Evroxim

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROXIME (EUROXIME)

Composition:

Active ingredient: 1 vial contains cefuroxime sodium (equivalent to cefuroxime)

750 mg or 1.5 g.

Pharmaceutical form. Powder for injection.

Main physicochemical properties: white or almost white crystalline powder.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Cefuroxime inhibits microbial 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 forms of 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:

Microorganism	Breakpoint concentrations (mg/l)
	Susceptible	Resistant
Enterobacteriaceae 1	≤82	>8
Staphylococcus spp.	See note3	See note3
Streptococcus groups A, B, C and G	See note4	See note4
Streptococcus pneumoniae	≤0.5	>1
Streptococcus (other)	≤0.5	>0.5
Haemophilus influenzae	≤1	>2
Moraxella catarrhalis	≤4	>8
Non-species-related breakpoint concentrations1	≤45	>85
1 Breakpoint concentrations for determining cephalosporin activity against Enterobacteriaceae detect all clinically important resistance mechanisms (including ESBLs and plasmid-mediated AmpC). Some strains producing beta-lactamases may be susceptible or moderately resistant to 3rd or 4th generation cephalosporins according to these breakpoints and should be reported as determined; thus, the presence or absence of ESBLs alone does not affect susceptibility categorization. In many regions, detection and characterization of ESBLs are recommended or mandatory for infection control purposes. 2 Breakpoint concentrations apply only to the 1.5 g × 3 daily dosage and to strains of E. coli, P. mirabilis, and Klebsiella spp. 3 Staphylococcal susceptibility to cephalosporins follows methicillin susceptibility, except for ceftazidime, cefixime, and cefditoren, which lack defined breakpoints and should not be used for treatment of staphylococcal infections. 4 Streptococcal susceptibility of groups A, B, C, and G to cephalosporins follows benzylpenicillin susceptibility. 5 Breakpoint concentrations refer to an intravenous daily dose of 750 mg × 3 and high-dose regimens of at least 1.5 g × 3.

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 demonstrates in vitro activity against the following microorganisms.

Susceptible strains

Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible)$, Streptococcus pyogenes, Streptococcus agalactiae

Gram-negative aerobes: Haemophilus parainfluenzae, Moraxella catarrhalis

Microorganisms for which acquired resistance may be a concern

Gram-positive aerobes: Streptococcus pneumoniae, Streptococcus mitis (viridans group)

Gram-negative aerobes: Citrobacter spp. excluding C. freundii, Enterobacter spp. excluding E. aerogenes and E. cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis, Proteus spp. excluding P. penneri and P. vulgaris, Providencia spp., Salmonella spp.

Gram-positive anaerobes: Peptostreptococcus spp., Propionibacterium spp.

Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp.

Microorganisms with inherent resistance

Gram-positive aerobes: Enterococcus faecalis, Enterococcus faecium

Gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia, Campylobacter spp., Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Proteus penneri, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia

Gram-positive anaerobes: Clostridium difficile

Gram-negative anaerobes: Bacteroides fragilis

Others: Chlamydia spp., Mycoplasma spp., Legionella spp.

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

In vitro, cefuroxime in combination with aminoglycoside antibiotics exerts at least additive effects, sometimes with signs of synergy.

Pharmacokinetics

Absorption

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

Following IM and IV administration, AUC and Cmax increased linearly with increasing dose within the 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 is 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 crosses the blood-brain barrier during meningitis.

Biotransformation

Cefuroxime is not metabolized.

Elimination

Cefuroxime is eliminated by 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 (85–90%) excreted unchanged in urine. The majority of the dose 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 elimination 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, dose 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 depending on 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 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.

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

• 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 (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 proper use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to cefuroxime or to any of the excipients of the 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 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 elimination of the antibiotic and results in increased serum concentrations.

Potential nephrotoxic agents and loop diuretics.

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

Other types of interactions.

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

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, which 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 history of severe hypersensitivity reactions to cefuroxime, other cephalosporins, or other beta-lactam agents. The drug should be administered with caution in patients with a history of hypersensitivity reactions to other beta-lactam antibiotics.

