Instructions Cefepime powder for solution for injection 1000 mg vial No. 1
Composition
active ingredient: cefepime;
1 vial contains cefepime 1000 mg (as a sterile mixture of cefepime hydrochloride and L-arginine).
Dosage form
Powder for solution for injection.
Main physicochemical properties: white to light yellow powder.
Pharmacotherapeutic group
Antibacterials for systemic use. β-lactam antibiotics. ATX code J01D E01.
Pharmacological properties
Pharmacodynamics
Cefepime is a broad-spectrum, fourth-generation b-lactam cephalosporin antibiotic for parenteral use. It has a bactericidal effect. It is active against gram-positive and gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporin antibiotics, such as ceftazidime. Cefepime is highly resistant to the action of most b-lactamases and rapidly penetrates gram-negative bacteria. The degree of binding of cefepime to the penicillin-binding protein PVR 3 significantly exceeds the affinity of other parenteral cephalosporins. The moderate affinity of cefepime for PVR 1a and 1b also determines the degree of its bactericidal activity. The ratio of MBC (minimum bactericidal concentration)/MIC for cefepime is less than 2 for more than 80% of isolates of all sensitive gram-positive and gram-negative bacteria.
Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against a variety of Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most β-lactamases, has low affinity for β-lactamases encoded by chromosomal genes, and rapidly penetrates Gram-negative bacterial cells.
Cefepime is active against the following microorganisms:
Gram-positive aerobes: Staphylococcus aureus (including strains producing b-lactamase), Staphylococcus epidermidis (including strains producing b-lactamase), other strains of staphylococci (including S. hominis, S. Saprophyticus), Streptococcus pyogenes (group A); Streptococcus agalactiae (group B), Streptococcus pneumoniae (including strains with intermediate resistance to penicillin - MIC from 0.1 to 0.3 μg / ml), other b-hemolytic streptococci (groups C, G, F), S. bovis (group D), Viridans group streptococci. (Most strains of enterococci, for example: Enterecoccus faecalis, and methicillin-resistant staphylococci, 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 (including subfamilies Anitratus, Iwoffi), Aeromonas hydrophila, Capnocytophaga spp., Citrobacter spp. (including C. diversus, C. freundii), Campylobacter jejuni, Gardnerella vaginalis, Haemophilus ducreyi, H. influenzae (including β-lactamase-producing strains), H. Parainfluenzae, Hafnia alvei, Legionella spp., Morganella morganii, Moraxella catarrhalis (Branhamella) catarrhalis (including β-lactamase-producing strains), Neisseria gonorrhoeae (including β-lactamase-producing strains), N. meningitidis, Providencia spp. (including P. rettgeri, P. stuartii), Salmonella spp., Serratia (including S. marcescens, S. liquefaciens), Shigella spp.; Yersinia enterocolitica. Cefepime is inactive against many strains of Xanthomonas (Pseudomonas) maltophilia;
anaerobes: Bacteroides spp. (including B. melaninogenicus and other oral microorganisms belonging to Bacteroides), Clostridium perfringens, Fusobacterium spp., Mobiluncus spp., Peptostreptococcus spp., Veillonella spp. Cefepime is inactive against Bacteroides fragilis and Clostridium difficile).
Pharmacokinetics
Cefepime is completely absorbed after intramuscular administration.
The mean plasma concentrations of cefepime in healthy adult patients after single intravenous (IV) and intramuscular (IM) administration are shown in the table.
Mean plasma concentrations of cefepime (μg/mL):
| Cefepime dose | 0.5 hours | 1 hour | 2 hours | 4 hours | 8 hours | 12 hours |
| 500 mg IV | 38.2 | 21.6 | 11.6 | 5 | 1.4 | 0.2 |
| 1 g IV | 78.7 | 44.5 | 24.3 | 10.5 | 2.4 | 0.6 |
| 2 g IV | 163.1 | 85.8 | 44.8 | 19.2 | 3.9 | 1.1 |
| 500 mg IM | 8.2 | 12.5 | 12 | 6.9 | 1.9 | 0.7 |
| 1 g intramuscularly | 14.8 | 25.9 | 26.3 | 16 | 4.5 | 1.4 |
| 2 g intramuscularly | 36.1 | 49.9 | 51.3 | 31.5 | 8.7 | 2.3 |
Therapeutic concentrations of cefepime are achieved in urine, bile, peritoneal fluid, bronchial mucus, sputum, prostate, appendix, and gallbladder.
The half-life of cefepime from the body is about 2 hours and is independent of dose within the range of 250 mg - 2 g. At a dose of up to 2 g intravenously at intervals of 8 hours for 9 days, no cumulation of the drug in the body was observed.
Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is excreted primarily by glomerular filtration (total clearance of cefepime is approximately 120 mL/min, mean renal clearance is 110 mL/min). Approximately 80–85% of the dose is recovered in the urine as unchanged cefepime, 1% as N-methylpyrrolidine, approximately 6.8% as N-methylpyrrolidine oxide, and approximately 2.5% as the cefepime epimer. The plasma protein binding of cefepime is less than 19% and is independent of serum concentration.
In patients with renal insufficiency, the half-life of cefepime is increased, with a linear relationship between total clearance and creatinine clearance. The half-life in patients with severe renal impairment requiring hemodialysis is 13 hours, and in patients on continuous ambulatory peritoneal dialysis is 19 hours. In patients with abnormal renal function, the dose should be adjusted individually.
The pharmacokinetics of cefepime are not altered in patients with impaired hepatic function or cystic fibrosis. No dose adjustment is necessary for these patients.
Children. Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after a single dose or multiple doses every 8 hours (n=29) and every 12 hours (n=13). After a single intravenous injection, the total body clearance and volume of distribution at steady state averaged 3.3 (1.0) mL/min/kg and 0.3 (0.1) L/kg, respectively. Urinary excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and the mean renal clearance was 2 (1.1) mL/min/kg. The age and gender of the patients (25 boys and 17 girls) did not significantly affect the total body clearance and volume of distribution when adjusted for body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours (n = 13), no accumulation of the drug was observed, while the maximum plasma concentration, area under the curve, and half-life were increased by approximately 15% at steady state when administered at a dose of 50 mg/kg every 8 hours. Cefepime exposure in children following a 50 mg/kg intravenous dose was similar to that in adults following a 2 g intravenous dose. Following intramuscular administration, the maximum plasma concentration of cefepime at steady state averaged 68 μg/mL at a median of 0.75 hours. Eight hours after intramuscular administration, the plasma concentration of cefepime averaged 6 μg/mL. The absolute bioavailability of cefepime following intramuscular injection averaged 82%.
Due to the inability to identify the pathogen and determine its sensitivity to antibiotics or due to lack of time, cefepime can be used as empirical therapy, since it has a broad spectrum of antibacterial activity. In patients at risk of mixed aerobic-anaerobic infection, treatment with cefepime in combination with an antianaerobic drug can be initiated before the pathogen is identified.
Indication
Adults.
Infections caused by microflora sensitive to the drug:
Respiratory tract infections, including pneumonia, bronchitis; Skin and subcutaneous tissue infections; Intra-abdominal infections, including peritonitis and biliary tract infections; Gynecological infections; Septicemia.
Empirical therapy of patients with neutropenic fever.
Prevention of postoperative complications in intra-abdominal surgery.
Children.
pneumonia; urinary tract infections, including pyelonephritis; skin and subcutaneous tissue infections; septicemia; empirical therapy of patients with neutropenic fever; bacterial meningitis.
Contraindication
Hypersensitivity to cefepime or L-arginine, as well as to cephalosporin class antibiotics, penicillins or other β-lactam antibiotics.
Interaction with other medicinal products and other types of interactions
When high doses of aminoglycosides are used concomitantly with cefepime, renal function should be closely monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant use of other cephalosporins with diuretics such as furosemide.
Cefepime in concentrations from 1 to 40 mg/ml is compatible with the following parenteral solutions: 0.9% sodium chloride solution for injection; 5 and 10% glucose solutions for injection; 6M sodium lactate solution for injection, 5% glucose and 0.9% sodium chloride solution for injection; lactated Ringer's solution and 5% glucose solution for injection.
To avoid possible drug interactions with other drugs, cefepime solutions (as with most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, and netilmicin sulfate. If cefepime must be administered with these drugs, each antibiotic should be administered separately.
Impact on laboratory test results.
Cefepime may cause a false-positive reaction for glucose in urine when Benedict's reagent is used. It is recommended to use glucose tests based on the enzymatic glucose oxidation reaction.
Application features
It is necessary to accurately determine whether the patient has previously had immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins or other β-lactam antibiotics. Antibiotics should be prescribed with caution to all patients with any form of allergy, especially to drugs. If an allergic reaction occurs, the drug should be discontinued. Serious immediate-type hypersensitivity reactions may require the use of adrenaline and other forms of therapy.
Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition if diarrhea occurs during treatment with cefepime. Mild colitis may resolve after discontinuation of the drug; moderate or severe cases may require specific treatment.
Use with caution in patients with digestive tract diseases, especially colitis.
