

Gram-negative: Escherichia coli, Haemophilus influenzae, including ampicillin-resistant strains, Klebsiella spp., Proteus spp. (indole-positive and indole-negative), Enterobacter spp., Neisseria spp. (including β-lactamase-producing strains of N. gonorrhoeae), Salmonella spp. (including Salmonella Typhi), Shigella spp., Providencia spp., Serratia spp., Citrobacter spp.

The medicinal product has frequently shown useful in vitro activity against Pseudomonas spp. and Bacteroides spp., although some strains of Bacteroides fragilis are resistant to the drug.

In vivo evidence exists for synergy between cefotaxime and aminoglycoside antibiotics, such as gentamicin, against certain gram-negative bacteria, including some strains of Pseudomonas. No in vitro antagonism has been demonstrated. In cases of severe infections caused by Pseudomonas spp., additional administration of an aminoglycoside antibiotic may be indicated.

Pharmacokinetics.

Absorption. Five minutes after a single intravenous bolus injection of 1 g cefotaxime, plasma concentrations typically range from 81 to 102 μg/mL. Following administration of 500 mg and 2000 mg doses, plasma concentrations are 38 μg/mL and 200 μg/mL, respectively. No accumulation occurs after intravenous (IV) doses of 1000 mg or intramuscular (IM) doses of 500 mg over 10–14 days. Bactericidal concentrations in blood are maintained for 12 hours.

Distribution. The theoretical volume of distribution at steady state is 21.6 L/1.73 m² following a 30-minute intravenous infusion of 1 g cefotaxime. Cefotaxime concentrations (usually measured by non-selective methods) have been detected in a wide range of human tissues and physiological fluids. Drug concentrations in cerebrospinal fluid (CSF) are low when meninges are not inflamed, but range from 3 to 30 μg/mL in children with meningitis.

Cefotaxime typically crosses the blood-brain barrier and achieves levels exceeding the minimum inhibitory concentration (MIC) for common susceptible pathogens when meningeal inflammation is present. Inhibitory concentrations (0.2–5.4 μg/mL) against most gram-negative bacteria are achieved in purulent sputum, bronchial secretions, and pleural fluid after doses of 1 g or 2 g. Effective concentrations against most susceptible organisms are also achieved in female reproductive organs, middle ear effusions, prostate tissue, interstitial fluid, kidney tissue, peritoneal fluid, and gallbladder wall following standard therapeutic doses. High concentrations of cefotaxime and its metabolite desacetylcefotaxime are achieved in bile.

Elimination. Cefotaxime undergoes partial metabolism prior to excretion. Its main metabolite, desacetylcefotaxime, possesses antibacterial activity. The majority of the administered dose is excreted by the kidneys. Approximately 60% of the dose is excreted unchanged, and 24% as desacetylcefotaxime. Plasma clearance ranges from 260 to 390 mL/min, and renal clearance from 145 to 217 mL/min.

After intravenous administration to healthy adult volunteers, the elimination half-life (t½) of the parent compound is 0.9–1.14 hours, while that of the desacetyl metabolite is approximately 1.3 hours.

In neonates, pharmacokinetics depend on gestational and chronological age; t½ is prolonged in preterm infants or full-term neonates with low birth weight.

In severe renal impairment, the t½ of cefotaxime is prolonged to at least 2.5 hours, while the t½ of desacetylcefotaxime is prolonged to approximately 10 hours. Total urinary recovery of cefotaxime and its main metabolite decreases with impaired renal function.

Clinical characteristics.

Indications.

The medicinal product Cefotaxime Comb acts is recommended for the treatment of the following infections, both prior to identification of the pathogen and after confirmation that the disease is caused by a pathogen with established sensitivity to the drug:

• respiratory tract infections, including acute and chronic bronchitis, bacterial pneumonia, bronchiectasis due to infectious diseases, lung abscess, and postoperative infections of the thoracic organs;
• urinary and genital tract infections, including acute and chronic pyelonephritis, cystitis, and asymptomatic bacteriuria;
• septicemia;
• soft tissue infections, including cellulitis, peritonitis, and wound infections;
• bone and joint infections, including osteomyelitis, septic arthritis;
• obstetrics and gynecology: inflammatory pelvic diseases;
• gonorrhea, particularly in cases where penicillin treatment has been ineffective or is contraindicated;
• other bacterial infections, meningitis, and other infections caused by pathogens sensitive to the drug, requiring parenteral antibiotic therapy.

