Axef

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AKSEF® (AKSEF®)

Composition:

Active substance: cefuroxime;

1 vial contains sterile sodium cefuroxime equivalent to anhydrous cefuroxime

750 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white slightly hygroscopic powder.

Pharmacotherapeutic group.

Antibacterials for systemic use. Second-generation cephalosporins. ATC code J01D C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cefuroxime inhibits the synthesis of the bacterial cell wall by binding to penicillin-binding proteins (PBPs). This inhibits 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 that have developed resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the resistance mechanism, organisms with acquired resistance to penicillins may show reduced susceptibility or resistance to cefuroxime.

Cefuroxime sodium breakpoint concentrations

The minimum inhibitory concentration (MIC) breakpoints for cefuroxime, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), are provided below:

Microbiological susceptibility

Acquired resistance to the antibiotic varies by region and over time for individual microorganisms. Local antibiotic susceptibility data should be consulted, especially when treating severe infections. If acquired resistance to the antibiotic is known and the benefit of using the medicinal product is at least questionable in the treatment of certain types of infections, consultation with a specialist is recommended.

Cefuroxime generally has in vitro activity 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 showing signs of synergy.

Pharmacokinetics.

Maximum serum concentration of cefuroxime is achieved within 30–45 minutes after intramuscular administration. The elimination half-life of cefuroxime following intravenous and intramuscular administration is approximately 70 minutes. Concomitant administration of probenecid slows the elimination of cefuroxime and leads to increased serum concentrations.

Protein binding of cefuroxime to serum proteins ranges from 33% to 50%.

Within 24 hours after administration, the drug is almost completely (85–90%) excreted unchanged in the urine, with the majority eliminated within the first 6 hours.

Cefuroxime is not metabolized and is excreted via glomerular filtration and tubular secretion.

Serum levels of cefuroxime decrease during dialysis.

Cefuroxime concentrations exceeding the MIC (minimum inhibitory concentration) for most common pathogenic microorganisms are achieved in bone tissue, synovial fluid, and intraocular fluid. Cefuroxime penetrates the blood-brain barrier during meningitis.

Clinical characteristics.

Indications.

Cefuroxime is indicated for the treatment of the following infections in adults and children, including neonates (from birth) (see sections "Pharmacological properties" and "Special instructions"):

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

When treating and 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 cephalosporin antibiotics.

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

Interaction with other medicinal products and other types of interactions.

Cefuroxime may affect the intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Cefuroxime is eliminated via glomerular filtration and tubular secretion. Concomitant administration of probenecid is not recommended. Simultaneous administration of probenecid slows the elimination of the antibiotic and leads to increased serum concentrations.

Potentially nephrotoxic agents and loop diuretics

Cephalosporin antibiotics in high doses should be administered with caution to patients receiving treatment with potent diuretics (such as furosemide) or potentially nephrotoxic agents (such as aminoglycoside antibiotics), since renal function impairment cannot be excluded with such combinations.

Other types of interactions

Regarding plasma glucose determination: see section "Special instructions".

Concomitant use with oral anticoagulants may lead to an increased international normalized ratio (INR).

Special precautions for use.

Hypersensitivity reactions

As with other beta-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, cefuroxime therapy should be discontinued immediately and appropriate emergency measures should be initiated.

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

Cephalosporin antibiotics can generally be administered safely to patients with penicillin hypersensitivity, although cross-sensitivity reactions have been reported. However, cefuroxime should be used with particular caution in patients who have experienced an anaphylactic reaction to penicillin.

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, which may be life-threatening or fatal, have been reported during cefuroxime therapy (see section "Adverse reactions").

Patients should be informed about the signs and symptoms of these reactions, and closely monitored for skin reactions during treatment. If signs or symptoms suggestive of these reactions occur, cefuroxime should be discontinued immediately and alternative therapy considered. If a serious reaction such as SJS, TEN, or DRESS syndrome develops during cefuroxime treatment, re-administration of cefuroxime in this patient is absolutely contraindicated.

Concomitant treatment with potent diuretics or aminoglycosides

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

Overgrowth of resistant microorganisms

Cefuroxime use may result in overgrowth of nonsusceptible microorganisms (such as Candida, Enterococci, Clostridium difficile), which may necessitate discontinuation of therapy (see section "Adverse reactions").

