Cefoxime-o

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT cefoxim-o (Cefoxim-o)

Composition:

Active substance: cefotaxime;

1 vial contains cefotaxime sodium equivalent to cefotaxime 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physical and chemical properties: powder from white to light-yellow color.

Pharmacotherapeutic group.

Antibacterials for systemic use. Third-generation cephalosporins. Cefotaxime. ATC Code J01D D01.

Pharmacological Properties

Pharmacodynamics.

Cefotaxime is a semisynthetic antibiotic of the third-generation cephalosporin group for parenteral administration. It has a broad spectrum of bactericidal activity, including against microorganisms resistant to other cephalosporin- and penicillin-group antibiotics. The following microorganisms are susceptible to the drug:

Gram-positive:

Staphylococci, including gram-positive, gram-negative, and penicillinase-producing strains.

Beta ─ hemolytic and other streptococci, such as Streptococcus mitis (viridans) (many strains of enterococci are resistant, e.g., Streptococcus faecalis).

Streptococcus (Diplococcus) pneumoniae.

Clostridium spp.

Gram-negative:

Escherichia coli (E. coli).

Haemophilus influenzae, including ampicillin-resistant strains.

Klebsiella spp.

Proteus spp. (both 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 drug may exhibit in vitro therapeutic activity against Pseudomonas and Bacteroides spp., although some strains of Bacteroides fragilis are resistant. In vitro studies have also confirmed synergy between cefotaxime and aminoglycoside antibiotics, such as gentamicin, against certain gram-negative bacteria, including some strains of Pseudomonas. Therefore, in severe infections caused by Pseudomonas spp., the addition of aminoglycoside antibiotics may be indicated.

Pharmacokinetics.

Absorption. Five minutes after a single intravenous administration of 1 g of the drug, the Cmax in blood plasma reaches 100 μg/mL. After intramuscular administration, Cmax is achieved within 0.5 hours and ranges from 20**─**30 μg/mL. Bactericidal concentrations in the blood are maintained for up to 12 hours. The volume of distribution is 0.3 L/kg body weight.

Distribution. Plasma protein binding (primarily to albumin) averages 25**─**40%. The drug penetrates well into tissues and body fluids and reaches therapeutic concentrations in mucous membranes, sputum, bone tissue, and cerebrospinal fluid. It crosses the blood-brain barrier, placental barrier, and is excreted into breast milk. It undergoes biotransformation, forming an active metabolite.

Metabolism. The drug is metabolized in the liver, forming three metabolites: desacetylcefotaxime and two lactam-in metabolites. Desacetylcefotaxime exhibits a synergistic effect with cefotaxime.

Excretion. Approximately 90% of the administered dose is excreted in the urine, with 50% unchanged and the remainder as metabolites (desacetylcefotaxime—15**─25%, lactam-in metabolites—15─30%). A small portion is excreted in bile, with about 10% eliminated in feces. The elimination half-life (T½) is approximately 1 hour after intravenous administration and 1─**1.5 hours after intramuscular administration. In elderly patients with renal insufficiency, T½ increases by approximately two-fold. In newborns, T½ ranges from 0.75 to 1.5 hours, and in premature infants, from 1.4 to 6.4 hours.

Clinical characteristics.

Indications.

Cefoxime-O is indicated for the treatment of infections caused by microorganisms sensitive to the drug.

Treatment:

• Respiratory tract infections, such as bronchitis, pneumonia, lung abscess;
• Urinary and genital system infections;
• Septicemia, bacteremia;
• Intra-abdominal infections (including peritonitis);
• Skin and soft tissue infections;
• Bone and joint infections;
• Meningitis (except listerial) and other central nervous system infections.

Prophylaxis of infections following gastrointestinal, urological, and obstetric-gynecological surgical procedures.

Contraindications.

Hypersensitivity to cephalosporin antibiotics, cefotaxime, and/or to any component of the medicinal product.

If the patient has hypersensitivity to penicillin antibiotics, possible cross-allergic reactions between penicillins and cephalosporins should be taken into account.

Gastrointestinal disorders in medical history, particularly non-specific ulcerative colitis.

Contraindications to lidocaine use, if lidocaine is used as a solvent: known cases of hypersensitivity to lidocaine or other amide-type local anesthetics; history of epileptiform seizures induced by lidocaine, severe bradycardia, severe arterial hypotension, cardiogenic shock, severe forms of chronic heart failure (II–III degree), sinus node weakness syndrome, Wolff–Parkinson–White syndrome, Adams–Stokes syndrome, second- and third-degree atrioventricular (AV) block, hypovolemia, severe hepatic/renal dysfunction, porphyria, myasthenia, intravenous administration, patient age under 30 months.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with nephrotoxic agents (aminoglycosides) and potent diuretics (ethacrynic acid, furosemide), colistin, polymyxin, nephrotoxic effects of these drugs may be enhanced and the risk of renal failure increased. Renal function should be monitored.