Prophylaxis:

Administration of the medicinal product for prophylactic purposes may reduce the occurrence of certain postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated, or in clean surgical procedures where infections could lead to serious consequences.

Optimal protection is achieved by ensuring adequate drug concentration in local tissues at the time of potential contamination. Therefore, cefotaxime should be administered immediately before surgery and, if necessary, continued during the early postoperative period.

Drug administration is usually discontinued within 24 hours, as prolonged use of any antibiotic in most surgical procedures does not reduce the risk of subsequent infection.

Cefotaxime may also be used prophylactically in combination with non-absorbable oral antibiotics to reduce the risk of infection in certain patients undergoing intensive therapy and expected to remain in the intensive care unit for more than 48 hours.

Contraindications.

Hypersensitivity to cephalosporin antibiotics and to other β-lactam antibiotics.

The preparation reconstituted with lidocaine is contraindicated in patients with:

• history of hypersensitivity to lidocaine or other amide-type anesthetics (for intramuscular administration);
• AV-block without an implanted cardiac pacemaker;
• severe heart failure;
• children under 30 months of age;
• for intravenous administration.

Cross-allergic reactions between penicillins and cephalosporins may occur.

Interaction with other medicinal products and other types of interactions.

When used concomitantly with nephrotoxic medicinal products (aminoglycosides) and potent diuretics (ethacrynic acid, furosemide), colistin, polymyxin, nephrotoxic effects are enhanced. Renal function tests should be monitored.

Probenecid blocks tubular secretion of cefotaxime and prolongs its t½, thereby increasing plasma levels.

Special precautions for use.

Like other antibiotics, cefotaxime, especially with prolonged use, may lead to overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Effect on laboratory test results. As with other cephalosporins, false-positive Coombs' test reactions have been observed in some patients receiving cefotaxime. This phenomenon may interfere with cross-matching of blood. False-positive results may occur when glucose in urine is tested by nonspecific reduction methods. To avoid this, the glucose oxidase method should be used.

Anaphylactic reactions. Administration of cephalosporins requires careful assessment of allergic history (atopic diathesis, hypersensitivity reactions to β-lactam antibiotics). If a hypersensitivity reaction occurs in a patient, treatment should be discontinued. Cefotaxime is strictly contraindicated in patients with a history of immediate-type hypersensitivity reactions to cephalosporins. In case of any doubts, a physician must be present during the first administration of the drug due to the risk of anaphylactic reaction. Since cross-allergenicity exists between penicillins and cephalosporins, the latter should be administered with particular caution to patients with known penicillin sensitivity. Hypersensitivity reactions (anaphylaxis) to these two classes of antibiotics may be severe or even fatal.

Severe cutaneous adverse reactions (SCARs). In the post-marketing period, cases of severe cutaneous adverse reactions associated with cefotaxime therapy have been reported, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of skin reactions when the drug is prescribed.

If signs or symptoms suggestive of these reactions occur, cefotaxime should be discontinued immediately. If AGEP, SJS, TEN, or DRESS develops during cefotaxime therapy, re-administration of cefotaxime is contraindicated and treatment must be permanently discontinued.

In children, the appearance of rash may be mistakenly attributed to the primary infection or an alternative infectious process; therefore, physicians should consider the possibility of a reaction to cefotaxime in children who develop rash and fever during therapy.

Clostridium difficile-associated disease (e.g., pseudomembranous colitis). Diarrhea, particularly severe and/or persistent, occurring during or within the first weeks after treatment may be a symptom of Clostridium difficile-associated disease. The severity of Clostridium difficile-associated disease ranges from mild to life-threatening, with pseudomembranous colitis being the most severe form.

This rare condition, which nevertheless may be fatal, can be diagnosed by endoscopy and/or histological examination. This diagnosis should be considered in patients who develop diarrhea during or after cefotaxime therapy. If pseudomembranous colitis is suspected, cefotaxime should be discontinued immediately and appropriate specific antibiotic therapy should be initiated without delay. Clostridium difficile-associated disease may cause fecal impaction. Medicinal products that inhibit peristalsis should not be administered.

