Neotsan-1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOTSAN-1000 (NEOTSAN-1000)

Composition:

Active substance: cefepime;

One vial contains cefepime hydrochloride equivalent to cefepime 1000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder from white to light yellow in color.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Fourth-generation cephalosporins. ATC code J01D E01.

Pharmacological Properties

Pharmacodynamics

Cefepime acts by inhibiting the synthesis of bacterial cell wall enzymes. The drug has a broad spectrum of activity against both gram-positive and gram-negative bacteria, high stability against hydrolysis by most beta-lactamases, low affinity for chromosomally mediated beta-lactamases, and rapidly penetrates into gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes:

Staphylococcus aureus (including beta-lactamase-producing strains); Staphylococcus epidermidis (including beta-lactamase-producing strains); other staphylococcal strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (Group A streptococci); Streptococcus agalactiae (Group B streptococci); Streptococcus pneumoniae (including strains with intermediate resistance to penicillin — MIC [minimum inhibitory concentration] from 0.1 to 1 mcg/mL); other beta-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci.

Most enterococcal strains, such as Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to most cephalosporin antibiotics, including cefepime.

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, Iwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; Haemophilus influenzae (including beta-lactamase-producing strains); Haemophilus parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase-producing strains); Neisseria gonorrhoeae (including beta-lactamase-producing strains); Neisseria meningitidis; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Cefepime is inactive against certain strains of Xanthomonas maltophilia (Pseudomonas maltophilia).

Anaerobes:

Bacteroides spp., including B. melaninogenicus and other oral cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. (cefepime is inactive against Bacteroides fragilis and Clostridium difficile).

Pharmacokinetics

Elimination half-life is approximately 2 hours. In healthy individuals, no drug accumulation has been observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Total clearance of cefepime is approximately 120 mL/min. Cefepime is primarily eliminated by the kidneys (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 cefepime epimer. Protein binding of cefepime to plasma proteins is independent of drug concentration in serum and is less than 19%.

Cefepime is well distributed throughout the body and achieves therapeutic concentrations in urine, bile, peritoneal fluid, bronchial mucous secretions, sputum, prostate, appendix, and gallbladder.

Plasma concentrations of cefepime in healthy adult males after single intravenous/intramuscular administration are shown in Table 1.

Table 1. Mean plasma concentrations of cefepime (mcg/mL)

Cefepime dose	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
1 g intravenously	78.7	44.5	24.3	10.5	2.4	0.6
1 g intramuscularly	14.8	25.9	26.3	16.0	4.5	1.4

In patients with impaired renal function, the elimination half-life of cefepime is prolonged.

In patients with severe renal dysfunction undergoing dialysis, the elimination half-life is 13 hours for hemodialysis and 19 hours for peritoneal dialysis.

The pharmacokinetics of cefepime are not altered in patients with hepatic impairment or cystic fibrosis. Dose adjustment is not required for such patients.

Children

In children aged 2 months to 11 years, following a single intravenous injection, the total clearance and steady-state volume of distribution are 3.3 (±1.0) mL/min/kg and 0.3 (±0.1) L/kg, respectively.

Approximately 60.4 (±30.4)% of the administered dose of cefepime is excreted unchanged in urine, and the renal clearance is 2.0 (±1.1) mL/min/kg. After intramuscular administration, the mean peak plasma concentration at steady state is 68 mcg/mL at 0.75 hours. Eight hours after intramuscular administration, the plasma concentration of cefepime is 6 mcg/mL. The absolute bioavailability of cefepime following intramuscular injection averages 82%. Patient age and sex do not influence drug clearance.

Table 2. Drug concentrations in cerebrospinal fluid (CSF) and blood plasma in children with bacterial meningitis

Time after administration (hours)	Plasma concentration (µg/mL)*	CSF concentration (µg/mL)*	CSF/plasma concentration ratio*
0.5	67.7 ± 51.2	5.7 ± 0.14	0.12 ± 0.14
1	44.1 ± 7.8	4.3 ± 1.5	0.10 ± 0.04
2	23.9 ± 12.9	3.6 ± 2.0	0.17 ± 0.09
4	11.7 ± 15.7	4.2 ± 1.1	0.87 ± 0.56
8	4.9 ± 5.9	3.3 ± 2.8	1.02 ± 0.64

* Age from 3.1 months to 12 years with a standard deviation of ± 3 years.

