Sanfur - 1500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANFUR – 1500 (SANFUR – 1500)

Composition:

active substance: cefuroxime;

1 vial contains sodium cefuroxime equivalent to cefuroxime 1500 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: powder from white to slightly yellowish.

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 cell wall (peptidoglycan) biosynthesis, leading to lysis and death of bacterial cells.

Mechanism of resistance

Bacterial resistance to cefuroxime may be associated with one or more of the following mechanisms:

• hydrolysis by β-lactamases, including (but not limited to) extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, which may be inducible or stably expressed in certain aerobic Gram-negative bacterial species;
• reduced affinity of PBPs for cefuroxime;
• outer membrane impermeability limiting access of cefuroxime to PBPs in Gram-negative bacteria;
• bacterial efflux pump systems.

Organisms that have developed resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the resistance mechanism, organisms with acquired resistance to penicillins may 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:

Microbiological susceptibility

Acquired resistance to the antibiotic varies by region and over time for individual microorganisms. It is advisable to consult local antibiotic susceptibility data, especially when treating severe infections. If known acquired resistance to the antibiotic exists 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 generally has in vitro activity against the following microorganisms.

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

In vitro, cefuroxime in combination with aminoglycoside antibiotics exerts at least an additive effect, sometimes 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, 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 the single-dose range of 250 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 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 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, cefuroxime is almost completely (85–90%) excreted unchanged in urine. The majority of cefuroxime 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 IV 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 decreased renal function, cefuroxime dosage should be selected with caution in this patient group, 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 cefuroxime 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 predominantly eliminated by the kidneys, hepatic impairment is not expected to affect the pharmacokinetics of cefuroxime.

Pharmacokinetic/pharmacodynamic interaction

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy is the percentage of the dosing interval (%T) during which the concentration of the free fraction of cefuroxime exceeds the MIC of cefuroxime for specific target strains (i.e., %T > MIC).

Clinical characteristics

Indications

The medicinal product is indicated for the treatment of the following infections in adults and children, including newborns (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 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 results in increased serum concentrations of the drug.

Potential nephrotoxic agents and loop diuretics

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

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 β-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 discontinued immediately and appropriate emergency measures should be initiated.

Prior to initiating therapy, patients should be questioned about previous history of severe hypersensitivity reactions to cefuroxime, other cephalosporins, or other β-lactam agents. Cefuroxime should be administered with caution to patients with a history of hypersensitivity reactions to other β-lactam antibiotics.

Severe cutaneous adverse reactions (SCARs)

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

Patients receiving the drug should be informed about signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions occur, cefuroxime should be discontinued immediately and alternative therapy considered. Cefuroxime must never be re-administered to patients who have experienced a serious reaction such as SJS, TEN, or DRESS syndrome during treatment with cefuroxime.

Concomitant therapy with potent diuretics or aminoglycosides

High-dose cephalosporin antibiotics 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 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 therapy may result in overgrowth of Candida species. Prolonged use of cefuroxime may lead to overgrowth of resistant microorganisms (such as Enterococci, Clostridium difficile), which may necessitate discontinuation of therapy (see section "Adverse reactions").

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

Intracameral administration and ocular adverse reactions

The medicinal product 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 IV/IM 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 should not be used for the treatment of infections caused by gram-negative non-fermenting bacteria (see section "Pharmacodynamics").

Effects 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’s, Fehling’s, Clinitest) may occur. However, this should not lead to false-positive results, as may occur with some other cephalosporins.

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

Important information about excipients

The medicinal product (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 an adult.

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. Cefuroxime should be administered to pregnant women only when the 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 to 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 benefit of breastfeeding for the infant and the benefit of therapy for the mother.

Fertility

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

Ability to affect performance when driving or operating machinery

No studies on the effects of cefuroxime on the ability to drive vehicles or operate machinery have been conducted. However, based on 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

Table 2

Children with body weight < 40 kg

Renal dysfunction

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

Table 3

Recommended dosage of the medicinal product in renal dysfunction

Hepatic impairment

Cefuroxime is primarily eliminated via 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 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

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

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

Compatibility

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

1.5 g of cefuroxime 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.

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

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

Cefuroxime is compatible with most commonly used intravenous infusion solutions. It retains its properties for 24 hours at room temperature in the following solutions: 0.9 % sodium chloride injection solution; 5 % glucose injection solution; 0.18 % sodium chloride with 4 % glucose injection solution; 5 % glucose with 0.9 % sodium chloride injection solution; 5 % glucose with 0.45 % sodium chloride injection solution; 5 % glucose with 0.225 % sodium chloride injection solution; 10 % glucose injection solution; 10 % invert sugar solution in water for injections; Ringer's solution; Ringer's lactate solution; M/6 sodium lactate solution; Hartmann's solution.

The stability of the medicinal product in 0.9 % sodium chloride injection solution 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 solution:

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

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

Children

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

Overdose

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

Serum levels of cefuroxime can be reduced by hemodialysis and 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 injection site reactions. The frequency of adverse reactions listed below is approximate, as sufficient data are not available for most reactions to allow precise calculation. In addition, the frequency of adverse reactions associated with cefuroxime administration varies depending on the indication. Data from clinical trials were used to classify adverse effects from very common to rare. The frequency of other adverse effects (e.g., <1 in 10,000) is primarily based on 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 applied: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting of adverse reactions following registration of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance 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 and sight of children.

The prepared solution should not be stored for longer than 24 hours in a refrigerator (2–8 °C).

Incompatibilities

The medicinal product must not be mixed in the same syringe with aminoglycoside antibiotics. The pH of 2.74% sodium bicarbonate solution for injection significantly affects the color of the solution; therefore, this solution is not recommended for dilution of Sanfur – 1500. However, if necessary, when a patient is receiving sodium bicarbonate solution intravenously by infusion, the medicinal product may be administered directly into the infusion line.

Packaging

1 vial of powder in a cardboard package.

Prescription status

Prescription only.

Manufacturer

Sens Laboratories Pvt. Ltd.

Manufacturer's address and place of business

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