Cefuroxime

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT cefuroxime (cefuroxime)

Composition:

Active substance: cefuroxime;

1 vial contains cefuroxime (as cefuroxime sodium) 0.75 g or 1.5 g.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or almost white powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use.
Second-generation cephalosporins. ATC code J01D C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Cefuroxime inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This inhibition halts the biosynthesis of the cell wall (peptidoglycan), leading to lysis and death of bacterial cells.

Mechanism of resistance. Bacterial resistance to cefuroxime may be associated with one or more of the following mechanisms:

• hydrolysis by β-lactamases, including (but not limited to) extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, which may be inducible or stably expressed in certain aerobic Gram-negative bacterial species;
• reduced affinity of PBPs for cefuroxime;
• outer membrane impermeability limiting access of cefuroxime to PBPs in Gram-negative bacteria;
• bacterial efflux pump systems.

Organisms resistant to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the resistance mechanism, organisms with acquired resistance to penicillins may exhibit reduced susceptibility or resistance to cefuroxime.

Cefuroxime sodium breakpoints

Cefuroxime susceptibility breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST):

Microbiological susceptibility. Acquired resistance to antibiotics varies by region and over time for individual microorganisms. It is advisable to consult local antibiotic susceptibility data, especially when treating severe infections. If known antibiotic resistance renders the utility of the drug at least questionable for treatment of certain types of infections, expert advice should be sought.

Cefuroxime is generally active in vitro against the following microorganisms:

All methicillin-resistant S. aureus are resistant to cefuroxime.

In vitro, cefuroxime in combination with aminoglycoside antibiotics exerts at least an additive effect, sometimes with evidence of synergy.

Pharmacokinetics

Absorption. After intramuscular (IM) administration of cefuroxime to healthy volunteers, the mean peak serum concentration ranged from 27 mcg/mL to 35 mcg/mL for a 750 mg dose and from 33 mcg/mL to 40 mcg/mL for a 1000 mg dose, achieved within 30–60 minutes after administration. Fifteen minutes after intravenous (IV) infusion of 750 mg and 1500 mg doses, serum concentrations were approximately 50 mcg/mL and 100 mcg/mL, respectively.

Following IM or IV administration, the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) increase linearly with increasing dose within a single dose range of 250 mg to 1000 mg. There was no evidence of accumulation of cefuroxime in serum in healthy volunteers after repeated IV infusions of 1500 mg every 8 hours.

Distribution. Protein binding ranges from 33% to 50%, depending on the method of determination. The mean volume of distribution ranges from 9.3 to 15.8 L/1.73 m² after IM or IV administration within the dose range of 250 mg to 1000 mg. Concentrations of cefuroxime exceeding the MIC for most common pathogenic microorganisms are achieved in tonsillar tissue, nasal sinuses, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum, and intraocular fluid. Cefuroxime crosses the blood-brain barrier during meningitis.

Biotransformation. Cefuroxime is not metabolized.

Elimination. Cefuroxime is eliminated by glomerular filtration and tubular secretion. The elimination half-life (t½) from serum after intramuscular or intravenous injection is approximately 70 minutes. Within 24 hours after administration, the drug is almost completely (85–90%) excreted unchanged in urine. Most of the drug is excreted within the first 6 hours. Mean renal clearance ranges from 114 to 170 mL/min/1.73 m² after IM or IV injection within the dose range of 250 mg to 1000 mg.

Special patient groups

Gender. No differences in the pharmacokinetics of cefuroxime were observed between men and women after a single 1000 mg intravenous bolus injection of cefuroxime as cefuroxime sodium.

Elderly patients. After intramuscular or intravenous administration, absorption, distribution, and excretion of cefuroxime in elderly patients are similar to those observed in younger patients with equivalent renal function. Since elderly patients are more likely to have reduced renal function, cefuroxime dosage should be selected with caution and renal function should be monitored (see section "Dosage and administration").