Drug dosage 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma concentration and MIC were determined at the end of infusion on day 2 or 3 of drug administration.

Clinical characteristics

Indications

Adults

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia, bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• urinary tract infections, including pyelonephritis;
• gynecological infections;
• sepsis.

For empirical therapy in patients with febrile neutropenia.

For prevention of postoperative complications in intra-abdominal surgery.

Children

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and soft tissue infections;
• sepsis;
• bacterial meningitis.

For empirical therapy in patients with febrile neutropenia.

Contraindications

Hypersensitivity to cefepime or to L-arginine, as well as to cephalosporin antibiotics, penicillins, or to other β-lactam antibiotics.

Interaction with other medicinal products and other types of interactions

Cefepime solution is compatible with the following parenteral solutions: 0.9% sodium chloride solution, 5% or 10% glucose solution, 6 M sodium lactate solution for injection, Ringer's lactate solution with 5% dextrose solution for injection.

Due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics, when high doses of these agents are used concomitantly with cefepime, renal function should be monitored.

Concomitant use of cephalosporins with diuretics (e.g., furosemide) may increase the nephrotoxicity of the former.

To avoid potential drug interactions with other agents, cefepime solutions (like most other beta-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, and netilmicin sulfate. When Neotsan-1000 is prescribed together with these agents, each antibacterial agent must be administered separately.

Concomitant therapy with bacteriostatic antibiotics may interfere with the activity of beta-lactam antibiotics.

Effect on laboratory test results. Administration of cefepime may result in false-positive glucose in urine tests when using Benedict's reagent. It is recommended to use glucose tests based on enzymatic glucose oxidation reactions.

Special precautions for use

Hypersensitivity

Before administration of the medicinal product, it is necessary to determine whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other beta-lactam antibiotics.

Cefepime should be administered with caution in patients with asthma or allergic diathesis. Close monitoring of the patient is required during the first administration. If an allergic reaction occurs, treatment should be discontinued immediately.

Antibiotics should be prescribed with caution to all patients with any form of allergy, particularly to medicinal products. If an allergic reaction occurs, the drug should be discontinued. Severe immediate-type hypersensitivity reactions may require administration of adrenaline and other forms of therapy.

For patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation, impaired bone marrow function due to malignant hemolytic disorders with severe progressive neutropenia), monotherapy may be insufficient, and combination antimicrobial therapy is indicated.

Antibacterial activity of cefepime

It is unlikely that administration of cefepime in the absence of proven or suspected bacterial infection or its prophylactic use will be beneficial, but it may increase the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to development of superinfection. Repeated assessment of the patient's condition is necessary. If superinfection develops, appropriate therapy should be initiated.

Renal impairment

The dose of the medicinal product should be adjusted in patients with impaired renal function (creatinine clearance < 50 mL/min) to compensate for reduced renal elimination. Since high serum concentrations of the antibiotic may occur with standard doses in patients with renal impairment or other conditions that may impair renal function, the maintenance dose should be reduced when administering cefepime to such patients. The next dose of the medicinal product should be determined based on the degree of renal impairment, severity of infection, and susceptibility of the causative microorganisms.

During post-marketing surveillance, serious adverse reactions have been reported: reversible encephalopathy (disturbances of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including epileptic status), and/or renal failure. Most cases occurred in patients with renal impairment who received cefepime doses exceeding the recommended ones. Symptoms of nephrotoxicity were mostly reversible and resolved after discontinuation of cefepime and/or hemodialysis.

Clostridium difficile-associated diarrhea

Antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported during treatment with nearly all antibiotics, including cefepime, and may range from mild diarrhea to fatal colitis. Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after cefepime therapy. If antibiotic-associated diarrhea or antibiotic-associated colitis is suspected or confirmed, antibacterial therapy, including cefepime, should be discontinued and appropriate therapeutic measures should be initiated immediately. Medicinal products that inhibit peristalsis are contraindicated in this case.

