Norfepim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMEPIM (NORFEPIM)

Composition:

Active substances: 1 vial (1 g/0.5 g) contains: cefepime (as sterile mixture of cefepime hydrochloride and L-arginine) 1 g; sulbactam (as sulbactam sodium) 0.5 g;

1 vial (2 g/1 g) contains: cefepime (as sterile mixture of cefepime hydrochloride and L-arginine) 2 g; sulbactam (as sulbactam sodium) 1 g.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: almost white or light-yellow powder.

Pharmacotherapeutic group. Beta-lactam antibiotics, cephalosporin group.

ATC code J01D A.

Pharmacological Properties.

Pharmacodynamics.

Cefepime is a fourth-generation cephalosporin antibiotic.

Cefepime has higher affinity than third-generation cephalosporins for the main penicillin-binding proteins (PBPs) of Gram-negative bacteria: PBPs 1, PBPs 2, PBPs 3 (PBPs1, PBPs2, PBPs3 in E. coli; PBPs1 and PBPs3 in Ps. aeruginosa; PBPs2 and PBPs3 in E. cloacae). Its ability to bind and inhibit penicillin-binding proteins of Gram-positive bacteria (1a, 1b, 2 – S. aureus, S. pneumoniae) also exceeds that of third-generation cephalosporins. Overall, cefepime's activity against PBPs of Gram-negative bacteria is higher than against PBPs of Gram-positive bacteria.

Cefepime is a zwitterion; due to the presence of both positive and negative charges in its molecule, it is highly water-soluble and easily penetrates through the porin channels of the cell wall of Gram-negative microorganisms.

Cefepime has low affinity and high stability against hydrolysis by most beta-lactamases, including chromosomal and plasmid-mediated extended-spectrum beta-lactamases that degrade third-generation cephalosporins.

The higher activity compared to third-generation cephalosporins against major PBPs of both Gram-positive and Gram-negative bacteria, resistance to beta-lactamases, and ease of penetration through the cell wall of Gram-negative bacteria confer cefepime with a balanced antimicrobial spectrum and high activity against both Gram-negative and Gram-positive flora.

Sulbactam is a derivative of the beta-lactam ring. Chemically, it is a penicillanic acid sulfone and acts as an irreversible inhibitor of beta-lactamases. It inhibits plasmid-mediated (including extended-spectrum) and chromosomal beta-lactamases of class A, thereby preventing the inactivation of cephalosporins by beta-lactamases. Sulbactam effectively inhibits most beta-lactamases produced by anaerobic microorganisms, including Bacteroides spp. Sulbactam also possesses intrinsic antibacterial activity against Neisseriaceae spp. (for N. gonorrhoeae, MIC90 is 0.39 µg/mL; for N. meningitidis, MIC90 ≤ 0.5 µg/mL), Acinetobacter spp. (for A. calcoaceticus, MIC90 is 0.19–1 µg/mL; for A. baumannii, 1–32 µg/mL), and certain anaerobes, including Bacteroides spp. (for B. fragilis, MIC90 is 6.25–12.5 µg/mL).

When cefepime and sulbactam act simultaneously on microorganisms, the efficacy of this combination is higher than that of cefepime administered alone. The antimicrobial spectrum of this combination is broader, and activity against multidrug-resistant strains is enhanced. The increased efficacy is explained by potentiation of cefepime’s action at the target site.

Among all PBPs, sulbactam most effectively inhibits PBPs-2. Since most cephalosporins, including cefepime, primarily inhibit PBPs1 and PBPs3, the addition of sulbactam to cefepime enhances its activity against various Gram-negative microorganisms, including Ps. aeruginosa and B. fragilis. Another factor contributing to increased efficacy is sulbactam’s ability to inhibit plasmid-mediated (broad- and extended-spectrum) and chromosomal class A beta-lactamases.

Norfepime is active against the following microorganisms:

Gram-positive microorganisms:
Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, coagulase-negative staphylococci, Streptococcus pneumoniae (including penicillin-intermediate strains with penicillin MIC90 of 0.1–1 µg/mL and penicillin-resistant strains with penicillin MIC90 > 1 µg/mL), Streptococcus pyogenes (beta-hemolytic streptococcus group A), Streptococcus agalactiae (beta-hemolytic streptococcus group B), and other beta-hemolytic streptococci (groups C, G, F).