Blood disorders. During cefotaxime therapy, leukopenia and neutropenia may develop; less commonly, bone marrow suppression, pancytopenia, or agranulocytosis may occur. For treatment courses lasting longer than 7–10 days, leukocyte counts should be monitored, and treatment should be discontinued if neutropenia occurs.

There have been reports of eosinophilia and thrombocytopenia, which resolved rapidly after discontinuation of therapy. Cases of hemolytic anemia have also been reported (see section "Adverse reactions").

Patients with renal impairment. Dosage adjustments should be made according to calculated creatinine clearance. Caution is required when cefotaxime is used concomitantly with aminoglycosides or other nephrotoxic drugs (see section "Interaction with other medicinal products and other forms of interaction"). Renal function should be monitored in these patients, in elderly patients, and in those with pre-existing renal impairment.

Encephalopathy. β-lactams, including cefotaxime, may cause encephalopathy (which may include seizures, confusion, altered consciousness, and movement disorders), particularly in cases of overdose or impaired renal function (see section "Adverse reactions").

Patients should be advised to contact their physician immediately if such reactions occur.

The medicinal product Cefotaxime Comb contains 2.2 mmol (or 50.5 mg) of sodium in 1 g of powder for solution for injection. Caution is required when administering the drug to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

The use of this medicinal product during pregnancy is contraindicated.

Breastfeeding should be discontinued during treatment with this medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of adverse reactions and administration of high doses of cefotaxime, particularly in patients with renal impairment, encephalopathy (seizures, confusion, altered consciousness, movement disorders) may occur (see section "Adverse reactions"). Patients should be advised to refrain from driving or operating machinery if any of these symptoms occur.

Method of Administration and Dosage.

The medicinal product is intended for intravenous bolus and infusion, as well as intramuscular administration. The dose, route, and frequency of administration are determined based on the severity of infection, pathogen sensitivity to the antibiotic, and the patient's condition. Therapy may be initiated before obtaining results of pathogen susceptibility testing.

For intravenous bolus injection, 1 g of powder should be dissolved in 4 mL of sterile water for injections. Administer slowly over 3–5 minutes.

The medicinal product may also be administered via intravenous infusion. Dissolve 1–2 g of the drug in 40–100 mL of water for injections or in infusion fluids listed below.

The prepared solution may be administered over 20–60 minutes.

For intramuscular injection, dissolve 1 g of powder in 4 mL of sterile water for injections or in 1% lidocaine solution, and inject deeply into the gluteal muscle.

Intermittent intravenous injection: The solution should be administered over 3–5 minutes. During post-marketing surveillance, cases of potentially life-threatening arrhythmia have been reported in a very small number of patients who received cefotaxime rapidly via central venous catheter.

The duration of treatment is determined individually by the physician.

Adults and children with body weight of 50 kg or more should receive Cefotaxime Combi at a dose of 1 g every 12 hours; in severe cases – 1 g 3–4 times daily. The maximum daily dose is 12 g. For treatment of infections caused by susceptible Pseudomonas spp., daily doses exceeding 6 g are usually required.

For gonorrhea: a single intramuscular or intravenous injection of 1 g.

Children: The usual dosage range is 100–150 mg/kg/day, divided into 2–4 doses. However, doses up to 200 mg/kg/day may be required in cases of very severe infections.

Neonates: The recommended dose is 50 mg/kg/day, divided into 2–4 doses. In severe infections, doses of 150–200 mg/kg/day divided into several administrations have been used.

Renal impairment. In patients with creatinine clearance below 10 mL/min, after the initial standard dose, the maintenance dose should be reduced to half the usual dose without changing the dosing interval.

Patients undergoing hemodialysis: 1–2 g daily, depending on the severity of infection; cefotaxime should be administered after hemodialysis on dialysis days.

Patients undergoing peritoneal dialysis: 1–2 g daily, depending on the severity of infection; cefotaxime is not removed by peritoneal dialysis.

Cefotaxime and aminoglycosides should not be mixed in the same syringe or infusion fluid.