As with other antibiotics, superinfection may occur and appropriate precautions should be taken. In patients with impaired renal function (creatinine clearance < 60 ml/min), the dose of cefepime should be adjusted to compensate for the slow rate of renal excretion. Because prolonged serum concentrations of the antibiotic may occur with usual doses in patients with renal insufficiency or other conditions that may impair renal function, the maintenance dose should be reduced when cefepime is administered to such patients. The degree of renal impairment, the severity of the infection, and the susceptibility of the organisms causing the infection should be considered when determining the next dose. During post-marketing surveillance, serious adverse reactions that were life-threatening or fatal were reported: encephalopathy (impaired consciousness, including confusion, hallucinations, stupor and coma), myoclonus and convulsions. Most cases were reported in patients with impaired renal function who received doses of cefepime that exceeded the recommended dose. Some cases occurred in patients who received doses that were adjusted to take into account their renal function. In most cases, symptoms of nephrotoxicity were reversible and disappeared after discontinuation of cefepime and/or after hemodialysis.
The use of antibacterial agents causes changes in the normal flora of the colon and may lead to the overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the main cause of antibiotic-associated colitis. Once the diagnosis of pseudomembranous colitis is confirmed, therapeutic measures should be taken. Cases of pseudomembranous colitis of moderate severity may resolve after discontinuation of the drug. In cases of moderate to severe severity, the need for fluid and electrolyte administration, protein supplementation, and the use of an antibacterial agent effective against Clostridium difficile should be considered.
Reservation.
The use of cefepime in the absence of a known or suspected bacterial infection or for prophylactic purposes is unlikely to be beneficial, but may increase the risk of the development of bacteria resistant to the drug. Prolonged use of cefepime (as with other antibiotics) may result in the development of superinfection. The patient should be re-evaluated. Appropriate measures should be initiated if superinfection occurs. Many cephalosporins, including cefepime, are associated with decreased prothrombin activity. Patients at risk include those with impaired hepatic or renal function, those who are malnourished, and those receiving prolonged antimicrobial therapy. Prothrombin should be monitored in patients at risk and vitamin K should be administered as necessary.
During the period of use of cefepime, positive results of the direct Coombs test may be obtained. When performing hematological or transfusion procedures, when determining the blood group by cross-matching, when performing an antiglobulin test or during the Coombs test for newborns whose mothers received cephalosporin antibiotics before delivery, it should be borne in mind that a positive Coombs test may be the result of the use of the drug. Cefepime (cefepime hydrochloride) should be prescribed with caution to patients with a history of gastrointestinal diseases, especially colitis.
L-arginine has been shown to alter glucose metabolism and simultaneously increase serum potassium levels at doses 33 times the maximum recommended dose of cefepime. Effects at lower doses are currently unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
Since adverse reactions from the central nervous system may occur during treatment, you should refrain from driving or operating other mechanisms.
Use during pregnancy or breastfeeding
The drug can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Cefepime passes into breast milk in small amounts, so breastfeeding should be discontinued during treatment with the drug.
Method of administration and doses
The usual adult dosage is 1 g, administered intravenously or intramuscularly at 12-hour intervals. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.
However, the dosage and route of administration vary depending on the susceptibility of the causative microorganisms, the severity of the infection, and the functional state of the patient's kidneys. Recommendations for the dosage of cefepime for adults are given in the table.
When using lidocaine solution as a solvent for intramuscular administration of the drug, it is necessary to take into account information on the safety of lidocaine and perform a skin test for its tolerance.
| Mild to moderate urinary tract infections | 500 mg – 1 g intravenously or intramuscularly | every 12 hours |
| Other mild to moderate infections | 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 |
For the prevention of infections during surgical interventions. 60 minutes before the start of surgery, adults should administer 2 g of the drug intravenously over 30 minutes. After completion, administer an additional 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before the administration of metronidazole.
During prolonged (more than 12 hours) surgical operations, it is recommended to repeat the administration of an equal dose of the drug 12 hours after the first dose, followed by the administration of metronidazole.
Renal impairment: In patients with renal impairment (creatinine clearance less than 30 ml/min), the dose of the drug should be adjusted.
Recommended doses of cefepime for adults
| Creatinine clearance (ml/min) | Recommended doses | | | |
| > 50 | The usual dosage is adequate for the severity of the infection (see previous table), no dose adjustment is required. | | | |
| 2 g every 8 hours | 2 g every 12 hours | 1 g every 12 hours | 500 mg every 12 hours | |
| 30–50 | Dose adjustment according to creatinine clearance | | | |
| 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 | 500 mg each 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, then creatinine clearance can be determined using the following formula:
Men:
body weight (kg) * (140 - age)
creatinine clearance (ml/min) = ---------------------------------------------------;
72 * serum creatinine (mg/dL)
Women:
body weight (kg) * (140 - age)
creatinine clearance (ml/min) = -------------------------------------------------- × 0.85.