Most strains of enterococci (Enterococcus faecalis, Enterococcus faecium) are resistant to Norfepime.

Methicillin-resistant staphylococci are resistant to Norfepime, as well as to most cephalosporin antibiotics.

Anaerobes:

Gram-positive cocci (including Peptococcus spp.).
Gram-positive rods (including Clostridium spp., Eubacterium spp., and Lactobacillus spp.).

Gram-negative aerobes:
Pseudomonas spp., including P. aeruginosa, P. putida, P. stutzeri; Escherichia coli; Klebsiella spp., including K. pneumoniae, K. oxytoca, K. ozaenae; Enterobacter spp., including E. cloacae, E. aerogenes, E. sakazakii; Proteus spp., including P. mirabilis, P. vulgaris; Acinetobacter calcoaceticus (subsp. anitratus, lwoffi); Acinetobacter baumannii; Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including beta-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase-producing strains); Neisseria gonorrhoeae (including beta-lactamase-producing strains); N. meningitidis; Pantoea agglomerans (formerly Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Gram-negative anaerobes:
Bacteroides spp., including B. fragilis, B. melaninogenicus, and other anaerobic microorganisms from the abdominal cavity, pelvic region, and oral cavity belonging to the genus Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

Norfepime, as a combination of sulbactam and cefepime, is active against all microorganisms susceptible to cefepime. Due to sulbactam’s intrinsic activity and the synergistic interaction between cefepime and sulbactam, Norfepime’s activity significantly exceeds that of cefepime alone against Acinetobacter spp. (Acinetobacter calcoaceticus subsp. anitratus, lwoffi; Acinetobacter baumannii), Neisseriaceae spp., and anaerobes (including B. fragilis). Sulbactam potentiates cefepime’s activity against Enterobacteriaceae producing extended-spectrum beta-lactamases (which degrade third-generation cephalosporins). The combination of cefepime/sulbactam demonstrates higher activity against P. aeruginosa than cefepime alone. Due to the presence of sulbactam, Norfepime is more active against Staphylococcus spp.

Moreover, when the combination of cefepime and sulbactam is used, synergistic effects of its components are observed (manifested as a 2- to 4-fold reduction in the minimum inhibitory concentrations of the combination compared to cefepime alone) against the following microorganisms: Haemophilus influenzae; Enterobacter aerogenes; Escherichia coli; Proteus mirabilis; Klebsiella pneumoniae; Morganella morganii; Citrobacter freundii; Enterobacter cloacae; Citrobacter diversus.

Pharmacokinetics.

Pharmacokinetics of cefepime: In plasma of healthy adult volunteers (aged 20–40 years), the elimination half-life of cefepime is approximately 2 hours. In elderly individuals (65–81 years), the half-life is 50% longer, averaging about 3 hours.

Plasma protein binding of cefepime is approximately 20% and is independent of cefepime concentration in blood. Approximately 85% of the administered dose is excreted unchanged in urine, and 10–10.5% as metabolites.

Pharmacokinetics of sulbactam: In plasma of healthy adult volunteers, the elimination half-life of sulbactam is approximately 1 hour. Bioavailability after intramuscular and intravenous administration is equivalent.

Plasma protein binding of sulbactam is 38–40% and independent of sulbactam concentration in blood. Approximately 71–85% of the administered dose is excreted in urine. No data are available on pharmacokinetic interactions between sulbactam and cefepime when Norfepime is administered.

Table 4.

Norcefepim 1500 mg
	Intravenous infusion, 30 min		Intramuscular
	Cefepime	Sulbactam	Cefepime 1000	Sulbactam 500
Cmax, mcg/ml	66.9 (±4.6)	23.3	29.6 (4.4)	14.2±3.7
AUC, h x mcg/ml	137 ±9	34.4	137 (11)	35.5±7.7
T1/2, hours	2 (±0.3)	0.96 ± 0.2	2.2±0.42	1.16 ± 0.21
Tmax, hours			1.6 ± 0.4	1.04±0.25

Norfeppim 3000 mg
	Intravenous, 30-minute infusion
	Cefepime 2000	Sulbactam 1000
Cmax, mcg/mL	133 (±35.5)	52.21 ± 14.76
AUC, h x mcg/mL	263 (±33)	67.95 ± 14.41
T1/2, hours	2 (±0.3)	0.93 ± 0.15

Penetration into cerebrospinal fluid: cefepime penetrates into the cerebrospinal fluid after intravenous and intramuscular administration. During meningitis, concentrations in the cerebrospinal fluid are higher than in healthy volunteers and amount to approximately 20% of serum concentrations. These concentrations are many times higher than the MICs for bacterial pathogens causing meningitis.

