Cefepime

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFEPIME

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride 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. Other β-lactam antibiotics. Fourth-generation cephalosporins. Cefepime. ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a broad spectrum of activity against various Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most β-lactamases, has low affinity for chromosomally mediated β-lactamases, and rapidly penetrates Gram-negative bacterial cells.

Cefepime is active against the following microorganisms:

Gram-positive aerobes:

Staphylococcus aureus and Staphylococcus epidermidis (including β-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 penicillin resistance — minimal inhibitory concentration (MIC) from 0.1 to 1 μg/mL); other β-hemolytic streptococci (Groups C, G, F), S. bovis (Group D), Viridans group streptococci (most Enterococcus strains, e.g., 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, lwoffi); 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; Pantoea agglomerans (formerly known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia spp. (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

(Cefepime is inactive against many strains of Xanthomonas maltophilia and 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.

Cefepime is completely absorbed after intramuscular administration.

Mean plasma concentrations of cefepime in healthy adult patients at various time points after single intravenous (IV) and intramuscular (IM) administration are shown in Table 1.

Mean plasma concentrations of cefepime (μg/mL) following intravenous (IV) and intramuscular (IM) administration

Table 1

Therapeutic concentrations of cefepime are also achieved in urine, bile, peritoneal fluid, bronchial mucous secretion, sputum, prostate, appendix, and gallbladder.

The average elimination half-life of cefepime is approximately 2 hours. In healthy individuals receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. The mean total clearance is 120 mL/min. Cefepime is excreted almost exclusively via renal mechanisms, primarily by glomerular filtration (mean renal clearance – 110 mL/min). Approximately 85% of the administered dose is recovered 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 less than 19% and is independent of drug concentration in serum.

Dose adjustment is not required for patients aged 65 years and older with normal renal function, despite their lower renal clearance compared to younger patients.

In patients with various degrees of renal impairment, an increased elimination half-life is observed.

The average half-life in patients with severe renal impairment requiring dialysis is 13 hours during hemodialysis and 19 hours during peritoneal dialysis. In patients with abnormal renal function, the dose should be individually adjusted.

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

Children. Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple intravenous doses administered every 8 or every 12 hours. After a single intravenous injection, the mean total body clearance and steady-state volume of distribution were 3.3 (±1.0) mL/min/kg and 0.3 (±0.1) L/kg, respectively. Renal excretion of unchanged cefepime accounted for 60.4 (±30.4)% of the administered dose, and mean renal clearance was 2 (±1.1) mL/min/kg. Age and gender did not significantly affect total body clearance or volume of distribution when corrected for body weight. When cefepime was administered at a dose of 50 mg/kg every 12 hours, no drug accumulation was observed, whereas with the regimen of 50 mg/kg every 8 hours, maximum plasma concentration, area under the curve, and elimination half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is comparable to that in adults receiving a 2 g intravenous dose. At steady state, the mean maximum plasma concentration of cefepime after intravenous administration was 68 mcg/mL, reached within 0.75 hours. Eight hours after intramuscular injection, the mean plasma concentration of cefepime was 6 mcg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Concentrations of the drug in cerebrospinal fluid (CSF) and plasma in children with bacterial meningitis

Table 2

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

The dose of the drug is 50 mg/kg body weight administered intravenously over 5–20 minutes every 8 hours. Plasma concentration and CSF levels were determined at the end of infusion on day 2 or 3 of treatment with the drug.

Clinical characteristics.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• Lower respiratory tract infections, including pneumonia and bronchitis;
• urinary tract infections (both complicated, e.g. pyelonephritis, and uncomplicated);
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• septicemia.

Empirical therapy in patients with febrile neutropenia.

Prophylaxis of postoperative complications in intra-abdominal surgery.

Children

• Pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and subcutaneous tissue infections;
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

The drug is contraindicated in patients with hypersensitivity reactions to cefepime or L-arginine, as well as to cephalosporin antibiotics, penicillins, or other β-lactam antibiotics.

Special safety precautions.

Release of the medicinal product into the external environment should be minimized. Avoidance of contamination of sewage systems or household waste with the medicinal product is required.

Interaction with other medicinal products and other types of interactions.

When administering high doses of aminoglycosides concomitantly with cefepime, renal function should be closely monitored due to the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with diuretics such as furosemide.