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 receiving the drug should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms indicating 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 must never be re-administered to this patient.

Concomitant treatment with potent diuretics or aminoglycosides

Cephalosporin antibiotics in high doses should be administered with caution to patients receiving concomitant therapy with potent diuretics such as furosemide or aminoglycosides. Cases of renal function impairment have been reported with such drug combinations. Renal function should be monitored in these patients as in elderly patients and in patients with pre-existing renal impairment (see section "Dosage and administration").

Overgrowth of resistant microorganisms

Cefuroxime use may lead to overgrowth of Candida species. Prolonged use of cefuroxime may result in overgrowth of resistant microorganisms (such as Enterococci, Clostridium difficile), which may necessitate discontinuation of treatment (see section "Adverse reactions").

Cases of pseudomembranous colitis of varying 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

Euraxim is not intended for intracameral administration. Individual cases and series of serious ocular adverse reactions have been reported following 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.

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").

Impact on diagnostic tests

Positive Coombs test results have been reported during cefuroxime therapy. This phenomenon may interfere with blood 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.

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.

Important information on excipients

The medicinal product Euraxim (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 Euraxim (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. Euraxim should be administered to pregnant women only 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 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 cefuroxime sodium on fertility in humans. Studies on reproductive function in animals have not shown any effect of this medicinal product on fertility.

Ability to affect performance when driving or operating machinery

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

Method of administration and dosage.

Dosage

Table 1. Adults and children with body weight ≥ 40 kg

Indications	Dosage
Community-acquired pneumonia and acute exacerbation of chronic bronchitis	750 mg every 8 hours (intravenously or intramuscularly)
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections
Complicated urinary tract infections, including pyelonephritis	1.5 g every 8 hours (intravenously or intramuscularly)
Severe infections	750 mg every 6 hours (intravenously) 1.5 g every 8 hours (intravenously)
Prophylaxis of postoperative infections following gastrointestinal surgery, orthopedic and gynecological surgeries (including cesarean section)	1.5 g during induction of anesthesia. May be supplemented with two additional doses of 750 mg (intramuscularly) at 8 and 16 hours
Prophylaxis of postoperative infections following cardiovascular surgery and esophageal surgery	1.5 g during induction of anesthesia, followed by 750 mg (intramuscularly) every 8 hours for additional 24 hours

Table 2. Children with body weight < 40 kg

Indications	Infants and children older than 3 weeks and children with body weight < 40 kg	Neonates (from birth to 3 weeks)
Community-acquired pneumonia	30 to 100 mg/kg/day (intravenously) divided into 3 or 4 doses; for most infections, the optimal dose is 60 mg/kg/day	30 to 100 mg/kg/day (intravenously) divided into 2 or 3 doses
Complicated urinary tract infections, including pyelonephritis
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections

Renal dysfunction

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

Table 3. Recommended doses of Eroxim in renal dysfunction

Creatinine clearance	T½ (hours)	Dosage (mg)
> 20 mL/min/1.73 m²	1.7–2.6	No need to reduce the standard dose (750 mg – 1,500 mg three times daily).
10–20 mL/min/1.73 m²	4.3–6.5	750 mg twice daily
< 10 mL/min/1.73 m²	14.8–22.3	750 mg once daily
Patients undergoing hemodialysis	3.75	During hemodialysis, administer 750 mg intravenously or intramuscularly at the end of each dialysis session. In addition to parenteral administration, sodium cefuroxime can be added to peritoneal dialysis fluid (usually 250 mg per 2 liters of dialysis fluid).
Patients with renal impairment undergoing continuous arteriovenous hemodialysis (CAVH) or high-flux hemofiltration (HFH) in intensive care units	7.9–12.6 (CAVH) 1.6 (HFH)	750 mg twice daily. Patients undergoing low-flux hemofiltration should follow the dosing regimen appropriate for treatment in renal dysfunction.