Therapeutic concentrations of cefepime and sulbactam are also achieved in urine, bile, peritoneal fluid, bronchial mucous secretions, sputum, prostate, appendix, and gallbladder, ranging from 20% to 80% of serum concentrations at the time of tissue/fluid sampling.

Metabolism.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. The mean total clearance is 120 mL/min. Cefepime is eliminated almost exclusively via renal mechanisms—primarily through glomerular filtration (mean renal clearance is 110 mL/min). Approximately 85% of the administered dose is excreted in urine as unchanged cefepime, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as the cefepime epimer.

Less than 25% of the administered dose of sulbactam is metabolized, and metabolites are excreted in urine.

Clinical characteristics.

Indications.

Considering the broad spectrum of Norfepim (cefepime/sulbactam), most infections are effectively treated with monotherapy using this drug.

Monotherapy.

Treatment of infections caused by microorganisms sensitive to the combination cefepime/sulbactam:

• respiratory tract infections (including pneumonia, including hospital-acquired pneumonia caused by multidrug-resistant pathogens, aspiration pneumonia, ventilator-associated pneumonia, bronchitis, purulent bronchitis, lung empyema, lung abscess);
• intra-abdominal infections (including peritonitis, cholecystitis, cholangitis, infected pancreatic necrosis, pancreatogenic abscess, prevention of pancreatic necrosis infection);
• retroperitoneal space infections (perinephritis);
• purulent-inflammatory diseases in proctology — periproctitis;
• urinary tract infections (pyelonephritis, renal abscess, apostematous nephritis, cystitis);
• septicemia;
• bacterial meningitis;
• skin and soft tissue infections (abscesses, phlegmons, infected wounds, ulcers, infected fistulas, limb gangrene; treatment of purulent-septic complications in the diabetic foot syndrome);
• bone and joint infections (including bacterial arthritis, osteomyelitis);
• pelvic inflammatory diseases, endometritis, gonorrhea;
• genitourinary infections in males — prostatitis, orchitis, epididymitis;
• treatment of infected burns;
• empirical therapy of febrile neutropenia.

Combination therapy.

The broad antimicrobial spectrum of Norfepim allows treatment of most infections as monotherapy, but combination therapy may be used when necessary.

To identify the causative microorganism(s) and determine susceptibility to cefepime, appropriate tests should be performed. However, Norfepim may be used as monotherapy even before identification of the causative microorganism, as the drug has a broad antibacterial spectrum against both aerobic and anaerobic gram-positive and gram-negative microorganisms.

Contraindications.

Hypersensitivity to the components of the drug or to L-arginine, as well as to other cephalosporin-class antibiotics, penicillins, or other beta-lactam antibiotics. The drug is not recommended for patients with allergic reactions to penicillin-group antibiotics due to the possibility of cross-allergy. Pediatric use under 1 month of age.

Interaction with other medicinal products and other types of interactions.

Cases of increased activity of oral anticoagulants may occur in patients receiving cephalosporins.

Norfepim at concentrations from 1 to 40 mg/mL is compatible with the following parenteral solutions: 0.9% sodium chloride injection; 5% and 10% dextrose injection; 5% dextrose and 0.9% sodium chloride injection; Ringer's lactate with 5% dextrose injection.

To avoid potential drug interactions, Norfepim solutions should not be administered in the same infusion system or syringe with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate solutions. If Norfepim is prescribed together with these drugs, they should be administered separately.

In vitro studies have shown antagonism between chloramphenicol and cefepime in most strains of Enterobacteriaceae.

When high doses of aminoglycosides are used concomitantly with Norfepim, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported after concomitant use of other cephalosporins with diuretics such as furosemide.

Effect on laboratory test results.