Cefepime at concentrations from 1 to 40 mg/mL is compatible with the following parenteral solutions:

0.9% sodium chloride injection solution; 5% and 10% glucose injection solutions; 6M sodium lactate injection solution; 5% glucose and 0.9% sodium chloride injection solution; Ringer's solution with lactate and 5% glucose injection solution.

To avoid potential drug interactions with other agents, solutions of cefepime (as with most other β-lactam antibiotics) should not be administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If co-administration with these agents is necessary, each antibiotic should be administered separately.

Effect on laboratory test results.

Cefepime administration may result in false-positive urine glucose tests when using Benedict's reagent. It is recommended to use glucose tests based on enzymatic glucose oxidation reactions.

Special precautions.

Hypersensitivity. It is essential to determine precisely whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any type 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 therapeutic interventions.

For patients at high risk of severe infections (e.g., patients with a history of bone marrow transplantation associated with reduced marrow activity due to severe progressive hemolytic disease with severe progressive neutropenia), monotherapy may be insufficient; therefore, combination antimicrobial therapy is indicated.

Cases of pseudomembranous colitis have been reported during the use of nearly all broad-spectrum antibiotics. Therefore, the possibility of this condition should be considered in any patient who develops diarrhea during treatment with Cefepime. Mild forms of colitis are reversible and resolve after discontinuation of cefepime; moderate or severe cases may require specific treatment.

Use with caution in patients with gastrointestinal disorders, particularly colitis.

A skin sensitivity test must be performed before administration.

During prolonged treatment, it is necessary to monitor regularly liver and kidney function tests and hematopoietic parameters.

Dose adjustment of cefepime is required in patients with impaired renal function (creatinine clearance < 60 mL/min) to compensate for reduced renal elimination. Since prolonged antibiotic serum concentrations may occur at standard doses in patients with renal impairment or other conditions that may impair kidney function, the maintenance dose should be reduced when administering cefepime to such patients. The degree of renal impairment, severity of infection, and susceptibility of the causative organisms should be considered when determining the subsequent dose.

Serious adverse reactions, including reversible encephalopathy (confusion, including clouding of consciousness), myoclonia, seizures, and/or renal failure, have been observed most frequently in patients with renal impairment receiving doses exceeding the recommended dose, as well as in elderly patients with renal impairment receiving recommended doses of cefepime. Some cases occurred in patients receiving doses adjusted according to their renal function. In most cases, symptoms of nephrotoxicity were reversible and resolved after discontinuation of cefepime and/or hemodialysis.

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

Administration of antibacterial agents alters the normal flora of the colon and may lead to overgrowth of Clostridia. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. After confirmation of the diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be taken. Mild pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate or severe colitis, consideration should be given to fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

Warnings.

It is unlikely that prescribing cefepime in the absence of proven or suspected bacterial infection or for 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 superinfection. The patient's condition should be re-evaluated periodically. If superinfection develops, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. Patients at risk include those with impaired liver or kidney function, patients with poor nutrition, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in patients at risk, and vitamin K should be administered if necessary.

Positive results in the direct Coombs' test may occur during cefepime therapy. When performing hematological or transfusion procedures involving blood group determination by cross-matching, or during Coombs' testing in newborns whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs' test may be due to drug administration.

When lidocaine is used as a solvent for pediatric administration, 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.

As with other antibiotics, cefepime use may lead to colonization by resistant microflora. If superinfection develops during treatment, appropriate measures should be taken.

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, cefepime should 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 very low concentrations. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Since adverse reactions affecting the central nervous system may occur during treatment, patients should refrain from driving or operating machinery.

Method of administration and dosage.

The usual dosage for adults is 1 g, administered intravenously or intramuscularly every 12 hours. The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

However, the dosage and route of administration should be adjusted depending on the susceptibility of the causative microorganisms, the severity of the infection, and the patient's renal function. Dosage recommendations for Cefepime in adults are provided in Table 2.

Table 2

Prophylaxis of infections during surgical procedures. 2 g of the drug should be administered intravenously over 30 minutes, 60 minutes prior to the start of surgery. After completion, an additional 500 mg of metronidazole should be administered intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system should be flushed before administration of metronidazole.

During prolonged surgical procedures (exceeding 12 hours), a repeat dose of cefepime equal to the initial dose is recommended 12 hours after the first dose, followed by administration of metronidazole.

Renal function impairment. Dose adjustment of the drug is required in patients with impaired renal function (creatinine clearance less than 30 mL/min). The initial dose should be the same as that for patients with normal renal function. Recommended maintenance doses of cefepime are shown in Table 3.

