Cefotaxime

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOTAXIME

Composition:

Active substance: cefotaxime;

1 vial contains cefotaxime sodium equivalent to cefotaxime 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder ranging from almost white to pale yellow.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics.

Third-generation cephalosporins. 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. Microorganisms susceptible to the drug include: Streptococcus (except group D), including Streptococcus pneumoniae; Staphylococcus aureus, including penicillinase-producing and non-penicillinase-producing strains; Bacillus subtilis and Mycoides; Neisseria gonorrhoeae (both penicillinase-producing and non-penicillinase-producing strains); Neisseria meningitidis; other Neisseria species; Escherichia coli; Klebsiella spp., including Klebsiella pneumoniae; Enterobacter spp. (some strains are resistant); Serratia spp.; Proteus (both indole-positive and indole-negative species); Salmonella; Citrobacter spp.; Providencia; Shigella; Yersinia; Haemophilus influenzae and Parainfluenzae (including ampicillin-resistant strains, both penicillinase-producing and non-producing); Bordetella pertussis; Moraxella; Aeromonas hydrophilia; Veillonella; Clostridium perfringens; Eubacterium; Propionibacterium; Fusobacterium; Bacteroides spp.; and Morganella.

Microorganisms with variable susceptibility to the drug include: Pseudomonas aeruginosa, Acinetobacter, Helicobacter pylori, Bacteroides fragilis, and Clostridium difficile.

Resistant microorganisms include: group D Streptococcus, Listeria, and methicillin-resistant staphylococci.

Pharmacokinetics

After intravenous administration of 1 g of cefotaxime, its serum concentration ranges from 81 to 102 µg/mL. Doses of 500 mg and 2000 mg achieve plasma concentrations of 38 and 200 µg/mL, respectively. Following administration of 1000 mg intravenously or 500 mg intramuscularly over 10 or 14 days, no drug accumulation was observed. The apparent volume of distribution at steady state was 21.6 L/1.73 m² after a 30-minute intravenous infusion of 1 g of the drug.

Distribution. Cefotaxime concentrations have been studied in a wide range of human tissues and body fluids. Cerebrospinal fluid (CSF) concentrations are low when meninges are not inflamed. However, in children with meningitis, CSF concentrations range from 3 to 30 µg/mL. Cefotaxime generally penetrates the blood-brain barrier, achieving concentrations exceeding the minimum inhibitory concentration (MIC) for common susceptible pathogens when the meninges are inflamed. Concentrations effective against most gram-negative bacteria (0.2–5.4 µg/mL) are achieved in purulent sputum, bronchial secretions, and pleural fluid after administration of 1 or 2 g doses. Effective concentrations against most susceptible organisms are similarly achieved in female reproductive organs, middle ear exudate, 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 is partially metabolized prior to excretion. The primary metabolite is desacetylcefotaxime, which retains microbiological activity. Most of the administered dose is excreted in urine: approximately 60% unchanged and an additional 24% as desacetylcefotaxime. Plasma clearance ranges from 260 to 390 mL/min, and renal clearance ranges from 145 to 217 mL/min.

Following intravenous administration, the elimination half-life of cefotaxime and its active metabolite in serum ranges from 0.9 to 1.14 hours, while the half-life of the desacetylated metabolite is approximately 1.3 hours.

In neonates, elimination half-life depends on both gestational and chronological age, with prolonged half-life observed in preterm and low-birth-weight infants of the same age.

In severe renal impairment, the elimination half-life of cefotaxime is slightly prolonged to approximately 2.5 hours, whereas the half-life of desacetylcefotaxime increases to about 10 hours. Total urinary excretion of cefotaxime and its main metabolite decreases as renal function declines.

Clinical characteristics.

Indications.