Cefepime administration may lead to false-positive glucose in urine tests when using Benedict's reagent. Enzymatic glucose tests based on glucose oxidase reaction are recommended.

Special precautions for use.

For patients at high risk of severe infections (e.g., patients who have undergone bone marrow transplantation with impaired marrow function due to severe malignant hematologic disorders and severe progressive neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated. It is essential to determine precisely whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactam antibiotics. In patients with increased sensitivity to penicillin, cross-allergic reactions should be considered. Antibiotics should be prescribed cautiously to all patients with any form of allergy, particularly drug allergies. If an allergic or hypersensitivity reaction occurs, Norfepim should be discontinued immediately, and appropriate measures should be taken. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders (particularly in medical history), especially colitis. Cases of pseudomembranous colitis have been reported during treatment with nearly all broad-spectrum antibiotics. Therefore, this diagnosis should be considered if diarrhea develops during Norfepim therapy. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is confirmed, appropriate therapeutic measures should be initiated. Mild cases of colitis may resolve after discontinuation of the drug; moderate or severe cases may require specific treatment. In cases of moderate to severe colitis, the need for fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile should be considered.

For patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because standard doses of cefepime in patients with renal insufficiency or other conditions that may impair renal function can lead to increased antibiotic exposure, the maintenance dose of cefepime should be reduced in such patients. The degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be considered when determining the subsequent cefepime dose. During post-marketing surveillance of cefepime-containing drugs, severe, life-threatening, or fatal adverse events have been reported, including encephalopathy (altered mental status, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received cefepime doses exceeding the recommended levels. Occasionally, severe reactions occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis.

Warnings.

It is unlikely that prescribing cefepime in the absence of documented or suspected bacterial infection, or for prophylactic use (except for prevention of postoperative complications), will be beneficial. Such use increases the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to superinfection. The patient's condition should be re-evaluated periodically. If superinfection develops, appropriate measures should be taken. As with other antibiotics, Norfepim use may result in colonization by resistant microorganisms or alter normal gut flora, leading to overgrowth of Candida species.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. High-risk patients include those with impaired liver or kidney function, malnourished patients, and those undergoing prolonged antimicrobial therapy. Prothrombin levels should be monitored in high-risk patients, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs test may occur. When performing hematological or transfusion procedures involving cross-matching blood using the antiglobulin test, or when performing the Coombs test in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs test may be due to drug administration.

It has been demonstrated that L-arginine alters glucose metabolism and simultaneously increases serum potassium levels when administered at doses 33 times higher than the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.

When lidocaine is used as a solvent, safety information regarding lidocaine should be taken into account.

False-positive results may occur in urine glucose testing. For this reason, urine glucose determination during Norfepim treatment should be performed using glucose oxidase methods.

Use during pregnancy or breastfeeding.

Comprehensive, well-controlled studies in pregnant women have not been conducted. The drug should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

The drug is excreted in small amounts in breast milk; therefore, it should be prescribed with caution to breastfeeding mothers.

Ability to influence reaction speed when driving or operating machinery.

Due to the possibility of nervous system adverse reactions, caution should be exercised when driving or operating other potentially hazardous machinery.

Method of Administration and Dosage.

The usual single dose for adults and children with a body weight of over 40 kg is 1.5–3 g. It is administered intravenously or intramuscularly every 12 hours.

The 1.5 g dose is administered intravenously or intramuscularly. The 3 g dose is administered either as an intravenous bolus over 5 minutes or as an intravenous infusion over 30 minutes. The maximum daily dose should not exceed 9 g of Norfepim (6 g cefepime and 3 g sulbactam).

The usual duration of treatment is 7–10 days; severe infections may require longer treatment. For nosocomial infections caused by methicillin-sensitive S. aureus, the recommended duration of treatment is 14 days.

The standard duration of treatment specified in the instructions may be adjusted by the physician according to the patient's condition.

However, dosage and route of administration vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function.

Dosage recommendations for Norfepim in adults are provided in Table 1.

Table 1.