Children. The serum half-life (t½) of cefuroxime is significantly prolonged in neonates depending on gestational age. However, in infants older than 3 weeks and in children, the serum half-life of the drug ranges from 60 to 90 minutes, similar to that observed in adults.

Renal impairment. Cefuroxime is primarily eliminated by the kidneys. As with other similar antibiotics, patients with severe renal impairment (e.g., creatinine clearance < 20 mL/min) should receive reduced doses of cefuroxime to compensate for slower drug excretion (see section "Dosage and administration"). Cefuroxime is effectively removed by hemodialysis and peritoneal dialysis.

Hepatic impairment. Since cefuroxime is primarily eliminated by the kidneys, hepatic impairment is not expected to affect its pharmacokinetics.

Pharmacokinetic/pharmacodynamic interaction. For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy is the percentage of the dosing interval (%T) during which the concentration of the free fraction of the drug exceeds the MIC of cefuroxime for specific target strains (i.e., %T > MIC).

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of the following infections in adults and children, including neonates (from birth) (see sections "Pharmacological properties" and "Special precautions for use").

• Community-acquired pneumonia.
• Acute exacerbation of chronic bronchitis.
• Complicated urinary tract infections, including pyelonephritis.
• Soft tissue infections: cellulitis, erysipelas, wound infections.
• Intra-abdominal infections (see section "Special precautions for use").
• Prophylaxis of postoperative infectious complications following gastrointestinal tract surgery, including esophageal surgery, orthopedic, gynecological surgery (including cesarean section), and cardiovascular surgery.

When treating or preventing infections caused by anaerobic microorganisms, cefuroxime should be used in combination with appropriate additional antibacterial agents.

Official recommendations regarding the appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to cefuroxime or to any of the excipients of the medicinal product.

Hypersensitivity to other cephalosporin antibiotics.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other β-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other types of interactions.

Cefuroxime may affect intestinal flora, resulting in reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Cefuroxime is eliminated by glomerular filtration and tubular secretion. Concomitant use of probenecid is not recommended. Concurrent administration of probenecid prolongs antibiotic excretion and results in increased serum peak levels.

Potential nephrotoxic drugs and loop diuretics

Cephalosporin antibiotics administered in high doses should be used with caution in patients receiving treatment with potent diuretics (such as furosemide) or potential nephrotoxic drugs (such as aminoglycoside antibiotics), since renal function impairment cannot be excluded when these medicinal products are used concomitantly.

Other types of interactions

Regarding plasma glucose measurement: see section "Special precautions for use".

Concomitant use of the medicinal product Cefuroxime with oral anticoagulants may lead to an increased international normalized ratio (INR).

Special precautions for use.

Hypersensitivity reactions. As with other β-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. Hypersensitivity reactions progressing to Kounis syndrome—acute allergic coronary artery spasm that may lead to myocardial infarction—have been reported (see section "Adverse reactions"). In case of severe hypersensitivity reactions, treatment with cefuroxime should be discontinued immediately and appropriate emergency measures should be initiated.

Prior to initiating therapy, patients should be questioned about previous hypersensitivity reactions to cefuroxime, cephalosporin antibiotics, or other β-lactam antibiotics. The drug should be administered with caution to patients who have experienced hypersensitivity reactions to other β-lactam antibiotics.

Concomitant treatment with potent diuretics or aminoglycosides. Cephalosporin antibiotics in high doses should be administered with caution to patients receiving treatment with potent diuretics such as furosemide or aminoglycoside antibiotics, as adverse effects on renal function have been reported with such combinations. Renal function should be monitored in these patients, as in elderly patients and in patients with renal impairment (see section "Dosage and administration").

Overgrowth of resistant microorganisms. As with other antibiotics, prolonged use of cefuroxime may result in overgrowth of nonsusceptible microorganisms (e.g., Candida, Enterococci, Clostridium difficile), which may necessitate discontinuation of therapy.

Cases of pseudomembranous colitis, ranging from mild to life-threatening, have been reported during or after antibiotic therapy. It is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic use. In case of persistent and significant diarrhea or if abdominal cramps occur, treatment should be discontinued immediately and further investigations should be performed, possibly including testing for Clostridium difficile. Antiperistaltic agents should not be administered.

