Cefotaxime yuria-pharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFOTAXIME YURIYA-FARM

Composition:

Active substance: cefotaxime;

1 vial contains cefotaxime sodium equivalent to cefotaxime 1000 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: crystalline powder ranging from almost white to pale yellow in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. β-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.

The drug is active against the following microorganisms: Streptococcus (except group D), including Streptococcus pneumoniae; Staphylococcus aureus, including penicillinase-producing and non-producing strains; Bacillus subtilis and Mycoides; Neisseria gonorrhoeae (both penicillinase-producing and non-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 (penicillinase-producing and non-producing strains, including ampicillin-resistant strains); Bordetella pertussis; Moraxella; Aeromonas hydrophilia; Veillonella; Clostridium perfringens; Eubacterium; Propionibacterium; Fusobacterium; Bacteroides spp.; and Morganella.

Microorganisms with variable sensitivity 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 ranged from 81 to 102 µg/mL. Doses of 500 mg and 2000 mg produce plasma concentrations of 38 and 200 µg/mL, respectively. No drug accumulation was observed after administration of 1000 mg intravenously or 500 mg intramuscularly for 10 or 14 days. 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 rapidly penetrates tissues, crosses the placental barrier, and reaches high concentrations in fetal tissues. Cerebrospinal fluid concentrations are low when meninges are not inflamed; however, in children with meningitis, concentrations range from 3 to 30 µg/mL. Cefotaxime generally crosses the blood-brain barrier in amounts exceeding the minimum inhibitory concentration (MIC) for common susceptible pathogens when the meninges are inflamed. Concentrations inhibiting 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. Concentrations likely effective against most susceptible organisms are also achieved in female reproductive organs, middle ear exudates, prostate tissue, interstitial fluid, kidney tissue, peritoneal fluid, and gallbladder wall following standard therapeutic doses. High concentrations of cefotaxime and desacetylcefotaxime are achieved in bile.

Elimination. Cefotaxime is partially metabolized prior to excretion. The main metabolite is desacetylcefotaxime, which has microbiological activity. The majority of the administered dose is excreted in urine: approximately 60% as unchanged drug 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.

After intravenous administration, the elimination half-life of cefotaxime and its active metabolite from 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 gestational and chronological age, with prolonged half-life observed in preterm infants and newborns with low body weight.

In cases of severe renal impairment, the elimination half-life of cefotaxime itself increases slightly to approximately 2.5 hours, whereas the half-life of desacetylcefotaxime increases to approximately 10 hours. Total urinary excretion of cefotaxime and its main metabolite decreases with impaired renal function.

Clinical characteristics.

Indications.

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

• Septicemia.
• 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. Gonorrhea, particularly in cases where penicillin has failed or is unsuitable.
• Other bacterial infections, meningitis, and other sensitive infections requiring parenteral antibiotic therapy.

Prophylactic use

The use of the medicinal product for prophylaxis may prevent the occurrence of certain postoperative infections in patients undergoing contaminated or potentially contaminated surgical procedures, or in cases of clean surgical procedures where infections may lead to serious consequences.

Optimal protection is achieved by attaining adequate drug concentrations 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 continued for no more than 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 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 — cross-allergic reactions between penicillins and cephalosporins may occur (see section "Special precautions for use").

The preparation reconstituted with lidocaine is contraindicated in: patients with hypersensitivity to lidocaine or other amide-type local anesthetics; patients with atrioventricular block without a cardiac pacemaker; severe heart failure; for intravenous administration; children under 30 months of age.

Interaction with other medicinal products and other types of interactions.

Probenecid blocks tubular secretion of cefotaxime, thereby delaying its elimination and increasing its plasma concentration. When used concomitantly with nephrotoxic medicinal products (aminoglycosides) and potent diuretics (ethacrynic acid, furosemide), colistin, polymyxin, the risk of developing renal failure increases. Renal function should be monitored (see section "Special precautions for use").

Special precautions for use.

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

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

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.

Due to the possibility of cross-allergenicity between penicillins and cephalosporins, particular caution is required when administering cefotaxime to 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 skin adverse reactions. In the post-marketing period, cases of severe skin adverse reactions associated with cefotaxime treatment 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 syndrome), which may be life-threatening or fatal. Patients should be informed about the signs and symptoms of skin reactions when prescribing the medicinal product.

If symptoms indicating these reactions occur, cefotaxime should be discontinued immediately. If AGEP, SJS, TEN, or DRESS syndrome develops during cefotaxime therapy, treatment with cefotaxime must not be continued and must be permanently discontinued.

In children, the appearance of rash may be mistakenly interpreted as the primary infection or another 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. Diarrhea, particularly severe and/or persistent, occurring during or within the first weeks after treatment may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD may range from mild to life-threatening, with pseudomembranous colitis being the most severe form.

The diagnosis of this rare but potentially fatal condition may be confirmed endoscopically and/or histologically. This diagnosis should be considered in patients experiencing diarrhea during or after cefotaxime therapy.