Urinary tract infections, mild to moderate	0.75–1.5 g IV or IM	every 12 hours
Other infections, mild to moderate	1.5 g IV or IM	every 12 hours
Severe infections	3.0 g IV	every 12 hours
Very severe and life-threatening infections (including bacterial meningitis)	3.0 g IV	every 8 hours

For prophylaxis of possible infections during surgical procedures. 3 g of the drug should be administered intravenously over 30 minutes, 60 minutes before the start of surgery in adults. In cases of high risk of anaerobic infection, additional intravenous administration of 500 mg metronidazole is possible. Metronidazole solution should not be administered simultaneously with Norfepim. The infusion system must be flushed before administration of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), 12 hours after the first dose, repeat administration of 3 g Norfepim is recommended, followed by possible administration of metronidazole.

Children aged 1 year and older. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children weighing less than 40 kg in complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, as well as empirical treatment of febrile neutropenia, is 75 mg/kg (50 mg/kg cefepime and 25 mg/kg sulbactam every 12 hours) (in patients with febrile neutropenia and bacterial meningitis—every 8 hours). The usual duration of treatment is 7–10 days; severe infections may require longer therapy.

Renal impairment. In patients with impaired renal function (creatinine clearance less than 50 mL/min), the dose of Norfepim should be adjusted. Dose adjustment should be calculated based on the amount of cefepime administered when using Norfepim.

Studies conducted in patients with varying degrees of renal insufficiency have demonstrated prolonged elimination half-life. On average, the half-life of cefepime contained in Norfepim in patients with severe renal impairment requiring dialysis is 13 hours during hemodialysis and 19 hours during peritoneal dialysis.

Recommended cefepime doses depending on the degree of renal impairment.

Table 2.

Creatinine clearance	Recommended maintenance doses
	Very severe and life-threatening infections (including bacterial meningitis)	Severe infections	Mild to moderate infections	Urinary tract infections, mild to moderate
> 60	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	500 mg every 12 hours
30-59	2 g every 12 hours	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours
11-29	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
<10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Hemodialysis	1 g every 24 hours	1 g first dose, 500 mg subsequent doses every 24 hours
Peritoneal dialysis	2 g every 24 hours	2 g every 24 hours	2 g every 48 hours	500 mg every 24 hours

If only serum creatinine concentration is known, creatinine clearance can be determined using the formula below.

Men:

Body weight (kg) × (140 − age)
Creatinine clearance (mL/min) = ---------------------------------------------------;
72 × serum creatinine (mg/dL)

Women:
Creatinine clearance (mL/min) = above value × 0.85.

Children with impaired renal function are recommended to have either a reduced dose or an extended dosing interval.

Calculation of creatinine clearance in children:

0.55 × height (cm)
Creatinine clearance (mL/min/1.73 m²) = ---------------------------------------------
Serum creatinine (mg/dL)

or

0.52 × height (cm)
Creatinine clearance (mL/min/1.73 m²) = ------------------------------------------ − 3.6
Serum creatinine (mg/dL)

Elderly patients (over 65 years of age). For patients over 65 years of age with normal renal function, dosage adjustment of Norfepim is not required, despite lower renal clearance compared to younger patients.

Patients with cystic fibrosis or impaired liver function. The pharmacokinetics of cefepime and sulbactam in patients with impaired liver function or cystic fibrosis is not significantly altered. Dosage adjustment is not necessary for such patients.

Administration of the drug. Norfepim can be administered intravenously by bolus or infusion, or by deep intramuscular injection.

Intravenous administration. For intravenous bolus administration, Norfepim is dissolved in 5 mL or 10 mL of sterile water for injection, 5 % dextrose solution for injection, or 0.9 % sodium chloride solution for injection, as specified in Table 3. Administered intravenously slowly over 3–5 minutes or via an intravenous infusion system.

For intravenous infusion, 1.5 g or 3 g of Norfepim should first be diluted in 10 mL of sterile water for injection or 0.9 % sodium chloride solution.

The resulting solution may be administered in the following infusion solutions:

• 0.9 % sodium chloride solution for intravenous infusion;
• 5 % or 10 % dextrose solution for intravenous infusion;
• 0.9 % sodium chloride and 5 % dextrose solution for intravenous infusion;
• Ringer-lactate solution;
• Ringer-lactate solution with 5 % dextrose.

The infusion solution should be administered over 30 minutes.