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

Euraxim should be administered by intravenous injection over 3–5 minutes directly into the vein or via an infusion line, or by intravenous 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 reconstitution of the medicinal product prior to administration

	Additional volumes and concentrations that may be useful when fractional doses are required
Vial volume	Routes of administration	Physical state	Amount of water added (ml)	Approximate cefuroxime concentration (mg/ml)**
	750 mg powder for solution for injection or infusion
750 mg	intramuscular intravenous bolus intravenous infusion	suspension solution solution	3 ml at least 6 ml at least 6 ml	216 116 116
	1.5 g powder for solution for injection or infusion
1.5 g	intramuscular intravenous bolus intravenous infusion	suspension solution solution	6 ml at least 15 ml 15 ml*	216 94 94

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

** The final volume of cefuroxime solution in the reconstituted medium increases due to the displacement factor of the active substance, resulting in the listed concentrations in mg/mL.

Compatibility

1.5 g of Eurexim, dissolved in 15 mL of water for injections, can be administered 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 Eurexim 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.

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

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

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

Eurexim is also compatible for 24 hours at room temperature when diluted in infusion solutions containing:

• heparin (10 or 50 units/mL) in 0.9 % sodium chloride injection solution;
• 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.

Eurexim 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.

Neurological complications, including encephalopathy, seizures, and coma, may occur in case of overdose. Overdose symptoms may arise 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, 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 injection site reactions.

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

The classification of adverse effects from very common to rare is based on data from clinical trials. The frequency of other adverse effects (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, and severity according to the MedDRA classification. The following frequency classification is used: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 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).

System Organ Class	Common	Uncommon	Unknown
Infections and infestations			Overgrowth of Candida or Clostridium difficile
Blood and lymphatic system disorders	Neutropenia, eosinophilia, decreased hemoglobin levels	Leukopenia, positive Coombs test	Thrombocytopenia, hemolytic anemia
Immune system disorders			Drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis
Cardiac disorders			Kounis syndrome
Gastrointestinal disorders		Discomfort in the gastrointestinal tract	Pseudomembranous colitis (see section "Special precautions")
Hepatobiliary disorders	Transient elevation of liver enzymes	Transient elevation of bilirubin levels
Skin and subcutaneous tissue disorders		Skin rash, urticaria, and pruritus	Multiform erythema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, drug-induced eosinophilia with systemic symptoms (DRESS syndrome)
Renal and urinary disorders			Increased serum creatinine, blood urea nitrogen, and decreased creatinine clearance (see section "Special precautions")
General disorders and administration site conditions	Reactions at the injection site, which may include pain and thrombophlebitis
Description of selected adverse reactions Cephalosporins as a class have the property of being absorbed on the surface of the erythrocyte membrane and interacting with antibodies, which may lead to a positive Coombs test result (which may affect cross-matching for blood compatibility) and, very rarely, to hemolytic anemia. Transient elevation of liver enzymes or serum bilirubin was reversible in nature. The likelihood of pain at the site of intramuscular injection is higher when higher doses are administered. However, this is unlikely to be a reason for discontinuation of treatment.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

Euroxime should not be mixed in the same syringe with aminoglycoside antibiotics.

The pH of a 2.74% solution of sodium bicarbonate for injection significantly affects the color of the solution; therefore, this solution is not recommended for dilution of Euroxime. However, if necessary, when a patient is receiving a sodium bicarbonate solution intravenously by infusion, Euroxime may be administered directly into the infusion tubing.

Packaging. Powder in vials made of clear glass. 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. S.C.S. Doffar S.p.A.

Address of manufacturer and place of business.
Via Alessandro Fleming, 2, Verona (VR), 37135, Italy.

INSTRUCTION

for medical use of the medicinal product

EUROXIME

(EUROXIME)

Composition:

Active substance: 1 vial contains cefuroxime sodium (equivalent to cefuroxime)

750 mg or 1.5 g.

Pharmaceutical form. Powder for injection.