72 * serum creatinine (mg/dL)
During hemodialysis, approximately 68% of the drug dose is removed from the body within 3 hours. After each dialysis session, a repeat dose equal to the initial dose should be administered. During continuous ambulatory peritoneal dialysis, the drug can be used in the initial recommended doses of 500 mg, 1 g or 2 g depending on the severity of the infection with an interval between administrations of 48 hours.
Children aged 1–2 months should be given the drug only if absolutely necessary. Children weighing up to 40 kg receiving cefepime treatment should be monitored closely.
For children with impaired renal function, it is recommended to reduce the dose or increase the interval between administrations.
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)
Children aged 1 to 2 months. The drug is prescribed only for vital indications 30 mg/kg of body weight every 12 or 8 hours, depending on the severity of the infection.
Children from 2 months of age. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children weighing up to 40 kg for complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and for empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours for patients with febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.
Children weighing 40 kg or more should be given the same dosage as adults.
Administration of the drug. The drug can be administered intravenously or by deep intramuscular injection into a large muscle mass (for example, into the upper outer quadrant of the gluteus maximus).
For intravenous administration, cefepime should be dissolved in sterile water for injection, 5% glucose for injection, or 0.9% sodium chloride solution as indicated in the table below. Administer intravenously slowly over 3–5 minutes or through an intravenous line.
Intramuscular administration. The drug can be dissolved in sterile water for injection, 0.9% sodium chloride solution for injection, 5% glucose solution for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution in the concentrations indicated in the table below.
When using lidocaine as a solvent, a skin test should be performed before administration to check for tolerance.
| Volume of dilution solution (ml) | Approximate volume of the resulting solution (ml) | Approximate concentration of cefepime (mg/mL) |
| Intravenous administration: | | | |
| 500 mg/vial | 5 | 5.6 | 100 |
| 1 g/vial | 10 | 11.3 | 100 |
| Intramuscular administration: | | | |
| 500 mg/vial | 1.3 | 1.8 | 280 |
| 1 g/vial | 2.4 | 3.6 | 280 |
As with other parenterally administered drugs, prepared drug solutions should be inspected for particulate matter prior to administration.
Appropriate microbiological studies should be performed to identify the causative organism(s) and determine susceptibility to cefepime. However, cefepime may be used as monotherapy before the causative organism is identified, given its broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms. In patients at risk of mixed aerobic/anaerobic infections (including Bacteroides fragilis), treatment with cefepime in combination with an anaerobe-active agent may be initiated before the causative organism is identified.
Children
The drug is used in children from 1 month of age.
Overdose
Symptoms: in cases of significant excess of recommended doses, especially in patients with impaired renal function, the manifestations of side effects are aggravated. Symptoms of overdose include encephalopathy, accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus; epileptiform seizures, neuromuscular excitability.
Treatment. The drug should be discontinued and symptomatic therapy should be administered. Hemodialysis accelerates the removal of cefepime from the body; peritoneal dialysis is ineffective. Severe immediate-type allergic reactions require the use of adrenaline and other forms of intensive care.
Adverse reactions
Immune system: hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema; respiratory system: cough, sore throat, shortness of breath; cardiovascular system: tachycardia; digestive tract: nausea, vomiting, dyspepsia, oral candidiasis, taste perversion, diarrhea, colitis (including pseudomembranous); nervous system: headache, insomnia, anxiety, convulsions; hepatobiliary system: hepatitis, cholestatic jaundice; skin and subcutaneous tissue: rash, itching, urticaria; others: asthenia, sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral edema. respiratory system: respiratory disorders; digestive tract: abdominal pain, constipation; Nervous system: dizziness, paresthesia; Cardiovascular system: vasodilation; Other: genital itching, fever and candidiasis; Immune system: anaphylaxis; Nervous system: epileptiform seizures.
Local reactions at the site of drug administration:
with intravenous administration – phlebitis and inflammation; with intramuscular administration – pain, inflammation.
Post-marketing studies:
encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptiform seizures, myoclonus, renal failure; anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia.
Laboratory parameters: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin; anemia, eosinophilia, increased prothrombin time or partial thromboplastin time and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in less than 0.5% of patients. Transient leukopenia and neutropenia were also observed.
Possible adverse reactions characteristic of cephalosporin antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, liver dysfunction, cholestasis, pancytopenia.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging.
Do not freeze.
Keep out of reach of children.
Store the prepared solution for 24 hours at a temperature not exceeding 30 °C or up to 7 days at a temperature of 2–8 °C.
Packaging
1 bottle of the drug in a cardboard box.
Vacation category
According to the recipe.
Producer
Nectar Life Sciences Limited-Unit VI.
Location of the manufacturer and its business address
Bhatolikalan Village, Near Jharmajri, E.P.I.P., P.V. Barotiwala, Tehsil Baddi, District Solan, Himachal Pradesh, 174103, India.