Intra-abdominal infections. Due to its spectrum of activity, cefuroxime is not indicated for the treatment of infections caused by gram-negative non-fermenting bacteria (see section "Pharmacodynamics").

Intracameral administration and ocular adverse reactions. The medicinal product is not intended for intracameral administration. Individual cases and a number of serious ocular adverse reactions have been reported after intracameral use of cefuroxime sodium intended for intravenous/intramuscular administration. These reactions included macular edema, retinal edema, retinal detachment, retinal toxicity, visual disturbances, decreased visual acuity, blurred vision, corneal opacity, and corneal edema.

Interference with diagnostic tests. Positive Coombs' test results have been reported during cefuroxime therapy. This phenomenon may affect blood cross-matching (see section "Adverse reactions").

Slight interference with copper reduction methods (Benedict’s, Fehling’s, Clinitest) may occur. However, this should not lead to false-positive results as may occur with some other cephalosporins.

As false-negative results may occur with the ferricyanide test, glucose oxidase or hexokinase methods are recommended for determination of glucose levels in blood/plasma of patients receiving cefuroxime sodium.

Severe cutaneous adverse reactions (SCARs). Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome, which may be life-threatening or fatal, have been reported in association with cefuroxime therapy (see section "Adverse reactions").

When prescribing the medicinal product, patients should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions appear, cefuroxime should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during cefuroxime treatment, cefuroxime therapy must never be restarted in that patient.

Important information on excipients

The medicinal product (750 mg vial) contains 42 mg of sodium per vial, equivalent to 2.1% of the WHO recommended maximum daily intake of 2 g sodium for adults.

The medicinal product (1.5 g vial) contains 83 mg of sodium per vial, equivalent to 4.15% of the WHO recommended maximum daily intake of 2 g sodium for adults.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of cefuroxime in pregnant women are limited. Reproductive toxicity has not been observed in animal studies. The drug should be administered to pregnant women only if the expected benefit outweighs the potential risk.

Cefuroxime crosses the placenta and reaches therapeutic levels in amniotic fluid and umbilical cord blood after intramuscular or intravenous dosing in the mother.

Breastfeeding period. Cefuroxime passes into breast milk in small amounts. Adverse reactions are not expected with therapeutic doses, but the risk of diarrhea or fungal mucosal infections in the infant cannot be excluded. Therefore, a decision should be made whether to discontinue breastfeeding or to discontinue/abstain from cefuroxime therapy, taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the mother.

Fertility. There are no data on the effect of cefuroxime sodium on fertility in humans. Studies on reproductive function in animals did not show any effect of this medicinal product on fertility.

Ability to influence the ability to drive and use machines.

No studies on the effect of cefuroxime on the ability to drive or operate machinery have been conducted. However, considering the known adverse reactions, it can be concluded that cefuroxime is unlikely to affect the ability to drive vehicles or operate machinery.

Method of administration and dosage.

Dosage

Table 1

Adults and children with body weight ≥ 40 kg

Table 2

Children with body weight < 40 kg

Renal impairment. Cefuroxime is primarily eliminated via the kidneys. Therefore, as with other similar antibiotics, patients with marked renal impairment should receive reduced doses to compensate for the slower excretion of the drug.

Table 3

Recommended doses of Cefuroxime in renal impairment

Hepatic impairment. Cefuroxime is primarily eliminated by the kidneys. No effect on the pharmacokinetics of cefuroxime has been observed in patients with hepatic dysfunction.

Method of administration. The medicinal product should be administered by intravenous injection over 3–5 minutes directly into the vein or via an infusion line or infusion over 30–60 minutes, or by deep intramuscular injection.

The site for intramuscular injection is the large gluteal muscle, and no more than 750 mg should be administered at a single site. Doses exceeding 1.5 g should be administered intravenously.

Instructions for dilution of the medicinal product prior to administration

* Reconstituted solution for addition to 50 mL or 100 mL of a compatible infusion fluid (see compatibility information below).