Main physicochemical properties: white or almost white crystalline 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 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 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 resistant to other parenteral 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

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

Microorganism	Breakpoint concentrations (mg/l)
	Susceptible	Resistant
Enterobacteriaceae 1	≤82	>8
Staphylococcus spp.	Note3	Note3
Streptococcus A, B, C and G	Note4	Note4
Streptococcus pneumoniae	≤0.5	>1
Streptococcus (other)	≤0.5	>0.5
Haemophilus influenzae	≤1	>2
Moraxella catarrhalis	≤4	>8
Non-species related breakpoint concentrations1	≤45	>85
1Breakpoint concentrations for determining cephalosporin activity against Enterobacteriaceae detect all clinically important resistance mechanisms (including ESBLs and plasmid-mediated AmpC). Some strains producing beta-lactamases may be susceptible or exhibit intermediate resistance to 3rd or 4th generation cephalosporins according to these breakpoints and should be reported as determined, i.e., the presence or absence of ESBLs alone does not affect susceptibility categorization. In many regions, detection and characterization of ESBLs are recommended or mandatory for infection control purposes. 2 Breakpoint concentrations apply only to the dose of 1.5 g × 3 daily and to strains of E. coli, P. mirabilis, and Klebsiella spp. 3 Staphylococcal susceptibility to cephalosporins follows methicillin susceptibility, except for ceftazidime, cefixime, and cefditoren, which have no defined breakpoints and should not be used for treatment of staphylococcal infections. 4 Susceptibility of group A, B, C, and G streptococci to cephalosporins follows benzylpenicillin susceptibility. 5 Breakpoint concentrations refer to an intravenous daily dose of 750 mg × 3 and high-dose regimens of at least 1.5 g × 3.

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 should be considered.

Cefuroxime is usually active in vitro against the following microorganisms.

Susceptible strains

Gram-positive aerobes: Staphylococcus aureus (methicillin-susceptible), Streptococcus pyogenes, Streptococcus agalactiae

Gram-negative aerobes: Haemophilus parainfluenzae, Moraxella catarrhalis

Microorganisms for which acquired resistance may be a problem

Gram-positive aerobes: Streptococcus pneumoniae, Streptococcus mitis (viridans group)

Gram-negative aerobes: Citrobacter spp. excluding C. freundii, Enterobacter spp. excluding E. aerogenes and E. cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis, Proteus spp. excluding P. penneri and P. vulgaris, Providencia spp., Salmonella spp.

Gram-positive anaerobes: Peptostreptococcus spp., Propionibacterium spp.

Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp.

Microorganisms with inherent resistance

Gram-positive aerobes: Enterococcus faecalis, Enterococcus faecium

Gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia, Campylobacter spp., Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Proteus penneri, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia

Gram-positive anaerobes: Clostridium difficile

Gram-negative anaerobes: Bacteroides fragilis

Others: Chlamydia spp., Mycoplasma spp., Legionella spp.

$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 signs of synergy.

Pharmacokinetics

Absorption

After intramuscular (IM) administration of cefuroxime to healthy volunteers, mean peak serum concentrations were 27 to 35 µg/mL for a 750 mg dose and 33 to 40 µg/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 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 cefuroxime accumulation in serum in healthy volunteers after repeated intravenous 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 is 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 excreted by 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 (85–90%) excreted unchanged in urine. The majority of the drug is excreted within the first 6 hours. Mean renal clearance is 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 cefuroxime pharmacokinetics 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 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 in this population, 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 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.

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

• Community-acquired pneumonia.
• Acute exacerbation of chronic bronchitis.
• Complicated urinary tract infections, including pyelonephritis.
• Skin and soft tissue infections: cellulitis, erysipelas, wound infections.
• Intra-abdominal infections (see section "Dosage and administration").
• Prophylaxis of postoperative infections following gastrointestinal tract surgery (including esophageal surgery), orthopedic, gynecological (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 guidelines on the appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to cefuroxime or to any of the excipients.

Hypersensitivity to other cephalosporin antibiotics.