Use for the treatment of the following serious infections caused by, or highly likely to be caused by, microorganisms sensitive to cefotaxime:

• Septicaemia.
• Respiratory tract infections, such as acute and chronic bronchitis, bacterial pneumonia, infected bronchiectasis, lung abscess, and postoperative chest infections.
• Urinary tract infections, such as acute and chronic pyelonephritis, cystitis, and asymptomatic bacteriuria.
• Soft tissue infections, such as cellulitis, peritonitis, and wound infections.
• Bone and joint infections, such as osteomyelitis, septic arthritis.
• Obstetrical and gynecological infections, such as pelvic inflammatory disease. Gonorrhoea, particularly in cases where penicillin has failed or is unsuitable.
• Other bacterial infections, meningitis, and other sensitive infections requiring parenteral antibiotic therapy.

Prophylaxis

• Administration of the drug for prophylactic purposes may reduce the risk of developing certain postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated, or in clean surgical procedures where infections may lead to serious consequences.
• Optimal protection is achieved by attaining adequate drug concentrations in tissues at the time of likely contamination. Therefore, cefotaxime should be administered immediately before surgery and, if necessary, continued during the early postoperative period.
• Usually, administration of the drug is discontinued within 24 hours, as prolonged use of any antibiotic in most surgical procedures does not reduce the likelihood of subsequent infection.
• Cefotaxime may also be used for prophylaxis in combination with orally administered antibiotics that are not yet absorbed, to reduce the risk of infection in certain patients undergoing intensive care, with an anticipated stay in the intensive care unit exceeding 48 hours.

Contraindications.

Hypersensitivity to cephalosporin antibiotics and to other β-lactam antibiotics. Cross-allergic reactions between penicillins and cephalosporins may occur (see section "Special precautions").

Cefotaxime reconstituted with lidocaine is contraindicated:

• In patients with a known history of hypersensitivity to lidocaine or other amide-type local anesthetics;
• In patients with atrioventricular block without an implanted cardiac pacemaker;
• In patients with severe heart failure;
• In children under 30 months of age;
• For intravenous administration.

Interaction with other medicinal products and other forms of interactions.

Probenecid blocks tubular secretion of cefotaxime, prolongs its elimination half-life, and increases its plasma concentration.

Like other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of certain nephrotoxic drugs, such as aminoglycosides or potent diuretics (e.g., furosemide). Renal function should be monitored (see section "Special precautions").

Concomitant use with nephrotoxic drugs (aminoglycosides) and potent diuretics (ethacrynic acid, furosemide), colistin, or polymyxin increases the risk of renal failure.

Special precautions for use.

As with other antibiotics, the use of cefotaxime, especially prolonged use, may lead to overgrowth of non-susceptible microorganisms. The patient's condition should be regularly monitored. If superinfection occurs during treatment, appropriate measures should be taken (see section "Adverse reactions").

Anaphylactic reactions.

Severe, including fatal, hypersensitivity reactions have been reported in patients receiving cefotaxime (see sections "Contraindications" and "Adverse reactions").

If a hypersensitivity reaction develops in a patient, treatment should be discontinued.

Cefotaxime is strictly contraindicated in patients with a history of immediate-type hypersensitivity reactions to cephalosporins.

Because of cross-allergenicity between penicillins and cephalosporins, cefotaxime should be administered with particular caution in patients with hypersensitivity to penicillins. Hypersensitivity reactions (anaphylaxis) associated with the use of 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 result in death.

Patients should be informed about the signs and symptoms of skin reactions when prescribing the medicinal product.

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, 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.

Pseudomembranous colitis.

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

The diagnosis of this rare but potentially fatal condition can be confirmed endoscopically and/or histologically. This diagnosis should be considered in patients who develop diarrhea during or after cefotaxime administration.

If pseudomembranous colitis is suspected, cefotaxime should be discontinued. Appropriate specific antibiotic therapy should be initiated immediately. Clostridium difficile-associated disease may be exacerbated by constipation. Antiperistaltic agents should not be used.

Hematopoietic disorders.

