Axetin®

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

Composition:

Active substance: cefuroxime;

1 vial contains sodium cefuroxime equivalent to cefuroxime 0.750 g or 1.5 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white to yellowish powder.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Cefuroxime inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This interrupts 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 beta-lactamases, including (but not limited to) extended-spectrum beta-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 exhibit decreased susceptibility or resistance to cefuroxime.

Cefuroxime sodium breakpoints

• 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. It is advisable to consult local antibiotic susceptibility data, 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, expert advice should be sought.

Cefuroxime generally has activity against the following microorganisms in vitro.

$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.

Absorption. After intramuscular (IM) administration of cefuroxime to healthy volunteers, mean peak serum concentrations ranged from 27 to 35 µg/mL for a 750 mg dose and from 33 to 40 µg/mL for a 1000 mg dose, and were 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 and 100 µg/mL, respectively.

Following IM and IV administration, AUC and 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, sinus tissue, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum, and intraocular fluid. Cefuroxime penetrates the blood-brain barrier during inflammation of the meninges.

Biotransformation. Cefuroxime is not metabolized.

Excretion. Cefuroxime is eliminated via glomerular filtration and tubular secretion. The serum elimination half-life after intramuscular or intravenous injection is approximately 70 minutes. Within 24 hours after administration, the drug is almost completely excreted unchanged in urine (85–90%). The majority 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 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 decreased renal function, dosage selection for this population should be cautious, and renal function should be monitored (see section "Dosage and administration").

Children. The serum elimination half-life of cefuroxime is significantly prolonged in neonates according to gestational age. However, in infants older than 3 weeks and in children, the serum elimination half-life of approximately 60–90 minutes is similar to that observed in adults.

Renal impairment. Cefuroxime is predominantly 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 the pharmacokinetics of cefuroxime.

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.

Axitin® is indicated for the treatment of the following infections in adults and children, including newborns (from birth) (see sections "Special precautions" and "Pharmacological properties").

• Community-acquired pneumonia.
• Acute exacerbations of chronic bronchitis.
• Complicated urinary tract infections, including pyelonephritis.
• Skin and soft tissue infections: cellulitis, erysipelas, wound infections.
• Intra-abdominal infections (see section "Special precautions").

• Prophylaxis of postoperative infections following gastrointestinal surgery, including oesophageal surgery, orthopaedic and gynaecological surgery (including caesarean 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 proper 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 beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interactions.

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

Cefuroxime is eliminated via glomerular filtration and tubular secretion. Concomitant use with probenecid is not recommended. Simultaneous administration of probenecid slows 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 in patients receiving treatment with potent diuretics such as furosemide, or potentially nephrotoxic agents such as aminoglycoside antibiotics, since renal impairment cannot be excluded with such drug combinations.

Other interactions. Blood/plasma glucose measurement (see section "Special precautions"). Concomitant use with oral anticoagulants may lead to 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 immediately discontinued and appropriate emergency measures initiated.

Prior to initiating therapy, patients should be questioned about previous hypersensitivity reactions to cefuroxime, other cephalosporins, or other beta-lactam antibiotics. The drug should be administered with caution in patients with a history of hypersensitivity reactions to penicillins or other β-lactam antibiotics.

Severe cutaneous adverse reactions (SCARs). Severe cutaneous 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 treatment with cefuroxime (see section "Adverse reactions").

Patients receiving the medicinal product should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions occur, cefuroxime should be immediately discontinued and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN, or DRESS syndrome during cefuroxime treatment, cefuroxime therapy must never be restarted in this patient.

Concomitant use with potent diuretics and aminoglycoside antibiotics. Cephalosporin antibiotics in high doses should be used with caution in patients receiving treatment with potent diuretics such as furosemide or aminoglycoside antibiotics, as there have been reports of nephrotoxic effects when these drugs are used in combination. Renal function should be monitored in these patients, as in elderly patients and in those with existing renal impairment (see section "Dosage and administration").

Overgrowth of non-susceptible microorganisms. The use of cefuroxime may lead to overgrowth of Candida species. Prolonged treatment may also result in overgrowth of resistant microorganisms (e.g., Enterococci and Clostridium difficile), which may necessitate discontinuation of therapy (see section "Adverse reactions").

Pseudomembranous colitis, ranging in severity from mild to life-threatening, has been reported with the use of antibiotics. Therefore, this should be considered if patients develop severe diarrhea during or after cefuroxime treatment (see section "Adverse reactions"). Therapy with cefuroxime should be discontinued and specific treatment directed against Clostridium difficile initiated. Antiperistaltic agents are not recommended.

Intracameral use and ocular adverse reactions. Axetin® is not intended for intracameral use. Individual cases and series of serious ocular adverse reactions have been reported following intracameral administration of sodium cefuroxime intended for intravenous/intramuscular use. These reactions included macular edema, retinal edema, retinal detachment, retinal toxicity, visual disturbances, decreased visual acuity, blurred vision, corneal opacity, 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 cross-matching of blood (see section "Adverse reactions"). Slight interference with copper reduction methods (Benedict, Fehling, Clinitest) may occur. However, this should not lead to false-positive results as may be observed with some other cephalosporins. False-negative results may occur with the ferricyanide test; therefore, for determination of glucose levels in blood/plasma of patients treated with sodium cefuroxime, glucose oxidase or hexokinase methods are recommended.