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

Interaction with other medicinal products and other forms of interaction.

Cefuroxime may affect 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 administration of probenecid is not recommended. Simultaneous administration of probenecid slows elimination of the antibiotic and leads to increased serum concentrations.

Potentially nephrotoxic drugs and loop diuretics.

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

Other types of interactions.

Regarding plasma glucose measurement: see section "Dosage and administration".

Concomitant use with oral anticoagulants may lead to an increase in the 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, which may lead to myocardial infarction – have been reported (see section "Side effects"). 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, other cephalosporins, or other beta-lactam agents. The drug should be administered with caution to patients who have had hypersensitivity reactions to other beta-lactam antibiotics.

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 in association with cefuroxime therapy (see section "Side effects").

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

Concomitant treatment with potent diuretics or aminoglycosides

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

Overgrowth of resistant microorganisms

Cefuroxime use may lead to overgrowth of Candida species. Prolonged use of cefuroxime may result in overgrowth of resistant microorganisms (such as Enterococci, Clostridium difficile), which may necessitate discontinuation of therapy (see section "Side effects").

Cases of pseudomembranous colitis of varying 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 "Side effects"). 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

Euroxim is not intended for intracameral administration. Individual cases and a series of serious ocular adverse reactions have been reported following 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 clouding, 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 "Side effects").

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.

A false-negative result 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 on excipients

The medicinal product Euroxim (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 Euroxim (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. Euroxim should be administered to pregnant women only when 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 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, in view of these potential reactions, 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 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 have not shown any effect of this medicinal product on fertility.

Ability to affect the speed of reaction when driving or operating machinery

No studies on the effect of cefuroxime on the ability to drive or operate machinery have been conducted. However, considering the known side effects, it can be concluded that cefuroxime is unlikely to affect the speed of reaction when driving or operating machinery.

Method of administration and dosage.

Dosage

Table 1. Adults and children with body weight ≥ 40 kg

Indications	Dosage
Community-acquired pneumonia and acute exacerbation of chronic bronchitis	750 mg every 8 hours (intravenously or intramuscularly)
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections
Complicated urinary tract infections, including pyelonephritis	1.5 g every 8 hours (intravenously or intramuscularly)
Severe infections	750 mg every 6 hours (intravenously) 1.5 g every 8 hours (intravenously)
Prophylaxis of postoperative infections following gastrointestinal surgery, orthopedic and gynecological surgeries (including cesarean section)	1.5 g during anesthesia induction. May be supplemented with two additional doses of 750 mg (intramuscularly) at 8 and 16 hours after surgery
Prophylaxis of postoperative infections following cardiovascular surgery and esophageal surgery	1.5 g during anesthesia induction, followed by 750 mg (intramuscularly) every 8 hours for additional 24 hours

Table 2. Children with body weight < 40 kg

Indications	Infants and children older than 3 weeks of age and children with body weight < 40 kg	Neonates (from birth to 3 weeks of age)
Community-acquired pneumonia	from 30 to 100 mg/kg/day (intravenously) divided into 3 or 4 doses; for most infections, the optimal dose is 60 mg/kg/day	from 30 to 100 mg/kg/day (intravenously) divided into 2 or 3 doses
Complicated urinary tract infections, including pyelonephritis
Soft tissue infections: cellulitis, erysipelas, wound infections
Intra-abdominal infections

Renal dysfunction

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

Table 3. Recommended doses of Eroxim in renal dysfunction

Creatinine clearance	T½ (hours)	Dosage (mg)
> 20 mL/min/1.73 m²	1.7–2.6	No need to reduce the standard dose (750 mg – 1,500 mg three times daily).
10–20 mL/min/1.73 m²	4.3–6.5	750 mg twice daily
< 10 mL/min/1.73 m²	14.8–22.3	750 mg once daily
Patients undergoing hemodialysis	3.75	During hemodialysis, administer 750 mg intravenously or intramuscularly at the end of each dialysis session. In addition to parenteral administration, cefuroxime sodium may be added to peritoneal dialysis fluid (usually 250 mg per 2 liters of dialysis fluid).
Patients with renal impairment undergoing continuous arteriovenous hemodialysis (CAVH) or high-flux hemofiltration (HFH) in intensive care units	7.9–12.6 (CAVH) 1.6 (HFH)	750 mg twice daily. Patients undergoing low-flux hemofiltration should follow the dosing regimen appropriate for treatment in renal dysfunction.