Leukopenia, neutropenia, and, less frequently, bone marrow suppression, pancytopenia, or agranulocytosis may develop during cefotaxime therapy. If treatment lasts longer than 7–10 days, leukocyte counts should be monitored. If neutropenia develops, treatment should be discontinued. Several cases of eosinophilia and thrombocytopenia, which resolved 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 should be adjusted according to calculated creatinine clearance. Caution should be exercised when cefotaxime is co-administered with aminoglycosides or other nephrotoxic medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). Renal function should be regularly monitored in these patients, in elderly patients, and in patients with pre-existing renal impairment.

Encephalopathy. Beta-lactam antibiotics, including cefotaxime, may contribute to the development of encephalopathy (which may include seizures, confusion, and movement disorders), particularly in cases of overdose or impaired renal function (see section "Adverse reactions"). Patients should be advised to seek immediate medical attention if such reactions occur before continuing treatment.

Precautions during administration.

During post-marketing surveillance, potentially life-threatening arrhythmias have been reported in a very small number of patients who received cefotaxime via rapid intravenous injection through a central venous catheter. Therefore, the recommended duration of administration or infusion should be strictly followed (see section "Dosage and administration").

For cefotaxime reconstituted with lidocaine, see section "Contraindications".

Effect on laboratory test results.

As with other cephalosporins, a positive Coombs' test has been observed in some patients receiving cefotaxime. This phenomenon may interfere with blood compatibility testing. False-positive results may occur when testing for urinary glucose using non-specific reducing agents. To avoid this, a glucose oxidase test should be used.

Reconstitution of the medicinal product with lidocaine.

Warnings regarding reconstitution of the medicinal product with lidocaine are provided in the section "Contraindications".

Sodium.

1 g of powder for solution for injection contains 2.2 mmol (50.5 mg) of sodium. The sodium content at the maximum daily dose exceeds 8.7 mmol (200 mg). This should be taken into account when prescribing cefotaxime to patients requiring sodium restriction.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown teratogenic effects of the drug. However, the safety of cefotaxime use during human pregnancy has not been established; therefore, the medicinal product should not be used during pregnancy.

Use in women of childbearing potential requires careful assessment of expected benefits versus potential risks.

Breastfeeding. Cefotaxime passes into breast milk. An effect on the infant's normal intestinal flora cannot be excluded, which may lead to diarrhea, colonization with yeast-like fungi, and sensitization of the child. Therefore, a decision must be made whether to discontinue breastfeeding or to discontinue therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of adverse reactions such as dizziness or encephalopathy (which may include seizures, confusion, impaired consciousness, and movement disorders), driving or operating vehicles or machinery should be avoided during treatment with the medicinal product.

High doses of cefotaxime, especially in patients with renal impairment, may cause encephalopathy (e.g., confusion, movement disorders, and seizures) (see section "Adverse reactions"). Patients should be advised not to drive or operate machinery if such symptoms develop.

Method of Administration and Dosage

The medicinal product is administered by intravenous bolus, intravenous infusion, and intramuscular injection.

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 susceptibility testing are available.

Adults.

The recommended dose for the treatment of mild to moderate infections is 1 g every 12 hours. In severe cases, the drug should be administered at a dose of 1 g 3–4 times daily. The maximum daily dose is 12 g.

For infections caused by susceptible Pseudomonas spp., daily doses exceeding 6 g are usually required.

Gonorrhea. A single 1 g intramuscular or intravenous injection.

Children.

The usual dose is 100–150 mg/kg/day, divided into 2–4 intramuscular or intravenous doses. However, doses up to 200 mg/kg/day may be required in very severe infections.

Neonates. The recommended dose is 50 mg/kg/day, divided into 2–4 doses. In cases of severe infection, the dose may be increased to 150–200 mg/kg/day, divided into multiple doses.

Dosing in Patients with Renal Impairment.

For patients with creatinine clearance less than 10 mL/min, after an initial standard dose, maintenance doses should be reduced to half the standard dose, without changing the interval between administrations.