Probenecid blocks tubular secretion of cefotaxime, thereby prolonging its half-life (T½).

Oral contraceptives. During treatment with cefotaxime, the efficacy of oral contraceptives may be reduced; therefore, additional contraceptive measures should be used during this period.

Tetracycline, erythromycin, chloramphenicol. Cefotaxime should not be used concomitantly with bacteriostatic antibiotics (e.g., tetracyclines, erythromycin, and chloramphenicol) due to possible antagonistic effects.

Aminoglycosides. In combined therapy, cefotaxime solutions should not be mixed with aminoglycoside solutions—they must be administered separately.

Nifedipine increases cefotaxime bioavailability by 70%.

Since the therapeutic index of cefotaxime is high, dose adjustment is not required in patients with normal renal function. Dose adjustment may be necessary in patients with impaired renal function.

Effect on laboratory test results: false-positive Coombs test may occur during treatment with cephalosporins. This phenomenon may also occur during cefotaxime therapy.

False-positive urine glucose reaction may occur when using reduction-based methods; therefore, a specific glucose oxidase method should be used.

Special precautions for use.

Anaphylactic reactions. The use of cephalosporins requires careful assessment of allergic history (allergic diathesis, hypersensitivity reactions to penicillin and other β-lactam antibiotics, as cross-allergy occurs in 5–10% of cases). Cefotaxime is strictly contraindicated in patients with a history of immediate-type hypersensitivity reactions to cephalosporins. Due to the possibility of cross-allergy between penicillins and cephalosporins, cefotaxime should be administered with particular caution in patients with penicillin sensitivity. Severe hypersensitivity reactions, sometimes fatal, have been reported in patients receiving cefotaxime. If a hypersensitivity reaction occurs, treatment must be discontinued. A physician must be present during the first administration of the drug, as anaphylactic reactions may occur.

Severe bullous reactions. Cases of severe bullous skin reactions, such as Stevens–Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome), have been reported during cefotaxime therapy. Medical consultation is required before continuing treatment if skin and/or mucous membrane reactions occur.

Pseudomembranous colitis. Diarrhea associated with Clostridium difficile may occur during antibacterial therapy, including cefotaxime, ranging from mild to life-threatening colitis. The most severe form is pseudomembranous colitis (diagnosed endoscopically and/or histologically).

C. difficile-associated diarrhea must be ruled out in all patients during antibiotic therapy. If pseudomembranous colitis is suspected, cefotaxime should be discontinued immediately and appropriate specific therapy initiated without delay.

C. difficile-associated diarrhea may lead to intestinal retention of fecal matter; therefore, drugs that suppress intestinal peristalsis should not be used.

Hematological disorders. Leukopenia, neutropenia, and, less frequently, pancytopenia or agranulocytosis may develop during cefotaxime therapy, especially with prolonged use. If treatment lasts longer than 7–10 days, leukocyte counts should be monitored. Cefotaxime therapy should be discontinued in case of neutropenia. Regular monitoring of peripheral blood cell counts is advisable. Elderly and debilitated patients should be given vitamin K (to prevent hypocoagulation).

Eosinophilia and thrombocytopenia, which resolve rapidly after discontinuation of therapy, have been observed. Cases of hemolytic anemia have also been reported.

Sodium intake. The medicinal product contains 48.2 mg of sodium per gram, which should be taken into account if the patient is on a sodium-controlled diet.

Renal function impairment. The drug should be administered with caution in patients with renal impairment. The dose should be reduced according to the degree of renal insufficiency and pathogen sensitivity, based on creatinine clearance. Renal and hepatic function should be monitored during prolonged treatment.

The drug should be used cautiously when co-administered with aminoglycosides, probenecid, or other nephrotoxic agents. Renal function should be monitored in such patients, as well as in elderly patients and those with renal insufficiency.

Neurotoxicity. High doses of β-lactam antibiotics, including cefotaxime, especially in patients with renal insufficiency, may cause encephalopathy (altered consciousness, abnormal movements, and convulsions). The physician should assess the possibility of continuing cefotaxime therapy in such patients.

Precautionary measures during use. There are reports of potentially life-threatening arrhythmias during rapid intravenous administration via central venous catheter. The recommended injection or infusion time must be strictly observed. Prolonged use of broad-spectrum antibiotics may lead to overgrowth of resistant microorganisms such as Enterococcus spp., Candida, and Pseudomonas aeruginosa, necessitating discontinuation of therapy. The patient's condition should be monitored continuously. If superinfection occurs during treatment, appropriate measures should be taken and adequate antimicrobial therapy initiated if clinically indicated.

