Sanfur - 750

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SINFUR – 750 (SANFUR – 750)

Composition:

Active substance: cefuroxime;

One vial contains sodium cefuroxime equivalent to cefuroxime 750 mg.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: powder from white to slightly yellowish color.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

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 cefuroxime access 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 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.	Footnote3	Footnote3
Streptococcus A, B, C and G	Footnote4	Footnote4
Streptococcus pneumoniae	≤ 0.5	> 1
Streptococcus (other)	≤ 0.5	> 0.5
Haemophilus influenzae	≤ 1	> 2
Moraxella catarrhalis	≤ 4	> 8
Breakpoint concentrations not species-related1	≤ 45	> 85
1 Breakpoints 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 have intermediate resistance to third- or fourth-generation cephalosporins according to these breakpoints and should be reported as detected; 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 Breakpoints apply only to the 1.5 g × 3 daily dose 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 Breakpoints refer to an intravenous daily dose of 750 mg × 3 and high dose, at least 1.5 g × 3.

Microbiological susceptibility

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

Cefuroxime generally shows 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 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 mcg/mL to 35 mcg/mL for a 750 mg dose and from 33 mcg/mL to 40 mcg/mL for a 1000 mg dose, achieved within 30–60 minutes after administration. Fifteen minutes after intravenous (IV) infusion of 750 mg and 1500 mg doses, serum concentrations were approximately 50 mcg/mL and 100 mcg/mL, respectively.

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

Distribution

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

Biotransformation

Cefuroxime is not metabolized.

Elimination

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 (85–90%) excreted unchanged in urine. 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 a dose range of 250 mg to 1000 mg.

Special patient groups

Gender

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

Elderly patients

After intramuscular or intravenous administration, absorption, distribution, and excretion of cefuroxime in elderly patients are similar to those observed in younger patients with equivalent renal function. Since elderly patients are more likely to have decreased renal function, dose selection for this patient group 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, dose reduction of cefuroxime is recommended in patients with severe renal impairment (e.g., creatinine clearance < 20 mL/min) 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 free fraction concentration of the drug exceeds the MIC of cefuroxime for specific target strains (i.e., % T > MIC).

Clinical characteristics.

Indications.

Treatment of the following infections in adults and children, including newborns (from birth) (see sections "Pharmacological properties" and "Special instructions").

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

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

Official recommendations regarding the 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 β-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 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 in high doses should be administered with caution to 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 combinations.

Other types of interactions

Information regarding plasma glucose level determination is provided in the section "Special instructions."

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

Special precautions for use.

Hypersensitivity reactions

As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. If severe hypersensitivity reactions occur, cefuroxime therapy 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 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 potent diuretics such as furosemide or aminoglycosides; cases of renal function impairment have been reported with such 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 require discontinuation of treatment (see section "Adverse reactions").

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

Cefuroxime is not intended for intracameral administration. Individual cases and a number 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 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 cross-matching of blood (see section "Adverse reactions").

Minor 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.

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

Important information about excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of cefuroxime in pregnant women are limited. Reproductive toxicity was not observed in animal studies. The drug should be prescribed to pregnant women only when the expected benefit outweighs the potential risk. Cefuroxime crosses the placenta and reaches therapeutic levels in amniotic fluid and umbilical cord blood after intramuscular or intravenous dosing in the mother.

Breastfeeding

Cefuroxime passes into breast milk in small amounts. With therapeutic doses, adverse reactions are not expected, 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 cefuroxime on fertility in humans. In animal reproductive studies, no effect of this medicinal product on fertility was observed.

Ability to affect driving and use of machines

No studies on the effect of cefuroxime on the ability to drive or use machinery have been conducted. However, considering the known adverse reactions, it can be concluded that cefuroxime is unlikely to affect the speed of reaction 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 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 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 and esophageal surgeries	1.5 g during induction of anesthesia, followed by 750 mg (intramuscularly) every 8 hours for an 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 function impairment

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

Table 3. Recommended doses of the drug in renal function 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, sodium cefuroxime 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 treatment in 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

The medicinal product 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 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 which may be useful when fractional doses are required
Bottle volume	Routes of administration	Physical state	Amount of water to be 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

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

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

Compatibility

Cefuroxime is compatible with solutions containing up to 1% lidocaine hydrochloride. The medicinal product 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-lactate solution; M/6 sodium lactate solution; Hartmann's solution.

The stability of the medicinal product in 0.9% sodium chloride injection with 5% glucose is not affected by the presence of sodium hydrocortisone phosphate. Cefuroxime is also compatible for 24 hours at room temperature when diluted in infusion 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.

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

Overdose.

Symptoms. 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 "Special precautions" and "Dosage and administration").

Treatment. Cefuroxime levels can be reduced by hemodialysis or peritoneal dialysis.

Adverse reactions

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

The frequency of adverse reactions provided below is approximate, as sufficient data for precise calculation are lacking for most reactions. In addition, the frequency of adverse reactions associated with cefuroxime varies depending on the indication.

Classification of adverse reactions from very common to rare is based on clinical trial data. The frequency of other adverse reactions (e.g., < 1 in 10,000) is primarily derived from post-marketing experience and reflects the reporting rate rather than the true incidence. All treatment-related adverse reactions are listed below by system organ class, frequency, 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); frequency not known (cannot be estimated from the available data).

Organ system class	Common	Uncommon	Frequency not known
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 precautions")
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			Increase in serum creatinine and blood urea nitrogen levels, and decrease in 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 individual 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 (which may affect the cross-matching test for blood compatibility), and very rarely to hemolytic anemia.

Transient increases in serum levels of liver enzymes or bilirubin were 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.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

The reconstituted solution should be stored for no more than 24 hours in a refrigerator (2–8 °C).

Incompatibilities.

The medicinal product should not be mixed in the same syringe with aminoglycoside antibiotics. The pH of a 2.74% sodium bicarbonate solution for injection significantly affects the color of the solution; therefore, this solution is not recommended for dilution of Sanfur – 750. However, if necessary, when a patient is receiving sodium bicarbonate solution intravenously by infusion, cefuroxime may be administered directly into the infusion line.

Packaging.

1 vial per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business.

VI/51B, Post Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.