For patients undergoing hemodialysis: 1–2 g daily, depending on the severity of infection. On the day of hemodialysis, cefotaxime should be administered after completion of the dialysis session.

For patients undergoing peritoneal dialysis: 1–2 g daily, depending on the severity of infection. Cefotaxime is not removed by peritoneal dialysis.

Method of Administration.

Intravenous and Intramuscular Administration.

Intravenous administration (injection or infusion): 1 g of the medicinal product should be dissolved in 4 mL of sterile water for injection. The solution should be shaken well until complete dissolution. The contents of the vial should be completely withdrawn into a syringe and used immediately.

For intravenous infusion, 1 g or 2 g of the medicinal product should be dissolved in 40–100 mL of sterile water for injection or infusion solution. The infusion duration is 20–60 minutes.

Intermittent intravenous injection: the solution should be administered over 3–5 minutes.

During post-marketing surveillance, there have been reports of potentially life-threatening arrhythmias in a very small number of patients who received cefotaxime rapidly via central venous catheter.

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

Intramuscular Administration.

For intramuscular injection, 1 g of cefotaxime should be reconstituted with 4 mL of sterile water for injection. The contents of the vial may also be dissolved in sterile water for injection or in 1% lidocaine solution for intramuscular administration. If lidocaine is used, intravenous administration of the medicinal product is strictly contraindicated.

Children.

The medicinal product should not be administered intramuscularly to children under 30 months of age (2.5 years).

Overdose

Symptoms of overdose largely correspond to the profile of adverse reactions. In particular, in patients with renal impairment and when high doses of beta-lactam antibiotics, including cefotaxime, are used, there is a risk of developing encephalopathy.

In case of overdose, cefotaxime therapy should be discontinued. Supportive treatment should be initiated, including measures to enhance elimination of cefotaxime from the body, and symptomatic management of adverse reactions (e.g., seizures). There is no specific antidote. Hemodialysis may reduce serum cefotaxime concentrations. Peritoneal dialysis is ineffective.

Adverse reactions.

* Beta-lactamases, including cefotaxime, may lead to encephalopathy (including seizures, impaired/ disturbed 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. Symptoms have been reported after several weeks of treatment for borreliosis: skin rashes, pruritus, fever, leukopenia, increased liver enzymes, dyspnea, joint pain.

Hepatobiliary disorders

Elevated levels of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (γ-GT), and/or alkaline phosphatase) and/or bilirubin have been observed. These values may in isolated cases exceed the upper limit of normal by up to two times and indicate hepatic involvement, usually cholestatic in nature, and generally asymptomatic.

Superinfection

As with other antibiotics, prolonged use of cefotaxime may result in overgrowth of non-susceptible microorganisms. Re-evaluation of the patient’s condition is necessary. If superinfection occurs during therapy, appropriate measures should be taken.

With intramuscular administration

When lidocaine is used as a solvent, systemic reactions to lidocaine may occur, particularly in case of inadvertent intravenous injection or overdose.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.

For the reconstituted solution, chemical and physical stability during use has been demonstrated for 24 hours at 25 °C and for 48 hours at 2–8 °C.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and conditions of storage are the responsibility of the user and, under controlled and validated aseptic conditions for reconstitution/dilution, the product is generally stable for up to 24 hours at 2–8 °C.

Incompatibilities.

The reconstituted solution of the medicinal product Cefotaxime is incompatible with solutions of other antibiotics in the same syringe or infusion solution, and with aminoglycoside solutions in the same syringe or infusion. Use only the diluents specified in the section “Directions for use and dosage.” The medicinal product is incompatible with diluents with a pH above 7.5, such as sodium bicarbonate.

Packaging.

1, 5, or 10 vials with powder per cardboard box.

Prescription status. Prescription only.

Manufacturer. NSPS Hebei Huamin Pharmaceutical Company Limited.

Manufacturer’s address and location of business operations.

No. 98 Huan Road, Economic and Technological Development Zone, Shijiazhuang, Hebei 052165, China.