When freshly prepared solutions for intravenous or intramuscular injection are desired, cefotaxime is compatible with several commonly used intravenous infusion fluids, which will retain adequate potency for up to 24 hours when stored refrigerated (2–8 °C): water for injections, sodium chloride solution, 5% dextrose solution, dextrose and sodium chloride injection solution, compound sodium lactate injection solution (Ringer's lactate solution).

Children.

Cefotaxime should be administered to children in appropriate doses (see section "Method of Administration and Dosage"). The medicinal product should not be administered intramuscularly to children under 2.5 years of age.

Overdose.

Symptoms of overdose largely correspond to the profile of adverse reactions.

There is a risk of encephalopathy, particularly in patients with renal impairment and when high doses of β-lactam antibiotics, including cefotaxime, are used.

In case of overdose, cefotaxime treatment should be discontinued. Supportive therapy should be initiated, including measures to enhance drug elimination, as well as symptomatic treatment of adverse reactions (e.g., seizures).

There is no specific antidote. Cefotaxime is removed by hemodialysis. Peritoneal dialysis is ineffective for cefotaxime elimination.

Adverse reactions.

* β-lactam antibiotics, including cefotaxime, increase the risk of encephalopathy (which may include convulsions, confusion, impaired consciousness, movement disorders), particularly in cases of overdose or impaired renal function;

** post-marketing surveillance.

Jarisch-Herxheimer reaction. During treatment of borreliosis, a Jarisch-Herxheimer reaction may occur within the first days of therapy.

Cases of the following symptoms have been reported after several weeks of borreliosis treatment: skin rashes, pruritus, fever, leukopenia, elevated liver enzymes, dyspnea, joint pain.

Hepatic and biliary disorders. Increased levels of liver enzymes (ALT, AST, LDH, γ-GT and/or alkaline phosphatase) and/or bilirubin have been observed. In isolated cases, these parameters may exceed the upper normal limit by up to two times, indicating liver involvement, usually cholestatic in nature and asymptomatic.

Superinfection. As with other antibiotics, cefotaxime, particularly when used long-term, may lead to overgrowth of non-susceptible organisms. Repeated assessment of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

For intramuscular administration: since the solvent contains lidocaine, systemic reactions to lidocaine are possible, especially in case of accidental intravenous injection, injection into highly vascularized tissues, or overdose.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. Cefotaxime, powder for injection solution – 3 years.

Lidocaine, injection solution, 10 mg/mL – 3 years.

Water for injections – 4 years.

The shelf life is determined by the component (powder or solvent) with the earlier expiration date.

Storage conditions. Store in the original packaging, in a place inaccessible to children.

Incompatibilities.

The medicinal product solution is incompatible with solutions of other antibiotics and aminoglycoside solutions in the same syringe or infusion. Use only the diluents specified in the section "Administration and dosage".

Packaging.

For the manufacturer Private Joint-Stock Company "Lekhym-Kharkiv":

0.5 g powder in a vial;

1, 10, or 50 vials with powder in a carton;

1 vial with powder and 1 ampoule of solvent (Water for injections, 5 mL per ampoule) in a blister; 1 blister per carton;

or 1 g powder in a vial; 1 vial with powder and 1 ampoule of solvent (Water for injections, 10 mL per ampoule) in a blister; 1 blister per carton; 1 vial with powder and 1 ampoule of solvent (Lidocaine, injection solution, 10 mg/mL, 5 mL per ampoule) in a blister; 1 blister per carton.

For the manufacturer LLC "Lekhym-Obukhiv":

0.5 g powder in a vial;

50 vials with powder in a carton;

1 vial with powder and 1 ampoule of solvent (Water for injections, 5 mL per ampoule) in a blister; 1 blister per carton;

1 vial with powder in a blister; 1 blister per carton;

5 vials with powder in a blister; 2 blisters per carton.

or 1 g powder in a vial; 1 vial with powder and 1 ampoule of solvent (Water for injections, 10 mL per ampoule) in a blister; 1 blister per carton; 1 vial with powder and 1 ampoule of solvent (Lidocaine, injection solution, 10 mg/mL, 5 mL per ampoule) in a blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhym-Kharkiv".

LLC "Lekhym-Obukhiv".

Manufacturer's address and location of business activity.

36 Severin Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

126A Kyivska Street, Obukhiv, Kyiv Oblast, 08700, Ukraine.