Important information about excipients

The medicinal product Axetin® (750 mg vial) contains 40.65 mg of sodium per vial, equivalent to 2.03% of the WHO recommended maximum daily intake of 2 g sodium for adults.

The medicinal product Axetin® (1.5 g vial) contains 81.45 mg of sodium per vial, equivalent to 4.07% 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. Axetin® should be administered to pregnant women only when clearly needed and when the benefit outweighs the potential risk. Cefuroxime crosses the placenta and reaches therapeutic concentrations in amniotic fluid and umbilical cord blood after intramuscular or intravenous dosing in the mother.

Breastfeeding. Cefuroxime passes into 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 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 sodium cefuroxime on fertility in humans. Reproductive function studies in animals have not shown 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 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 or operate machinery.

Administration and dosage.

Adults and children with body weight ≥ 40 kg

Children with body weight < 40 kg

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

Recommended doses of Acsetine® in renal impairment

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

Method of administration. Aksedin® should be administered by intravenous injection over 3–5 minutes directly into the 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, and no more than 750 mg should be injected 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 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 stated concentrations in mg/mL.

Compatibility

1.5 g of Axytin®, dissolved in 15 mL of water for injections, can be used concomitantly with metronidazole injection (500 mg/100 mL); both drugs retain their activity for 24 hours at temperatures below 25 °C.

1.5 g of Axytin® 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.

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

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

Axytin® 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; 5% glucose injection; 0.18% sodium chloride with 4% glucose injection; 5% glucose with 0.9% sodium chloride injection; 5% glucose with 0.45% sodium chloride injection; 5% glucose with 0.225% sodium chloride injection; 10% glucose injection; 10% invert sugar solution in water for injection; Ringer's solution; Ringer's lactate solution; M/6 sodium lactate solution; Hartmann's solution.

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

Axytin® is also compatible for 24 hours at room temperature when diluted in infusion solutions:

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

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

Children. Axytin® can be used in children from the first days of life. The safety profile of cefuroxime in children corresponds to that observed in adult patients.

Overdose.

Overdose with cephalosporins may cause neurological complications, including encephalopathy, seizures, and coma. Symptoms of overdose may occur if the drug dose has not been appropriately adjusted in patients with impaired renal function (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use"). Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

Adverse Reactions

The most commonly observed adverse reactions are neutropenia, eosinophilia, transient elevations in liver enzymes or bilirubin levels—particularly in patients with pre-existing liver disease—although there is no evidence of harmful hepatic effects or injection site reactions. The frequency of adverse reactions listed below is approximate, as sufficient data are not available for most reactions to allow precise quantification. In addition, the frequency of adverse reactions associated with cefuroxime use varies depending on the indication.

Adverse effects classified from very common to rare are based on clinical trial data. The frequency of other adverse effects (e.g., <1 in 10,000) is primarily derived from post-marketing surveillance data and reflects reporting rates rather than true incidence.

All treatment-related adverse reactions are listed below by system organ class, frequency, and severity according to the MedDRA classification. The following frequency classification is used: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10,000 to < 1/1000; very rare < 1/10,000; and frequency not known (cannot be estimated from available data).

Infections and infestations: frequency not known – overgrowth of Candida or Clostridium difficile.

Blood and lymphatic system disorders: common – neutropenia, eosinophilia, decreased hemoglobin levels; uncommon – leukopenia, positive Coombs test; frequency not known – thrombocytopenia, hemolytic anemia.

Immune system disorders: frequency not known – drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis.

Cardiac disorders: frequency not known – Kounis syndrome.

Gastrointestinal disorders: uncommon – gastrointestinal discomfort; frequency not known – pseudomembranous colitis (see section "Special precautions for use").

Hepatobiliary disorders: common – transient increase in liver enzymes; uncommon – transient increase in bilirubin levels.

Skin and subcutaneous tissue disorders: uncommon – rash, urticaria, pruritus; frequency not known – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Renal and urinary disorders: frequency not known – increased serum creatinine, blood urea nitrogen (BUN), and decreased creatinine clearance (see section "Special precautions for use").

General disorders and administration site conditions: common – reactions at the injection site, which may include pain and thrombophlebitis.

Description of selected adverse reactions. Cephalosporins as a class may adsorb to the surface of red blood cell membranes and interact with antibodies, potentially leading to a positive Coombs test (which may interfere with cross-matching blood) and, very rarely, hemolytic anemia. Transient elevations in serum liver enzymes or bilirubin have been reversible in nature. The likelihood of pain at the intramuscular injection site increases with higher doses, although this is unlikely to necessitate discontinuation of therapy.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, in a place inaccessible to children. If necessary, the prepared solution or suspension may be stored in a refrigerator for up to 24 hours at 2–8 °C.

Incompatibilities.

Axcetin® must not be mixed in the same syringe with aminoglycoside antibiotics. The pH of a 2.74% sodium bicarbonate injection solution significantly affects the color of the solution; therefore, this solution is not recommended for reconstituting Axcetin®. However, if clinically necessary and a patient is receiving intravenous sodium bicarbonate infusion, Axcetin® may be administered directly into the infusion line.

Packaging. 0.750 g or 1.5 g of powder in a vial, pack of 10 or 100 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and place of business.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.