Cefepime aurobindo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CEFEPIME AUROBINDO

Composition:

Active substance: cefepime;

1 vial contains cefepime hydrochloride equivalent to cefepime – 500 mg, 1000 mg or 2000 mg;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group. Antimicrobials for systemic use. Other beta-lactam antibiotics. Cephalosporins. ATC code J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime is a fourth-generation β-lactam cephalosporin antibiotic with a broad spectrum of activity for parenteral administration. It exhibits bactericidal action. It is active against both 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 effects of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 is significantly higher than that of other parenteral cephalosporins. Moderate affinity of cefepime to PBPs 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) ratio for cefepime is less than 2 for over 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits the synthesis of bacterial cell wall enzymes. The drug has low affinity for chromosomally mediated β-lactamases.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains (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 1 mcg/mL); other β-hemolytic streptococci (groups C, G, F); S. bovis (group D); viridans group streptococci (most enterococcal 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 (including subspecies 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 spp. (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 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 males at various time points after single intravenous and intramuscular administration are shown in Table 1.

Plasma concentrations of cefepime (mcg/mL) following intravenous (IV) and intramuscular (IM) administration

Table 1

Cefepime dose	0.5 hour	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 IM	14.8	25.9	26.3	16.0	4.5	1.4
2 g IM	36.1	49.9	51.3	31.5	8.7	2.3

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 and is independent of dose within the range of 250 mg – 2 g. No drug accumulation was observed with intravenous doses up to 2 g administered every 8 hours over 9 days.

Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted into the N-methylpyrrolidine oxide. Cefepime is primarily eliminated via glomerular filtration (total cefepime clearance is approximately 120 mL/min, with average hepatic clearance of 110 mL/min). Approximately 80–85% of the administered dose is excreted unchanged in urine, 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as the cefepime epimer. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in blood serum.

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

In patients with renal impairment, the elimination half-life of cefepime is prolonged, and a linear relationship exists between total drug clearance and creatinine clearance. The half-life in patients with severe renal dysfunction requiring hemodialysis is 13 hours, and 19 hours in those undergoing continuous ambulatory peritoneal dialysis. Dose adjustment should be individualized in patients with abnormal renal function.

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

Children. Pharmacokinetic studies of cefepime were conducted in children aged 2 months to 11 years after single or multiple doses administered every 8 or 12 hours. After a single intravenous injection, the average 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. Urinary excretion of unchanged cefepime was 60.4 (30.4)% of the administered dose, and average renal clearance was 2 (1.1) mL/min/kg. Patient age and sex did not significantly affect total drug 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, plasma maximum concentration, area under the curve, and half-life increased by approximately 15% at steady state. Cefepime exposure in children after intravenous administration of 50 mg/kg is similar to that in adults after intravenous administration of 2 g. After intravenous administration, the average steady-state maximum plasma concentration of cefepime was 68 µg/mL, reached within 0.75 hours. Eight hours after intramuscular administration, the average plasma concentration of cefepime was 6 µg/mL. The absolute bioavailability of cefepime after intramuscular injection averaged 82%.

Due to the inability to identify the causative infectious agent and determine its antibiotic susceptibility, or due to time constraints, cefepime may be used for empirical therapy, as it has a broad spectrum of antibacterial activity. In patients at risk of mixed aerobic-anaerobic infection, treatment with cefepime may be initiated before pathogen identification, in combination with an anti-anaerobic agent.

Indications.

Adults.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract infections, including pneumonia and bronchitis;
• skin and soft tissue infections;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• gynecological 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 soft tissue infections;
• septicemia;
• empirical therapy in patients with febrile neutropenia;
• bacterial meningitis.

Contraindications.

Cefepime is contraindicated in patients with hypersensitivity to cefepime or any excipients in the formulation, to other cephalosporins, or to other beta-lactam antibiotics (e.g., penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other forms of interaction.

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 after concomitant use 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; 5% and 10% dextrose injection; 6 M sodium lactate injection; 5% dextrose and 0.9% sodium chloride injection; Ringer’s lactate with 5% dextrose injection.

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

Effect on laboratory test results.

Cefepime may cause false-positive urine glucose tests when using Benedict’s reagent. It is recommended to use glucose tests based on the enzymatic glucose oxidase reaction.

Special precautions for use.

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

It is essential to determine whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any form of allergy, particularly drug allergies. If an allergic reaction occurs, the drug must be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders (particularly in the medical history), especially colitis.