Elderly patients

Cefepime is substantially excreted by the kidneys, and the risk of toxic reactions to this medicinal product is greater in patients with impaired renal function. Since elderly patients are more likely to have decreased renal function, dose selection should be cautious, and renal function should be monitored.

Serological testing

Cephalosporins tend to adsorb onto the surface of erythrocytes and react with antibodies directed against these drugs, resulting in a positive Coombs' test. A positive Coombs' test result has been observed in patients receiving cefepime twice daily in the absence of hemolysis.

False-positive results may occur when testing urine for glucosuria. For this reason, urine glucose testing during cefepime therapy should be performed using glucose oxidase methods.

Prothrombin time should be monitored.

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

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.

Use during pregnancy or breastfeeding

Animal studies have shown no effect on reproductive function and no harmful effects on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted; therefore, the medicinal product should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime passes into breast milk in very small amounts; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery

The effect of cefepime on reaction speed during driving or operating machinery has not been studied. If dizziness, hallucinations, confusion, or other nervous system adverse effects that may affect reaction speed occur, patients should refrain from driving or operating machinery.

Dosage and Administration

Dosage and route of administration may vary depending on the sensitivity, location, and type of microorganisms, severity of infection, as well as the patient's age and functional condition. Usually, adults should receive 1 g intravenously/intramuscularly every 12 hours. The treatment course lasts 7–10 days. Severe infections may require prolonged therapy. Dosage recommendations for the medicinal product Neotsan-1000 in adults are provided in Table 3.

Table 3

Urinary tract infections (mild to moderate severity)	500 mg – 1 g intravenously or intramuscularly	every 12 hours
Other infections (mild to moderate severity)	1 g intravenously or intramuscularly	every 12 hours
Severe infections	2 g intravenously	every 12 hours
Very severe and life-threatening infections	2 g intravenously	every 8 hours

Dose adjustment is not required for patients aged 65 years and older with normal renal function.

Prophylaxis of potential infection during surgical procedures. Administer 2 g of the medicinal product by intravenous infusion over 30 minutes, 1 hour prior to the start of surgery. After completion of the infusion, additionally administer 500 mg of metronidazole intravenously. Metronidazole solution should not be administered simultaneously with the medicinal product Neotsan-1000. If both antibiotics are used concomitantly, they should be administered through separate infusion systems. If a single infusion system is used for both medicinal products, the system must be flushed before infusion of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of the same amount of Neotsan-1000 is recommended 12 hours after the first dose, followed by administration of metronidazole.

Children aged 1 to 2 months. Use only when strictly indicated. Administer at a dose of 30 mg/kg body weight every 12 or 8 hours. Children with body weight below 40 kg receiving Neotsan-1000 should be continuously monitored.

Children aged from 2 months. The maximum dose for children should not exceed the recommended adult dose. For children with body weight below 40 kg, the recommended dose is 50 mg/kg every 12 hours (every 8 hours for patients with febrile neutropenia and bacterial meningitis). The duration of therapy is 7–10 days; severe infections may require longer treatment. Children with body weight of 40 kg and above should receive Neotsan-1000 in the same manner as adults.

Renal impairment. Dose regimen adjustment of the medicinal product is required for patients with impaired renal function (creatinine clearance less than 30 mL/min). The initial dose of Neotsan-1000 should be the same as for patients with normal renal function. Recommended maintenance doses of Neotsan-1000 are shown in Table 4.

Table 4

Creatinine clearance (ml/min)	Recommended maintenance doses
	Urinary tract infections (mild to moderate severity)	Other infections (mild to moderate severity)	Severe infections	Very severe and life-threatening infections
> 50	500 mg every 12 hours	1 g every 12 hours	2 g every 12 hours	2 g every 8 hours
	Standard dosing according to infection severity; dose adjustment not required
30–50	500 mg every 24 hours	1 g every 24 hours	2 g every 24 hours	2 g every 12 hours
11–29	500 mg every 24 hours	500 mg every 24 hours	1 g every 24 hours	2 g every 24 hours
≤ 10	250 mg every 24 hours	250 mg every 24 hours	500 mg every 24 hours	1 g every 24 hours
Hemodialysis	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

If only the 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) = value calculated by the above formula × 0.85

During hemodialysis, approximately 68% of the administered dose of the drug is eliminated from the body over 3 hours. After each hemodialysis session, a supplementary dose equivalent to the initial dose should be administered. For continuous ambulatory peritoneal dialysis, the drug can be administered at the normal recommended doses depending on the severity of infection, with a 48-hour interval between administrations of the single dose.