Effect on laboratory test results. In some patients receiving cefotaxime, the Coombs test may yield false-positive results. This phenomenon may interfere with blood cross-matching tests. In such cases, an enzyme-based test should be used.

False-positive results for glucose in urine may occur when non-enzymatic methods are used. During cefotaxime therapy, urine glucose levels should be determined using enzymatic analytical methods.

Alcohol consumption is contraindicated during treatment, as disulfiram-like effects may occur (facial flushing, abdominal and epigastric cramps, nausea, vomiting, headache, hypotension, tachycardia, and dyspnea).

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate any direct or indirect harmful effects on reproductive function. However, there are no adequate and well-controlled studies in pregnant women. Cefotaxime crosses the placental barrier. The use of the drug during pregnancy is contraindicated.

Breastfeeding. Cefotaxime passes into breast milk; therefore, effects on the infant’s normal intestinal flora cannot be excluded, potentially causing diarrhea, colonization with yeast-like fungi, and infant sensitization.

Therefore, breastfeeding should be discontinued during treatment, or therapy should be discontinued, taking into account the benefits of breastfeeding for the child and the therapeutic benefit for the mother.

Ability to affect reaction speed when driving or operating machinery.

High doses of Cefotaxime-O, especially in patients with renal insufficiency, may cause encephalopathy (altered consciousness, abnormal movements, and convulsions). Patients should be advised to refrain from driving or operating machinery during treatment.

Administration and Dosage

The medicinal product is administered intramuscularly or intravenously (by bolus or infusion).

The dosage, route, and frequency of administration are determined according to the severity of infection, pathogen sensitivity, and the patient's condition. Therapy may be initiated before the results of pathogen sensitivity testing are available. The duration of treatment is determined individually by the physician.

Adults and children with body weight ≥ 50 kg. The recommended dose for mild to moderate infections is 1 g every 12 hours. Dosage may be adjusted depending on the severity of infection, pathogen sensitivity, and the patient's condition. In severe cases, administer 1 g 3–4 times daily. The maximum daily dose is 12 g.

For uncomplicated infections, including urinary tract infections, administer 1 g intramuscularly or intravenously every 12 hours; for uncomplicated acute gonorrhea, administer 1 g intramuscularly or intravenously once daily; for moderate infections, administer 1–2 g every 12 hours; for severe infections (e.g., meningitis), administer 2 g intravenously every 6–8 hours.

For infections caused by susceptible strains of Pseudomonas spp., doses of up to 6 g per day are used.

Children with body weight < 50 kg. The recommended dose for mild to moderate infections is 50–100 mg/kg/day, divided into 3–4 intramuscular or intravenous doses. In severe infections (including meningitis), the daily dose may be increased to 100–200 mg/kg/day, divided into 4–6 intramuscular or intravenous doses.

Preterm infants and children up to 1 week of age. The daily dose is 50 mg/kg body weight, divided into 2 equal doses, administered intravenously.

Children aged 1–4 weeks. The recommended daily dose for mild to moderate infections is 50–100 mg/kg, divided into 3 equal doses, administered intravenously. In severe infections, the daily dose may be increased to 100–200 mg/kg/day, divided into 4–6 equal doses, if clinically justified.

The drug is not administered intramuscularly to children under 30 months of age.

Prophylaxis. For prevention of infections prior to surgical procedures, administer a single dose of 1 g. If necessary, administration may be continued on the first postoperative day. Prophylactic use of the drug more than 24 hours after surgery is not recommended.

Use in patients with renal impairment. When creatinine clearance is less than 10 mL/min, the daily dose should be halved without changing the frequency of administration.

Patients undergoing hemodialysis: The recommended dose is 1–2 g/day, depending on the severity of infection. On the day of hemodialysis, the drug should be administered after the dialysis session.

Administration method.

After adding the diluent (one of the compatible infusion fluids: water for injections, 0.9% sodium chloride, 5% glucose solution, or 0.9% sodium chloride with 5% glucose solution) to the vial, shake well until the contents are completely dissolved. Then withdraw the entire contents into a syringe and use immediately.

For intravenous bolus injection, 1 g of powder is dissolved in 8 mL of sterile water for injections. Administer slowly over 3–5 minutes. Cases of potentially life-threatening arrhythmia have been reported following rapid intravenous administration of cefotaxime via central venous catheter. The recommended injection or infusion time must be strictly observed.