Cases of pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with antibiotic use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy (see section "Adverse reactions"). Discontinuation of cefuroxime therapy and initiation of specific treatment against Clostridium difficile should be considered. Medicinal products that inhibit intestinal peristalsis are not recommended.

Intracameral administration and ocular adverse reactions

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

Intra-abdominal infections

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

Effect on diagnostic tests

Positive Coombs test results have been reported during cefuroxime therapy. This phenomenon may interfere with blood compatibility cross-matching (see section "Adverse reactions").

Minor 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.

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

Excipients

This medicinal product contains sodium. This should be taken into consideration in patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of cefuroxime in pregnant women are limited. Reproductive toxicity was not observed in animal studies. Axef® may be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Breastfeeding

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

Fertility

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

Ability to affect performance when driving or operating machinery

No studies on the effects of cefuroxime on the ability to drive vehicles 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 dysfunction

Cefuroxime is primarily excreted by the kidneys. Therefore, as with other similar antibiotics, patients with severe renal impairment should receive reduced doses of the medicinal product Aksеf® to compensate for the slower drug elimination.

Table 3

Recommended doses of the medicinal product Aksеf® in renal impairment

Hepatic impairment

Cefuroxime is primarily eliminated by the kidneys. Hepatic dysfunction has not been shown to influence the pharmacokinetics of cefuroxime.

Method of administration

Axeef® should be administered by intravenous injection over 3–5 minutes directly into a vein or via an infusion line or by infusion over 30–60 minutes, or by deep intramuscular injection.

The site for intramuscular injection is the large gluteal muscle; no more than 750 mg should be injected at a single site. Doses exceeding 1.5 g must 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 factor of the active substance, leading to the listed concentrations in milligrams per milliliter (mg/mL).

Compatibility

1.5 g of the medicinal product Axef®, dissolved in 15 mL of water for injections, can be used together with metronidazole injection (500 mg/100 mL); both drugs retain their activity for 24 hours at a temperature below 25 °C.

1.5 g of the medicinal product Axef® 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.

The medicinal product Axef® (5 mg/mL) can be stored for 24 hours at 25 °C in 5 % or 10 % xyliitol injection solution.

The medicinal product Axef® is compatible with solutions containing up to 1 % lidocaine hydrochloride.

Axef® is compatible with most commonly used intravenous infusion solutions. It retains its properties 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 % invert sugar solution in water for injections; Ringer's solution; Ringer's lactate solution; M/6 sodium lactate solution; Hartmann's solution.

The stability of Axef® in 0.9 % sodium chloride injection solution with 5 % glucose is not altered in the presence of sodium hydrocortisone phosphate.

Axef® 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.

Children.

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

Overdose.

Neurological complications, including encephalopathy, seizures, and coma, may occur in case of overdose. Symptoms of overdose may arise if the dose of the medicinal product has not been appropriately adjusted in patients with impaired renal function (see sections "Dosage and Administration" and "Special Warnings").

Cefuroxime levels 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 is no evidence of harmful effects on the liver or reactions at the site of administration.

The frequency of occurrence listed below is approximate, as there are insufficient data for most reactions to allow precise calculation. In addition, the frequency of adverse reactions varies depending on the indication.

Data from clinical trials were used to classify adverse effects from very common to rare. The frequency of other adverse effects (e.g., <1 in 10,000) is primarily based on marketing surveillance data and reflects the reporting rate rather than the actual incidence rate.

Criteria for assessing the frequency of adverse effects:
Very common ≥ 1/10;
Common ≥ 1/100 and < 1/10;
Uncommon ≥ 1/1,000 and < 1/100;
Rare ≥ 1/10,000 and < 1/1,000;
Very rare < 1/10,000;
Frequency not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting of adverse reactions following marketing authorization of a medicinal product is important. It enables continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and 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.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

After reconstitution for intravenous and intramuscular injection, the solution may be stored for up to 48 hours in a refrigerator (4 °C) and for up to 5 hours at temperatures up to 25 °C.

Incompatibilities.

The medicinal product 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 the medicinal product Axef®. However, if necessary, when a patient is receiving sodium bicarbonate solution intravenously by infusion, Axef® may be administered directly into the infusion line.

Packaging.

1 vial of powder in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and place of business

Sankaklar Quarter, Eskikarakoca Street No: 299, 81100 Duzce, Turkey.