In children with impaired renal function, dosage reduction or prolonged dosing intervals are recommended as indicated in Table 4.

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)

Administration of the drug

Neotsan-1000 can be administered intravenously or deeply intramuscularly into a large muscle mass (e.g., the upper outer quadrant of the gluteal muscle).

Intravenous administration. This route is preferred for patients with severe, life-threatening infections.

For intravenous administration, dissolve Neotsan-1000 in 5 or 10 mL of sterile water for injection, 5% dextrose solution, or 0.9% sodium chloride solution, as specified in Table 5. The prepared solution should be administered slowly as an intravenous bolus over 3–5 minutes or by intravenous infusion.

Intramuscular administration. Dissolve Neotsan-1000 in sterile water for injection, 0.9% sodium chloride solution, 5% dextrose solution for injection, bacteriostatic water for injection with parabens, or bacteriostatic water with benzyl alcohol, at concentrations specified in Table 5. As with other parenterally administered drugs, the prepared solution should be inspected visually for particulate matter prior to administration. The prepared solution can be stored for up to 24 hours at temperatures not exceeding 25°C or for up to 7 days at 2–8°C.

Table 5

	Volume of diluent (ml)	Approximate volume of reconstituted solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous administration
1 g/vial	10	11.4	90
Intramuscular administration
1 g/vial	3.0	4.4	230

Children

The medicinal product can be administered to children aged 1 month and older.

Overdose

Symptoms. In case of significant exceeding the recommended doses, adverse effects become more pronounced, especially in patients with impaired renal function. Symptoms of overdose include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Treatment. The administration of the drug must be discontinued and symptomatic therapy should be initiated. Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of adrenaline and other forms of intensive therapy.

Side effects

Adverse reactions are rare.

Infections: candidiasis, vaginitis, genital pruritus, pseudomembranous colitis, other superinfections.

Respiratory, thoracic and mediastinal disorders: dyspnea, cough, sore throat, shortness of breath.

Gastrointestinal disorders: nausea, vomiting, oral candidiasis, diarrhea, colitis, constipation, abdominal pain, dyspepsia, altered taste.

Hepatobiliary disorders: hepatitis, cholestatic jaundice.

Renal and urinary disorders: renal failure.

Nervous system disorders: dizziness, headache, restlessness, insomnia, paresthesia, confusion / loss of consciousness, seizures / epileptiform attacks, myoclonia, encephalopathy, hallucinations, stupor, coma.

Cardiovascular system disorders: tachycardia, vasodilation, chest pain.

Blood and lymphatic system disorders: anemia, eosinophilia, transient leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

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

Skin and subcutaneous tissue disorders: skin rashes, pruritus, urticaria.

General disorders and administration site conditions: increased body temperature, sweating, chest/back pain, asthenia, injection site reactions including inflammation, phlebitis, pain.

Investigations: increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; prolonged prothrombin time or partial thromboplastin time (PTT); positive Coombs test without hemolysis; transient increase in blood urea nitrogen and/or serum creatinine levels; false-positive urine glucose test.

In addition to the above-mentioned adverse reactions, side effects typical for cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhages, liver function disorders, cholestasis, pancytopenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in the original packaging, protected from light.

Keep out of reach of children.

Incompatibilities. The medicinal product should not be mixed in the same container with other drugs (such as metronidazole, vancomycin, gentamicin, tobramycin or netilmicin solutions), except for the solvents specified in the section "Dosage and administration".

Packaging. 1 vial with powder in a cardboard pack.

Prescription status. Prescription only.

Manufacturer: Sens Laboratories Pvt. Ltd.

Manufacturer's address and location of business activity: VI/51B, Post Box No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.