During prolonged treatment, regular monitoring of liver, kidney, and hematopoietic system function is required.

Cases of pseudomembranous colitis have been reported with the use of nearly all broad-spectrum antibiotics. Therefore, pseudomembranous colitis must be considered in the differential diagnosis whenever diarrhea occurs during cefepime therapy. The severity of pseudomembranous colitis may range from mild diarrhea to fatal colitis. Evidence suggests that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. Once pseudomembranous colitis is diagnosed, appropriate therapeutic measures should be initiated. Mild to moderate cases may resolve after discontinuation of the drug. In cases of moderate or severe colitis, appropriate management including fluid and electrolyte replacement, protein supplementation, and administration of an antimicrobial agent effective against Clostridium difficile should be considered.

In patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because prolonged serum antibiotic concentrations may occur when standard doses of cefepime are administered to patients with renal impairment or other conditions that may compromise renal function, the maintenance dose of cefepime should be reduced in such patients. The next dose of cefepime should be determined based on the degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic. During post-marketing surveillance of cefepime products, severe, life-threatening, or fatal adverse events have been reported, including encephalopathy (altered mental status, including confusion, hallucinations, stupor, and coma), myoclonia, and seizures. Most cases occurred in patients with impaired renal function who received doses exceeding the recommended levels. Some cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity 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, will be beneficial. Such use may increase the risk of emergence of bacteria resistant to this drug. 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. High-risk patients include those with hepatic or renal dysfunction, poor nutritional status, or those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in high-risk patients, and vitamin K should be administered if necessary.

Since the formulation contains L-arginine, the drug is also contraindicated in patients with hypersensitivity to L-arginine and in patients with acidosis. Therefore, the drug should be used with caution in patients with hyperkalemia.

During cefepime therapy, positive results in the direct Coombs test may occur. When performing hematological or transfusion procedures, including blood group cross-matching, antiglobulin testing, or Coombs test in newborns whose mothers received cephalosporin antibiotics before delivery, a positive Coombs test should be considered a potential consequence of 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.

Use during pregnancy or breastfeeding.

Cefepime may be administered during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime is excreted in breast milk in small amounts; therefore, breastfeeding should be discontinued during treatment with this drug.

Effect on the ability to drive or operate machinery.

The effect of cefepime on the ability to drive or operate machinery has not been studied. However, it should be noted that adverse reactions affecting the nervous system may occur during treatment.

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

Table 2

Infection	Dosage	Frequency of administration
Urinary tract infections of mild to moderate severity	500 mg - 1 g IV or IM	every 12 hours
Other infections of mild to moderate severity	1 g IV or IM	every 12 hours
Severe infections	2 g IV	every 12 hours
Very severe and life-threatening infections	2 g IV	every 8 hours

For prevention of infections during surgical procedures. Administer 2 g of the drug intravenously over 30 minutes, 60 minutes before the start of surgery. After completion, additionally administer 500 mg of metronidazole intravenously. Metronidazole solutions should not be administered simultaneously with cefepime. The infusion system must 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. Cefepime is eliminated by the kidneys via glomerular filtration; therefore, the dose must be adjusted in patients with impaired renal function (creatinine clearance less than 30 mL/min) (Table 3).

Recommended doses of cefepime for adults

Table 3

Creatinine clearance (mL/min)	Recommended doses
> 50	No dose adjustment 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 every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

*On the day of dialysis, the injection must be administered after the procedure.

If only serum creatinine concentration is known, creatinine clearance can be calculated using the formula provided 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 removed from the body over 3 hours. After each dialysis session, an additional dose equal to the initial dose should be administered. For continuous ambulatory peritoneal dialysis, the drug may be used at the standard initial recommended doses of 500 mg, 1 g, or 2 g, depending on the severity of infection, with a dosing interval of 48 hours.

Children aged 1 to 2 months. The drug should be administered only for life-threatening indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the severity of infection. Children weighing less than 40 kg receiving cefepime therapy must be closely monitored.

Children aged 2 months and older. The maximum dose in 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. Children weighing 40 kg or more should receive cefepime doses recommended for adults.

In 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)

The drug can be administered by deep intramuscular injection (0.5 g and 1 g), slow intravenous injection, or infusion (over 3–5 minutes up to 30 minutes).

Intravenous administration. Cefepime should be reconstituted with water for injection or any other compatible diluent at concentrations specified in Table 3. Solutions for intravenous administration may be given directly into the vein by slow (3–5 minutes) injection via an intravenous line or directly into a compatible infusion solution (administered over 30 minutes).