If pseudomembranous colitis is suspected, cefotaxime should be discontinued. Appropriate specific antibiotic therapy should be initiated immediately. Clostridium difficile-associated disease may be facilitated by fecal stasis. Medicinal products that inhibit peristalsis should not be used.

Blood disorders. During cefotaxime therapy, leukopenia and neutropenia may occur, and more rarely, bone marrow suppression, pancytopenia, or agranulocytosis. If treatment lasts longer than 7–10 days, leukocyte counts should be monitored. Treatment should be discontinued in case of neutropenia. 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 used concomitantly with aminoglycosides or other nephrotoxic medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). Renal function should be monitored regularly in these patients, as well as in elderly patients and those with renal impairment.

Encephalopathy. Beta-lactam antibiotics, including cefotaxime, may cause encephalopathy (which may manifest as seizures, confusion, disturbances of consciousness, or 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.

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

Use of the medicinal product reconstituted with lidocaine. See section "Contraindications".

Effect on laboratory test results. A positive Coombs' test reaction has been observed in some patients receiving cephalosporins, particularly cefotaxime. This phenomenon may interfere with cross-matching of blood.

Pseudopositive results may occur when testing urine glucose levels using non-specific reducing substance methods. To avoid this, a glucose oxidase test should be used.

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 the medicinal product to patients requiring sodium intake 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.

Administration to 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 should 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 influence the speed of reactions when driving vehicles or operating machinery.

Due to the possibility of adverse reactions such as dizziness or encephalopathy (which may manifest as seizures, confusion, disturbances of consciousness, or movement disorders), driving vehicles and operating machinery should be avoided during treatment. Encephalopathy may be caused by high doses of cefotaxime, particularly in patients with renal impairment (see section "Adverse reactions").

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 susceptibility to the antibiotic, and the patient's condition. Therapy may be initiated before susceptibility test results are available.

Adults. The recommended dose for the treatment of mild to moderate infections is 1 g every 12 hours.

In severe cases, administer the medicinal product at a dose of 1 g 3–4 times daily. The maximum daily dose is 12 g.

For the treatment of 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 daily dose is 100–150 mg/kg body weight, divided into 2–4 intramuscular or intravenous administrations. In severe infections, the dose may be increased up to 200 mg/kg body weight per day.

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

Patients with renal impairment. For patients with a creatinine clearance of less than 10 mL/min, after the initial standard dose, maintenance doses should be reduced by half without changing the interval between administrations.

For patients undergoing hemodialysis: 1 to 2 g per day, 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 to 2 g per day, depending on the severity of infection. Cefotaxime is not removed by peritoneal dialysis.

Administration Method

Intravenous and intramuscular administration

Intravenous administration (injection or infusion): dissolve 1 g of the medicinal product in 4 mL of sterile water for injections. Shake the vial well until complete dissolution. Then draw the entire contents of the vial into a syringe and use immediately.

For intravenous (IV) infusion, dissolve 1 g or 2 g of the medicinal product in 40–100 mL of sterile water for injections or infusion solution. The infusion duration is 20–60 minutes.

Intermittent intravenous injection: administer the solution 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 a central venous catheter.

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

Intramuscular administration

For intramuscular (IM) injection, dissolve 1 g of cefotaxime in 4 mL of sterile water for injections. For IM administration, cefotaxime may be dissolved in sterile water for injections or in 1% lidocaine solution. If lidocaine is used, intravenous administration of the medicinal product is strictly contraindicated.

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

Overdose.

Symptoms of overdose largely correspond to the adverse reaction profile. When beta-lactam antibiotics, particularly cefotaxime, are administered in high doses, there is a risk of encephalopathy, especially in patients with renal impairment. In case of overdose, cefotaxime therapy must be discontinued. Supportive treatment should be initiated, including measures to enhance elimination of the drug from the body and symptomatic treatment of adverse reactions (e.g., seizures). There is no specific antidote. Hemodialysis may reduce serum cefotaxime concentrations. Peritoneal dialysis is ineffective.

Adverse reactions.

* Beta-lactam antibiotics, including cefotaxime, may cause 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. 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 adverse reactions

Elevations in liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], gamma-glutamyl transferase [γ-GT], alkaline phosphatase) and/or bilirubin have been observed. These parameters may in some cases exceed twice the upper limit of normal and indicate liver involvement, usually of cholestatic type, typically asymptomatic.

Superinfection

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

Intramuscular administration

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

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is highly important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years (from the date of manufacture of the in bulk form).

Storage conditions.

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

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

Incompatibility.

Cefotaxime solution 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 "Administration and dosage".

Packaging. Vial with powder. Pack of 1 or 10 vials per carton.

Prescription status. Prescription only.

Manufacturer. LLC "Yuria-Pharm" (packaging of the in bulk form produced by the manufacturer NSPC Hebei Huamin Pharmaceutical Company Limited, China).

Manufacturer's address and location of business operations. 108, Kobzarska Street, Cherkasy, Cherkasy Region, Ukraine.

Tel.: (044) 281-01-01.