Intramuscular administration. Norfepim may be dissolved in sterile water for injection, 0.9 % sodium chloride solution for injection, 5 % dextrose solution for injection, sterile bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5 % or 1 % lidocaine hydrochloride solution, at the concentrations listed in Table 3.

Norfepim solutions containing lidocaine must not be administered intravenously.

When administering Norfepim to infants under 2 months of age, sterile bacteriostatic water for injection containing parabens or benzyl alcohol should not be used as a solvent.

Table 3.

Single dose for IV or IM administration	Volume of diluent (ml)	Approximate volume of resulting solution (ml)	Approximate concentration of cefepime/sulbactam (mg/ml)
1.5 g/vial IV 1.5 g/vial IM 3 g/vial IV	10 2.5 10	11.4 4 12.3	90/43 250/125 160/80

As with other parenteral medicinal products, prepared solutions of the drug should be inspected for the absence of mechanical particles prior to administration.

In children with impaired renal function, the same dosage regimen adjustments are recommended as in adults, since the pharmacokinetics of cefepime and sulbactam in children and adults are similar.

Preparation and storage instructions for ready-to-use solutions. Norfepim solutions at concentrations from 1 to 40 mg of cefepime/mL are compatible with the following parenteral infusion solutions: 0.9% sodium chloride injection, 5% or 10% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, lactated Ringer's solution, and 5% dextran injection.

Freshly prepared solutions of the drug for intravenous and intramuscular injection are stable for 12 hours at room temperature (20–25 °C) or for 48 hours when stored refrigerated at 2–8 °C.

Appropriate microbiological investigations should be performed to identify the causative microorganism(s) and determine susceptibility to cefepime. However, cefepime may be used as monotherapy prior to identification of the causative microorganism, considering the broad spectrum of antibacterial activity of the drug against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic infection (including Bacteroides fragilis), treatment with cefepime may be initiated in combination with an agent active against anaerobes, pending identification of the pathogen.

Children.

Norfepim is administered to children aged 1 year and older.

Overdose.

Symptoms: in cases of significant overdose, particularly in patients with impaired renal function, adverse effects are intensified. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma; myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment: administration of the drug should be discontinued and symptomatic therapy initiated. Dialysis accelerates elimination of the drug from the body, with hemodialysis being more effective than peritoneal dialysis (which is poorly effective). Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse Reactions

Norfepim is generally well tolerated; however, the following adverse reactions may occur:

Infections and infestations: vaginitis, candidiasis, oral candidiasis, vaginal candidiasis;

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioneurotic edema;

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, erythema, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis;

Blood and lymphatic system disorders: neutropenia, agranulocytosis, transient leukopenia, thrombocytopenia, aplastic anemia, hemolytic anemia, eosinophilia, pancytopenia, hemorrhage;

Gastrointestinal disorders: diarrhea, nausea, vomiting, constipation, abdominal pain, dyspepsia, colitis (including pseudomembranous colitis);

Hepatobiliary disorders: hepatitis, hepatic function abnormalities, cholestasis, cholestatic jaundice;

Cardiovascular disorders: vasodilation, chest pain, tachycardia, hemorrhage;

Respiratory system disorders: cough, respiratory disorders, throat pain, dyspnea;

Central nervous system disorders: headache, dizziness, insomnia, paresthesia, restlessness, seizures, myoclonia, confusion, epileptiform seizures, encephalopathy (loss of consciousness, hallucinations, stupor, coma);

Renal and urinary disorders: genital pruritus, renal failure, toxic nephropathy, renal dysfunction;

Other: asthenia, increased sweating, peripheral edema, back pain, altered taste sensation, fever;

Local reactions at the site of administration: local changes at the injection site, including phlebitis and inflammation with intravenous administration; pain and/or inflammation at the injection site with intramuscular administration;

Laboratory test abnormalities: increased levels of alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time (PTT), positive Coombs test, transient increase in blood urea nitrogen (BUN); transient leukopenia, thrombocytopenia, neutropenia, agranulocytosis; increased serum levels of blood urea nitrogen and/or creatinine, decreased phosphorus levels, hypocalcemia (more common in elderly patients), hypercalcemia. There are no reports of clinical consequences related to changes in calcium or phosphorus levels.

Shelf life: 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

Vial with powder, 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.