Cefotaxime

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOTAXIME

Composition:

Active substance: cefotaxime;

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

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or slightly yellowish powder.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. β-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 sensitivity 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 Sal. 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.

There is in vivo evidence of synergy between cefotaxime and aminoglycoside antibiotics (e.g., gentamicin) against certain species of 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 of cefotaxime, plasma concentrations typically range from 81 mcg/mL to 102 mcg/mL. Following doses of 500 mg and 2000 mg, plasma concentrations are 38 mcg/mL and 200 mcg/mL, respectively. There is no accumulation after intravenous (IV) doses of 1000 mg or intramuscular (IM) doses of 500 mg administered 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 of cefotaxime. Cefotaxime concentrations (usually measured by non-selective methods) have been detected in a wide range of human tissues and physiological fluids. Concentrations in cerebrospinal fluid (CSF) are low when meninges are not inflamed, but range from 3 to 30 mcg/mL in children with meningitis.

Cefotaxime generally 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 mcg/mL) against most Gram-negative bacteria are achieved in purulent sputum, bronchial secretions, and pleural fluid following doses of 1 g or 2 g. Effective concentrations against most susceptible organisms are consistently achieved in female reproductive organs, middle ear effusions, prostate tissue, interstitial fluid, kidney tissue, peritoneal fluid, and gallbladder wall after 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 ranges from 145 to 217 mL/min.

After intravenous administration of cefotaxime 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 body 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 excretion of cefotaxime and its main metabolite decreases with impaired renal function.

Clinical characteristics.

Indications.

The medicinal product Cefotaxime is indicated for the treatment of the following infections, both before and after identification of the causative pathogen, provided that the pathogen has been shown to be susceptible to the drug:

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

Prophylaxis:

Administration of the drug 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 likely 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 stay in the intensive care unit for more than 48 hours.

Contraindications.

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

The medicinal product reconstituted with lidocaine is contraindicated in patients with:

• history of hypersensitivity to lidocaine or to other amide-type local anesthetics (for intramuscular administration);
• AV block without a cardiac pacemaker;
• severe heart failure;
• infants 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, or polymyxin, nephrotoxic effects may be enhanced. Renal function tests should be monitored.

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

Special precautions for use

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

Effect on laboratory test results. As with other cephalosporins, false-positive Coombs' test reactions have been observed in some patients receiving cefotaxime therapy. This phenomenon may interfere with cross-matching blood. False-positive results may also occur when measuring glucose in urine using non-specific reducing substance methods. To avoid this, the glucose oxidase method should be used.

Anaphylactic reactions. Administration of cephalosporins requires careful evaluation of allergic history (allergic diathesis, hypersensitivity reactions to β-lactam antibiotics). If a hypersensitivity reaction develops in a patient, treatment must 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. Because of cross-allergenicity between penicillins and cephalosporins, cephalosporins should be administered with particular caution to patients known to be hypersensitive to penicillins. Hypersensitivity reactions (anaphylaxis) to these two classes of antibiotics may be severe or even fatal.

Severe cutaneous adverse reactions (SCARs). During 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 being prescribed the drug.

If signs or symptoms suggestive of these reactions occur, cefotaxime must be discontinued immediately. If a patient develops AGEP, SJS, TEN, or DRESS during cefotaxime therapy, re-administration of cefotaxime is not recommended and treatment must be permanently discontinued.

In children, the appearance of a 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 prolonged, occurring during or within the first weeks after treatment may be a symptom of Clostridium difficile-associated disease. Clostridium difficile-associated disease may range from mild to life-threatening, with pseudomembranous colitis being the most severe form.

This rare condition, which may nevertheless be fatal, can be diagnosed by endoscopy and/or histological examination. This diagnosis must be considered in patients who develop diarrhea during or after cefotaxime administration. If pseudomembranous colitis is suspected, cefotaxime must be discontinued immediately and appropriate specific antibiotic therapy should be initiated without delay. Clostridium difficile-associated disease may be exacerbated by constipation. Antiperistaltic agents must not be administered to the patient.

Blood disorders. Treatment with cefotaxime may lead to leukopenia, neutropenia, and rarely, bone marrow suppression, pancytopenia, or agranulocytosis. For treatment courses lasting longer than 7–10 days, white blood cell counts should be monitored, and therapy discontinued if neutropenia occurs.

Cases of eosinophilia and thrombocytopenia, which resolve rapidly after discontinuation of therapy, have been reported. 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 before continuing treatment.

The medicinal product Cefotaxime contains 2.2 mmol (or 50.5 mg) of sodium per 1 g of powder for solution for injection. Caution is advised 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 for the duration of treatment with this medicinal product.

Ability to influence the speed of reactions while driving or operating machinery.

Due to the possibility of adverse reactions and the 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 according to the severity of infection, pathogen sensitivity to the antibiotic, and the patient's condition. Therapy may be initiated before the results of pathogen sensitivity testing are available.

For intravenous bolus administration, dissolve 1 g of powder in 4 mL of sterile water for injection. Administer slowly over 3–5 minutes.

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

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

For intramuscular administration, dissolve 1 g of powder in 4 mL of sterile water for injection or in a 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, potentially life-threatening arrhythmias 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 ≥50 kg should be administered cefotaxime 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 1 g intramuscular or intravenous injection.

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

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 multiple doses 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 the hemodialysis procedure 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 solution.

If only freshly prepared solutions for intravenous or intramuscular injection are desired, cefotaxime is compatible with several commonly used intravenous infusion fluids, which will retain adequate stability for up to 24 hours when stored refrigerated (2–8 °C): water for injection, 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 intramuscular route should not be used in children under 2.5 years of age.

Overdose.

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

Encephalopathy may occur, particularly in patients with renal impairment and when high doses of β-lactam antibiotics, including cefotaxime, are administered.

In case of overdose, cefotaxime therapy should be discontinued. Supportive treatment should be initiated, including measures to enhance drug elimination, as well as symptomatic management 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.

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

** post-marketing surveillance.

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

Cases of the following symptoms have been reported after several weeks of treatment for borreliosis: 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 values may exceed the upper limit of normal by up to two times, indicating liver injury, usually cholestatic in nature and typically asymptomatic.

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

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

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Incompatibilities.

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

Packaging. 1 g of cefotaxime powder in a vial; 1, 5, or 50 vials per carton; or 1 or 5 vials in a blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint Stock Company "Lekhim-Kharkiv". LLC "Lekhim-Obukhiv".

Bulk production and packaging by the manufacturer Reyoung Pharmaceutical Co., Ltd., People's Republic of China.

Manufacturer's address and location of business operations:

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

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