Zepim

Cefepime hydrochloride.

Each vial contains Cefepime hydrochloride equivalent to Cefepime, USP 1 g and L-arginine 0.71 g.

Pharmacology: Pharmacokinetics: The average plasma concentrations of cefepime observed in healthy adult male volunteers at various times following single 30 minute infusion (IV) of cefepime 500 mg and 1 g are summarized as: (See Table 1.)

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Absorption: Following intramuscular (IM) administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single IM injection are summarized as: (See Table 2.)

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Distribution: The average steady state volume of distribution of cefepime is 18.0 (±2.0) L. The protein binding of cefepime is approximately 20%.
Average concentrations of cefepime in specific body fluids (mcg/mL) and in specific tissues (mcg/g). (See Table 3.)

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Metabolism and Excretion: Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide and 2.5% as an epimer of cefepime. Since renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.

For the treatment of infection due to susceptible organisms. They include infections of the urinary tract, respiratory tract, and skin.

The recommended adult dosages and routes of administration are outlined in the following table. It should be administered intravenously over approximately 30 minutes. Recommended Dosage Schedule for Cefepime: (See Table 4.)

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*including cases associated with concurrent bacteremia.
** or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently.
*** IM route of administration is indicated only for mild to moderate, uncomplicated or complicated UTI's due to E. coli when the IM route is considered to be a more appropriate route of drug administration.
Impaired Hepatic Function: No adjustment is necessary for patients with impaired hepatic function.
Impaired Renal Function: In patients with impaired renal function (creatinine clearance ≦60 mL/min), the dose of Cefepime hydrochloride should be adjusted to compensate for the slower rate of renal elimination. The recommended initial dose of It should be the same as in patients with normal renal function. The recommended maintenance doses of Cefepime HCl in patients with renal insufficiency are presented in Table 6. When only serum creatinine is available, the following formula (Cockcroft and Gault equation) 3 may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function: (See Table 5.)

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Recommended Dosing Schedule for Cefepime in Adult Patients (Normal Renal Function, Renal Insufficiency, and Hemodialysis): (See Table 6.)

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In patients undergoing continuous ambulatory peritoneal dialysis, Cefepime HCl may be administered at normally recommended doses at a dosage interval of every 48 hours. In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Cefepime HCl for hemodialysis patients is 1 g on Day 1 followed by 500 mg q24h for the treatment of all infections except febrile neutropenia, which is 1 g q24h. It should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days. Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patient' changes in the dosing regimen proportional to those in adults are recommended for pediatric patients.
Administration: For Intravenous Infusion: Constitute the 1 g or 2 g piggyback (100 mL) bottle with 50 or 100 mL of a compatible IV fluid listed in the Compatibility and Stability subsection. Alternatively, constitute the 500 mg, 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids. The resulting solution should be administered over approximately in 30 minutes. Intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.
For Intramuscular/Intravenous Administration: Cefepime hydrochloride should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection: After reconstitution, solution is stable for 48 hours at temperatures not exceeding 30⁰C and 72 hours under refrigeration (2⁰C to 8⁰C);
0.5% or 1.0% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol: Use immediately after reconstitution.
Preparation of Solutions of Cefepime HCl: (See Table 7.)

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Solutions of Cefepime HCl, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg/mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with it is indicated, each of these antibiotics can be administered separately.

Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. Accidental overdosing might occur if large doses are given to patients with reduced renal function. In clinical trials, its over dosage occurred in a patient with renal failure (creatinine clearance <11 mL/min) who received 2g q24h for 7 days. The patient exhibited seizures, encephalopathy, and neuromuscular excitability.

Cefepime hydrochloride is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Prescribing Cefepime HCl in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. As with other antimicrobials, prolonged use of it may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken. Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or p.o. nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated. Positive direct Coombs' tests have been reported during treatment with Cefepime HCl. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs' test may be due to the drug. It should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Arginine has been shown to alter glucose metabolism and elevate serum potassium transiently when administered at 33 times the amount provided by the maximum recommended human dose of Cefepime. The effect of lower doses is not presently known.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term animal carcinogenicity studies have been conducted with cefepime. A battery of in vivo and in vitro genetic toxicity tests, including the Ames Salmonella reverse mutation assay, CHO/HGPRT mammalian cell forward gene mutation assay, chromosomal aberration and sister chromatid exchange assays in human lymphocytes, CHO fibroblast clastogenesis assay, and cytogenetic and micronucleus assays in mice were conducted. The overall conclusion of these tests indicated no definitive evidence of genotoxic potential. No untoward effects on fertility or reproduction have been observed in rats, mice, and rabbits when cefepime is administered subcutaneously at 1 to 4 times the recommended maximum human dose calculated on a mg/m2 basis.
Use in children: The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Cefepime in these age groups is supported by evidence from adequate and well controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials. Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Cefepime HCl in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b.
Use in elderly: Of the more than 6400 adults treated with Cefepime HCl in clinical studies, 35% were 65 years or older while 16% were 75 years or older. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.
Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

Pregnancy: Teratogenic Effects- Pregnancy Category B: Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (4 times the recommended maximum human dose calculated on a mg/m2 basis) or to mice at doses up to 1200 mg/kg (2 times the recommended maximum human dose calculated on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m2 basis). There are, however, no adequate and well-controlled studies of cefepime use in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Cefepime is excreted in human breast milk in very low concentrations [0.5 mcg/mL]. Caution should be exercised when cefepime is administered to a nursing woman.
Labor and Delivery: Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.

In patients with impaired renal function (creatinine clearance ≤60 mL/min), the dose of it should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms. (See specific recommendations for dosing adjustment under Dosage & Administration). During postmarketing surveillance, serious adverse events have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma under Dosage & Administration), myoclonus, and seizures. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules.
However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Cefepime, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with it because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DE01 - cefepime ; Belongs to the class of fourth generation cephalosporins. Used in the systemic treatment of infections.

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