Zinacef®

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

Composition:

Active substance: cefuroxime;

1 vial contains cefuroxime (in the form of cefuroxime sodium) 750 mg or 1.5 g.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: white or cream-colored powder.

Pharmacotherapeutic group. Antibacterial agents 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 cephalosporins are expected to be resistant to cefuroxime. Depending on the resistance mechanism, organisms with acquired resistance to penicillins may demonstrate 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
1 Breakpoint concentrations for determining cephalosporin activity against Enterobacteriaceae reflect 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; thus, the presence of ESBL 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 E. coli, P. mirabilis, and Klebsiella spp. strains. 3 Staphylococcal susceptibility to cephalosporins is inferred from methicillin susceptibility, except for ceftazidime, cefixime, and cefetibuten, which have no defined breakpoints and should not be used for treatment of staphylococcal infections. 4 Streptococcal susceptibility (groups A, B, C, and G) to cephalosporins is inferred from benzylpenicillin susceptibility. 5 Breakpoint concentrations apply to a daily intravenous dose of 750 mg × 3 and high dose 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 generally 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 evidence 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, reached within 30–60 minutes after injection. Approximately 15 minutes after intravenous (IV) infusion of 750 mg and 1500 mg doses, serum concentrations were about 50 and 100 µg/mL, respectively.

Following IM and IV administration, AUC and Cmax increase linearly with increasing dose within the single-dose range of 250 mg to 1000 mg. There was no evidence of cefuroxime accumulation 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 used. 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. Cefuroxime concentrations 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 via glomerular filtration and tubular secretion. The serum 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. Most of the drug is excreted within the first 6 hours. Mean renal clearance ranges from 114 to 170 mL/min/1.73 m² after IM or IV injection within the dose range of 250 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 carefully selected in this population, and renal function should be monitored (see section "Dosage and administration").

Children

The serum 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 half-life of the drug is 60–90 minutes, similar to that observed in adults.

Renal impairment

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

Hepatic impairment

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

Pharmacokinetic/pharmacodynamic relationship

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.

Zinacef is indicated for the treatment of the infections listed below in adults and children, including newborns (from birth) (see sections "Dosage and Administration" 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 "Dosage and Administration").
• Prophylaxis of postoperative infectious complications following gastrointestinal tract surgery, including esophageal surgery, orthopedic, gynecological procedures (including cesarean section), and cardiovascular surgery.

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

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

Contraindications.

Hypersensitivity to cefuroxime or to any of the excipients of the drug.

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 interaction.

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

Cefuroxime is eliminated by 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 in high doses should be administered with caution in patients receiving treatment with potent diuretics (such as furosemide) or potentially nephrotoxic drugs (such as aminoglycoside antibiotics), as renal 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 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. If serious hypersensitivity reactions occur, treatment with cefuroxime should be discontinued immediately and appropriate emergency measures should be taken.

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 with a history of hypersensitivity reactions to other beta-lactam antibiotics.

Concomitant treatment with potent diuretics or aminoglycosides

Cephalosporin antibiotics should be administered with caution at high doses to patients receiving concomitant treatment with potent diuretics such as furosemide or aminoglycosides, as 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 therapy 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 "Adverse reactions").

Cases of pseudomembranous colitis of varying severity, ranging from mild to life-threatening, have been reported during or after antibiotic therapy. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic treatment (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

Zinacef 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 opacification, 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 cross-matching (see section "Adverse reactions").

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

Since 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 sodium cefuroxime.

Important information about excipients

The medicinal product Zinacef (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 Zinacef (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. Zinacef should be administered to pregnant women only when the expected benefit outweighs the potential risks.

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 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 benefits of breastfeeding for the infant and the benefits of therapy for the mother.

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 driving and use of machines

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

Method of administration and dosage.

Dosage

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

Indications	Dosage
Community-acquired pneumonia and acute exacerbations 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, 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
Prophylaxis of postoperative infections following cardiovascular and esophageal surgeries	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	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 impairment

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

Table 3. Recommended doses of Zinacef in renal impairment

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–1.5 g 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 insufficiency 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 renal impairment.

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

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

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

Instructions for dilution of the medicinal product prior to administration

	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	suспension 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 resulting volume of cefuroxime solution in the reconstituted medium increases due to the displacement factor of the active substance, resulting in the stated concentrations in mg/mL.

Compatibility

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

1.5 g of Zinacef 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.

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

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

Zinacef is compatible with most commonly used intravenous infusion solutions. It retains its stability 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% invertose in water for injection; Ringer's solution; Ringer-lactate solution; M/6 sodium lactate solution; Hartmann's solution.

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

Zinacef 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;
• 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.

Zinacef is 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 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 for Use").

Serum cefuroxime levels 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 levels, 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 provide precise estimates 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 data from clinical trials. The frequency of other adverse effects (e.g., < 1 in 10,000) is primarily derived from post-marketing 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 ≥ 1/1,000 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).

Organ system 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
Gastrointestinal disorders		Discomfort in the gastrointestinal tract	Pseudomembranous colitis (see section "Special warnings and precautions for use")
Hepatobiliary disorders	Transient increase in liver enzyme levels	Transient increase in bilirubin levels
Skin and subcutaneous tissue disorders		Skin rash, urticaria, and pruritus	Multiform erythema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema
Renal and urinary disorders			Increased serum creatinine and blood urea nitrogen levels, and decreased creatinine clearance (see section "Special warnings and precautions for use")
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 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 enzyme or bilirubin levels in serum were reversible in nature. The likelihood of pain at the site of intramuscular injection is greater with higher doses. However, this is unlikely to be a reason for discontinuation of treatment.

Shelf life.

2 years.

Storage conditions.

Store the vial with dry powder in the original packaging at a temperature below 25 °C. Keep out of reach of children.

After reconstitution, the preparation can be stored for up to 48 hours in a refrigerator (4 °C) or up to 5 hours at room temperature not exceeding 25 °C.

Incompatibilities.

Zinacef 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 reconstitution of Zinacef. However, if necessary, when the patient is receiving intravenous infusion of sodium bicarbonate solution, Zinacef may be administered directly into the infusion line.

Packaging. Clear glass vial stoppered with a bromobutyl or fluorocarbon-coated rubber stopper and sealed with an aluminum protective cap, packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer. A.C.S. Dobfar S.p.A., Italy / ACS Dobfar S.r.L., Italy.

Manufacturer's address and location of business operations.

Via Alessandro Fleming, 2, Verona, 37135, Italy / Via Alessandro Fleming, 2, Verona, 37135, Italy.