Recommended doses of cefepime for adults

Table 3

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

Men:

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

Women:

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

During hemodialysis, approximately 68% of the drug dose is eliminated from the body over 3 hours. A supplementary dose equal to the initial dose should be administered after each dialysis session. For continuous ambulatory peritoneal dialysis (CAPD), the drug may be administered at the usual recommended initial doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

For children with impaired renal function, dose reduction or extended dosing intervals are recommended.

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. Only in life-threatening situations: 30 mg/kg body weight every 12 or 8 hours. Children weighing less than 40 kg receiving cefepime should be closely monitored.

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 less than 40 kg in complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and empirical treatment of febrile neutropenia is 50 mg/kg every 12 hours (every 8 hours for febrile neutropenia and bacterial meningitis). The usual duration of treatment is 7–10 days; severe infections may require longer treatment.

Administration of the drug. Cefepime can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g., the upper outer quadrant of the gluteus maximus).

Intravenous administration. The intravenous route is preferred for patients with severe or life-threatening infections.

For intravenous administration, dissolve Cefepime in 5 mL or 10 mL of sterile water for injection, 5% dextrose solution for injection, or 0.9% sodium chloride solution, as specified in the table below. Administer intravenously slowly over 3–5 minutes or via an intravenous infusion system.

Intramuscular administration. Cefepime can be dissolved in sterile water for injection, 0.9% sodium chloride solution for injection, 5% dextrose solution for injection, bacteriostatic water for injection with parabens or benzyl alcohol, or 0.5% or 1% lidocaine hydrochloride solution, at the concentrations indicated in Table 4 below.

When using lidocaine as a solvent, a skin sensitivity test should be performed prior to administration.

Table 4

The reconstituted solution is chemically and physically stable for 24 hours at room temperature. To prevent microbial contamination, it is advisable to use the solution immediately after dilution. If the solution is not used immediately, the duration and storage conditions are the responsibility of the physician. The total time between reconstitution, dilution, refrigerated storage at 2–8 °C, and administration should not exceed 7 days. As with other parenteral medicinal products, prepared solutions should be inspected for the presence of particulate matter prior to administration.

Appropriate microbiological investigations should be carried out 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 due to its broad-spectrum antibacterial activity against both gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic/anaerobic (including Bacteroides fragilis) infections, treatment with cefepime may be initiated in combination with an agent active against anaerobes, pending identification of the causative organism.

Children.

May be administered to children aged 1 month and older.

Overdose.

Symptoms. In cases of significant overdose, especially in patients with impaired renal function, adverse reactions may intensify. 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.

Hemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is poorly effective. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy.

Adverse Reactions

Cefepime is generally well tolerated, and adverse effects occur infrequently.

Immune system disorders: hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, pruritus, rash, urticaria, fever;

Respiratory system disorders: cough, sore throat, dyspnea;

Cardiovascular system disorders: tachycardia, vasodilation, chest pain;

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

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

Hepatobiliary disorders: hepatitis, cholestatic jaundice;

Other adverse reactions: asthenia, sweating, fever, genital pruritus, vaginitis, back pain, peripheral edema.

Local reactions at the site of administration:

Intravenous administration: phlebitis and inflammation;

Intramuscular administration: pain at injection site, inflammation.

Laboratory test abnormalities occurring rarely and with transient character.

Laboratory findings: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin; anemia, eosinophilia, prolonged prothrombin time or partial thromboplastin time, and positive Coombs test without hemolysis. Transient increases in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, and transient thrombocytopenia were observed in less than 0.5% of patients. Leukopenia and neutropenia were also reported.

Local reactions at the site of intravenous infusion (phlebitis and inflammation) and following intramuscular injection occur rarely.

Adverse reactions characteristic of cephalosporin antibiotics are possible: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, bleeding, hepatic dysfunction, cholestasis, pancytopenia.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Administration and Dosage".

Packaging

1000 mg of powder for injection solution in vials, pack of 1 or 10 vials in cardboard boxes.

Prescription status

Prescription only.

Manufacturer

Zeiss Pharmaceuticals Pvt. Ltd.

Manufacturer's address

Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India

Marketing Authorization Holder

AAR PHARMA FZ-LLC, United Arab Emirates

Address of the Marketing Authorization Holder

Premises 702, 7th Floor, Building: DSC Tower, Post Box - 478837, Dubai, United Arab Emirates