For intravenous administration, cefepime is compatible with the following diluents: water for injection, 0.9% sodium chloride solution for injection (with or without 5% dextrose); 5% and 10% dextrose solutions for injection; 1/6 M sodium lactate solution for injection; Ringer's lactate solution (with or without 5% dextrose).

Intramuscular administration. The drug can be reconstituted with 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 concentrations specified in Table 4.

When lidocaine is used as a diluent, a skin test for tolerance should be performed before administration.

Table 4

Route of administration	Volume of diluent (ml)	Approximate volume of resulting solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous administration: 500 mg/vial 1 g/vial 2 g/vial	5 10 10	5.7 11.4 12.8	90 90 160
Intramuscular administration: 500 mg/vial 1 g/vial	1.5 3	2.2 4.4	230 230

As with other parenterally administered medicinal products, prepared solutions of the drug should be inspected for the presence of mechanical particles before administration.

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

Children.

The drug may be administered to children aged 1 month 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, disturbances of 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

Infections and infestations:

Uncommon: oral candidiasis, vaginal infections;
Rare: candidiasis.

Blood and lymphatic system disorders:

Very common: positive Coombs test;
Common: prolonged prothrombin time or partial thromboplastin time (PTT), anemia, eosinophilia;
Uncommon: thrombocytopenia, leukopenia, neutropenia;
Not known: aplastic anemia¹, hemolytic anemia¹, agranulocytosis.

Immune system disorders:

Rare: hypersensitivity reactions, including anaphylaxis, angioneurotic edema;
Not known: anaphylactic shock.

Metabolism and nutrition disorders:

Not known: pseudopositive glucose urine test.

Psychiatric disorders:

Not known: confusion, hallucinations.

Nervous system disorders:

Uncommon: headache;
Rare: seizures, paresthesia, dysgeusia, dizziness;
Not known: insomnia, restlessness, epileptiform seizures, encephalopathy (loss of consciousness, hallucinations, stupor, coma), myoclonia, altered state of consciousness.

Cardiac and vascular disorders:

Rare: vasodilation;
Not known: tachycardia, hemorrhage¹.

Respiratory system disorders:

Rare: respiratory disorders;
Not known: cough, sore throat, dyspnea.

Gastrointestinal disorders:

Common: diarrhea;
Uncommon: colitis, pseudomembranous colitis, nausea, vomiting;
Rare: abdominal pain, constipation;
Not known: dyspepsia, gastrointestinal disorders.

Hepatobiliary disorders:

Common: increased levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin;
Not known: hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders:

Common: rash;
Uncommon: pruritus, urticaria, erythema;
Not known: Stevens-Johnson syndrome¹, erythema multiforme¹, toxic epidermal necrolysis¹.

Renal and urinary disorders:

Uncommon: increased blood urea nitrogen, increased serum creatinine;
Not known: renal failure, nephrotoxicity.

Reproductive system and breast disorders:

Rare: genital pruritus.

General disorders and administration site conditions:

Common: infusion site reactions, injection site pain, injection site inflammation;
Uncommon: fever, infusion site inflammation;
Rare: chills;
Not known: phlebitis.

Laboratory findings:

Not known: increased alkaline phosphatase levels, transient increase in blood urea nitrogen and/or serum creatinine, transient leukopenia, neutropenia, agranulocytosis, transient thrombocytopenia.

Other:

Not known: asthenia, sweating, vaginitis, chest pain, back pain, peripheral edema.

Possible adverse reactions typical for cephalosporin antibiotics: aplastic anemia, hemolytic anemia, hemorrhage, liver function disorders, cholestasis, pancytopenia.

¹ Adverse reactions reported during use of other drugs of this class.

Pediatric patients

The safety profile of cefepime in pediatric patients is similar to that observed in adults.

The most frequently reported adverse reaction in clinical studies is rash.

Shelf life

2 years.

Storage conditions

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

The reconstituted solution should be stored for no more than 24 hours at room temperature, or for no more than 7 days at 2–8 °C.

Incompatibility

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

Packaging

1 vial of powder per carton.

Prescription status

Prescription only.

Manufacturer

Aurobindo Pharma Ltd.

Manufacturer's address

Unit-VI, Sy. No. 329/39 & 329/47, Chitkul Village, Patancheru Mandal Medak District, Andhra Pradesh, India.