Hepatic impairment

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

Method of administration

Euraxim should be administered by intravenous injection over 3–5 minutes directly into the vein or via an intravenous 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

	Additional volumes and concentrations that may be useful when fractional doses are required
Vial volume	Routes of administration	Physical state	Amount of water added (mL)	Approximate cefuroxime concentration (mg/mL)**
	750 mg powder for solution for injection or infusion
750 mg	Intramuscular Intravenous bolus Intravenous infusion	Suspension Solution Solution	3 mL At least 6 mL At least 6 mL	216 116 116
	1.5 g powder for solution for injection or infusion
1.5 g	Intramuscular Intravenous bolus Intravenous infusion	Suspension Solution Solution	6 mL At least 15 mL 15 mL*	216 94 94

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

** The final volume of the reconstituted cefuroxime solution increases due to the displacement volume of the active substance, resulting in the listed concentrations in mg/mL.

Compatibility

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

1.5 g of Eucrofim 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.

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

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

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

Eucrofim 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 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.

Eucrofim is indicated for use in children from the first days of life. The safety profile of cefuroxime in children corresponds to that observed in adult patients.

Overdose.

Neurological complications including encephalopathy, seizures, and coma may occur in case of overdose. Symptoms of overdose may arise 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").

Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

Adverse reactions

The most commonly observed 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 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 effects from very common to rare is based on clinical trial data. The frequency of other adverse effects (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, and severity according to the MedDRA classification. The following frequency classification is used: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 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).

System Organ Class	Common	Uncommon	Unknown
Infections and infestations			Overgrowth of Candida or Clostridium difficile
Blood and lymphatic system disorders	Neutropenia, eosinophilia, decreased hemoglobin levels	Leukopenia, positive Coombs test	Thrombocytopenia, hemolytic anemia
Immune system disorders			Drug fever, interstitial nephritis, anaphylaxis, cutaneous vasculitis
Cardiac disorders			Kounis syndrome
Gastrointestinal disorders		Discomfort in the gastrointestinal tract	Pseudomembranous colitis (see section "Special precautions for use")
Hepatobiliary and biliary disorders	Transient increase in liver enzymes	Transient increase in bilirubin levels
Skin and subcutaneous tissue disorders		Rash, urticaria, and pruritus	Multiform erythema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced eosinophilia with systemic symptoms (DRESS syndrome)
Renal and urinary disorders			Increased serum creatinine and blood urea nitrogen levels, decreased creatinine clearance (see section "Special precautions for use")
General disorders and administration site reactions	Reactions at the injection site, which may include pain and thrombophlebitis
Description of selected adverse reactions Cephalosporins as a class have the property of being absorbed on the surface of erythrocyte membranes and interacting with antibodies, which may lead to a positive Coombs test result (which may affect cross-matching blood compatibility) and, very rarely, to hemolytic anemia. Transient increases in liver enzymes or serum bilirubin levels were reversible in nature. The likelihood of pain at the site of intramuscular injection is higher with administration of higher doses. However, this is unlikely to be a reason for discontinuation of treatment.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

Euroxim should 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 dilution of Euroxim. However, if necessary, when the patient is receiving sodium bicarbonate solution intravenously by infusion, Euroxim may be administered directly into the infusion line.

Packaging. Powder in vials made of clear glass. 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer. S.C.S. Dobfar S.P.A.

Manufacturer's name and address of manufacturing site.

Nucleo Industriale S. Atto (loc. S. Nicola a Tordino), - 64100, Teramo (TE), Italy.