For intravenous infusion, 1–2 g of powder is dissolved in 50 mL of 0.9% sodium chloride solution or 5% glucose solution. The infusion duration should be 50–60 minutes.

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

Stability after reconstitution.

Unused solution should be discarded. Cefotaxime is compatible with metronidazole solution (500 mg/100 mL).

The prepared solution for intramuscular injection containing 1% lidocaine solution should be used immediately after preparation.

Children. The medicinal product may be administered to children from birth. Intramuscular administration is not recommended for children under 30 months of age.

Overdose.

Symptoms of overdose may largely correspond to the profile of adverse effects.

Fever, leukopenia, thrombocytopenia, acute hemolytic anemia, skin, gastrointestinal, and hepatic reactions, dyspnea, stomatitis, anorexia, transient hearing loss, disorientation, renal failure. In isolated cases, seizures and exacerbation of adverse effects may occur. Hypersensitivity reactions are possible. There is a risk of reversible encephalopathy (especially in renal impairment) with high doses of β-lactam antibiotics, including cefotaxime.

Treatment: There is no specific antidote. In case of overdose, discontinue the drug and take measures to reduce the drug concentration in the patient's blood, along with symptomatic therapy for intensified adverse reactions (e.g., seizures). Hemodialysis or peritoneal dialysis is effective.

If signs of hypersensitivity appear (skin rashes, urticaria, headache, nausea, loss of consciousness), administration of the drug should be discontinued. In case of severe hypersensitivity reaction/anaphylactic reaction, administration of epinephrine and/or glucocorticoids should be initiated.

In other clinical situations, additional measures may be required: artificial ventilation, administration of histamine receptor antagonists. In case of circulatory failure, resuscitation measures should be taken.

Adverse Reactions

Infections and infestations: possible development of superinfection (including candidiasis, vaginitis).

Immune system disorders: bronchospasm, anaphylactic reactions, angioneurotic edema; rarely – anaphylactic shock; Jarisch-Herxheimer reaction (skin rash, pruritus, fever, leukopenia, elevated liver enzymes, dyspnea, joint pain).

Cardiac disorders: arrhythmia after rapid intravenous infusion via central venous catheter.

Gastrointestinal disorders: nausea, vomiting, abdominal pain, diarrhea, flatulence, dysbiosis; rarely – stomatitis, glossitis, pseudomembranous colitis, candidiasis.

Hepatobiliary disorders: hepatitis, acute liver failure, liver function abnormalities, jaundice, cholestasis, elevated levels of liver transaminases (ALT, AST, GGT), which rarely exceed twice the upper limit of normal range, usually associated with cholestasis, do not cause liver damage, and are mostly asymptomatic; elevated lactate dehydrogenase, alkaline phosphatase, and bilirubin.

Blood and lymphatic system disorders: pancytopenia, granulocytopenia, neutropenia, transient leukopenia, thrombocytopenia, agranulocytosis, anisocytosis, eosinophilia, hypoprothrombinemia, autoimmune hemolytic anemia, hypocoagulation, hemorrhages, and bleeding.

Biochemical test abnormalities: increased blood urea nitrogen and creatinine concentrations, positive Coombs test.

Nervous system disorders: headache, dizziness, seizures, reversible encephalopathy, fatigue, weakness.

General disorders and administration site conditions: pain and infiltration at the site of intramuscular injection, tissue inflammation, pain along the vein, phlebitis, thrombophlebitis, fever. With intramuscular administration (since the solvent contains lidocaine): systemic reactions to lidocaine.

Skin and subcutaneous tissue disorders: hyperemia, rash, pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), urticaria, acute exanthematous pustulosis.

Renal and urinary system disorders: decreased kidney function, elevated creatinine levels (especially when administered concomitantly with aminoglycosides), interstitial nephritis, acute kidney function disorders.

Reporting of adverse reactions. Healthcare professionals should report any occurrence of adverse events, side effects, or lack of therapeutic efficacy through the pharmacovigilance system.

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.

Incompatibilities. The drug solution is incompatible with aminoglycoside solutions in the same syringe/infusion system. Use only the diluents specified in the section "Administration and dosage".

The drug should not be mixed with alkaline solutions such as sodium bicarbonate injection solution, or with solutions containing aminophylline.

In general, the drug should not be mixed with other medicinal products except those specified in the section "Administration and dosage".

Packaging.

1 g in a glass vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Nitin Lifesciences Ltd.

Manufacturer's address and location of operations.

Village-Rampur Road, Paonta Sahib, District Sirmour, Himachal Pradesh, India

Marketing Authorization Holder. Ochoa Impex.

Address of the Marketing Authorization Holder.

E-360, Greater Kailash part-II, New Delhi – 110048, India