** The resulting volume of cefuroxime solution in the reconstituted medium increases due to the displacement value of the active substance, leading to the stated concentrations in mg/mL.

Compatibility

1.5 g of cefuroxime dissolved in 15 mL of water for injections may be administered together with metronidazole injection (500 mg/100 mL); both agents retain their activity for 24 hours at temperatures below 25 °C.

1.5 g of cefuroxime is compatible with 1 g of azlocillin (in 15 mL of solvent) or with 5 g (in 50 mL of solvent) for 24 hours at 4 °C and for 6 hours at temperatures up to 25 °C.

Cefuroxime (5 mg/mL) may be stored for 24 hours at 25 °C in 5 % or 10 % xylirol injection solution.

Cefuroxime is compatible with solutions containing up to 1 % lidocaine hydrochloride.

Cefuroxime is compatible with most commonly used intravenous infusion solutions. It remains stable for 24 hours at room temperature in the following solutions: 0.9 % sodium chloride injection solution; 5 % glucose injection solution; 0.18 % sodium chloride with 4 % glucose injection solution; 5 % glucose with 0.9 % sodium chloride injection solution; 5 % glucose with 0.45 % sodium chloride injection solution; 5 % glucose with 0.225 % sodium chloride injection solution; 10 % glucose injection solution; 10 % invertose in water for injections; Ringer's solution; Ringer's lactate solution; M/6 sodium lactate solution; Hartmann's solution.

The stability of cefuroxime in 0.9 % sodium chloride injection solution with 5 % glucose is not affected by the presence of sodium hydrocortisone phosphate.

Cefuroxime is also compatible for 24 hours at room temperature when diluted in infusion solution:

• with heparin (10 or 50 units/mL) in 0.9 % sodium chloride injection solution;
• with potassium chloride solution (10 or 40 mEq/L) in 0.9 % sodium chloride injection solution.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children.

May be administered to children from the first days of life. The safety profile of cefuroxime in children is comparable to that in adult patients.

Overdose.

Overdose of cephalosporin antibiotics may lead to neurological complications, including encephalopathy, seizures, and coma. Symptoms of overdose may occur if the dose is not appropriately reduced in patients with renal impairment. Serum levels of cefuroxime can be reduced by hemodialysis or peritoneal dialysis.

Adverse reactions

The most commonly reported adverse reactions are neutropenia, eosinophilia, and transient elevations in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease. However, there are no data indicating harmful effects on the liver or injection site reactions.

The frequency of adverse reactions listed below is approximate, as there are insufficient data to determine precise frequencies for most reactions. In addition, the frequency of adverse reactions associated with cefuroxime varies depending on the indication.

Classification of adverse reactions from very common to rare is based on data from clinical trials. The frequency of other adverse reactions (e.g., < 1 in 10,000) is primarily derived from post-marketing experience and reflects the reporting rate rather than the true incidence.

All treatment-related adverse reactions are listed below by system organ class, frequency of occurrence, and severity according to the MedDRA classification. The following classification of adverse reaction frequencies is used: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and frequency not known (cannot be estimated from available data).

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

Shelf life. 3 years.

Storage conditions.

No special storage conditions are required.

Keep out of reach of children.

After reconstitution, the preparation may be stored for up to 48 hours in a refrigerator (from 2 to 8 °C) or up to 5 hours at a temperature not exceeding 25 °C.

Incompatibilities.

Cefuroxime must not be mixed in the same syringe with aminoglycoside antibiotics.

The pH of 2.74% sodium bicarbonate solution for injection significantly affects the color of the solution; therefore, this solution is not recommended for reconstitution of cefuroxime. However, if necessary, when a patient is receiving intravenous infusion of sodium bicarbonate solution, cefuroxime may be administered directly into the infusion line.

Packaging. 0.75 g or 1.5 g of 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 packaging manufactured by the manufacturer Reyoung Pharmaceutical Co., Ltd., People's Republic of China.

Manufacturer's address and location of its business operations.

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

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