- Description & Properties:
Cefepime dihydrochloride monohydrate is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration.
ACEPIME (cefepime dihydrochloride monohydrate) for injection is supplied for intramuscular or intravenous administration in strengths equivalent to 500mg, 1g and 2g of cefepime.
ACEPIME is a sterile, dry mixture of cefepime dihydrochloride monohydrate and L-arginine. Freshly constituted solutions of ACEPIME will range in color from colorless to amber.

- Mechanism of Action and Phaemacodynamics:
Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of gram-positive and gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most betalactamases and exhibits rapid penetration into gram-negative bacterial cells.
Cefepime has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:
Aerobic Gram-Negative Microorganisms: Enterobacter, Escherichia coli, Klebsiella pneumoniae, proteus mirabilis, pseudomonas aeruginosa.
Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (methicillinsusceptible strains only), Streptococcus pneumoniae, Streptococcus pyogenes (Lancefield`s Group A streptococci).

- Pharmacokinetics:
Following intramuscular (IM) administration, Cefepime is completely absorbed. The pharmacokinetics of Cefepime are linear over the range of 500mg to 2g IM and do not vary with respect to treatment duration.
Elimination of Cefepime is principally via renal excretion with an average half-life of 2.0 hours and total body clearance of 120.0 ml/min in healthy volunteers.
The serum protein binding of Cefepime is approximately 20% and is independent of its concentration in serum. Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 ml of human milk per day would receive approximately 0.5mg of Cefepime per day. Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide).
Approximately 85% of the administered dose is recovered in the urine as unchanged Cefepime and the rest is recovered as metabolites. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment. Dosage administration of Cefepime in the elderly should be adjusted as appropriate if the patient`s creatinine clearance is 60 ml/min or less.

- Indications:
ACEPIME (Cefepime dihydrochloride monohydrate) is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:
- Pneumonia (moderate to severe) caused by Stretococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
- Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate.
- Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae.
- Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
- Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, virdans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.

- Contraindications:
ACEPIME (cefepime dihydrochloride monohydrate) is contraindicated in patients who have shown immediate hypersensitivity reactions to Cefepime or the cephalosporin class of antibiotics, penicillin or other betalactam antibiotics.

- Side Effects:
The most common adverse events related to Cefepime include Local reactions, including phlebitis, pain and / or inflammation; and rash. The less common adverse events include colitis (including pseudomembranous colitis), diarrhea, fever, headach, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting.

- Precautions & Warnings :
Before therapy with Cefepime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to Cefepime, Cephalosporines, Penicillines, or other drugs. If an allergic reaction occurs, the drug should be discontinued. Serious acute hypersensitivity reactions require treatment with epinephrine and other emergency measures.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ACEPIME, 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 difficileis a primary cause of “ antibiotic-associated colitis”.
As with other antimicrobials, prolonged use of ACEPIME 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, 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.
ACEPIME should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
In patients with impaired renal function (creatinine clearance ≤ 60 ml/min), the dose of ACEPIME should be adjusted to compensate for the slower rate of renal elimination. Serious adverse events including encephalopathy, myoclonus, seizures, and renal failure have been reported postmarketing in patients with renal impairment treated with unadjusted doses of Cefepime.
If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
Precautions should be taken to  adjust daily dosage in patients with renal insufficiency or other conditions that may compromise renal function to reduce antibiotic concentrations that can lead or contribute to these and other serious adverse events, including renal failure.
This product is intended for use in patients 12 years of age and older.
This drug should be used during pregnancy only if clearly needed. Caution should be exercised when Cefepime is administered to a nursing woman.

- Drug & Food Interactions:
Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with ACEPIME 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.

- Drug \ Clinical Laboratory Test Interactions:
The administration of Cefepime may result in a false-positive reaction for glucose in the urine when using Clinitest ® tablets. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Cefepime may also cause positive Coombs` test (without hemolysis); decreased phosphorous; increased SGPT, SGOT, eosinophils; and abnormal PTT, and PT.

- Dosage & Administration:
- Moderate to Severe Pneumonia : 1- 2 g  IV, every 12h , for 10 days.
- Empiric Therapy for Febrile Neutropenic Patients: 2 g IV , every 8h , for 7 days.
- Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis: 0.5- 1g , IV/ IM, every 12h , for 7- 10 days.
- Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis: 2 g IV , every 12h , for 10 days.
- Moderate to Severe Uncomplicated Skin and Skin Structure Infections: 2 g IV, every 12h , for 10 days.
- Complicated Intra-abdominal Infections (used in combination with metronidazole, separately): 2 g IV, every 12h , for 7- 10 days.
- Impaired Renal Function: The recommended initial dose of ACEPIME should be the same as in patients with normal renal function. The recommended maintenance doses of ACEPIME in patients with renal insufficiency are presented in the following table:
Recommended Maintenance Schedule in Adult Patients with Renal Impairment Relative to Normal Recommended Dosing Schedule: 

Creatinine Clearance (ml/min)	Recommended Maintence Schedule
>60 normal recommended dosing schedule	500mg q 12h	1g q 12h	2g q 12h	2g q 8h
30- 60	500mg q 24h	1g q 24h	2g q 24h	2g q 12h
11- 29	500mg q 24h	500mg q 24h	1g q 24h	2g q 24h
<11	250mg q 24h	250mg q 24h	500mg q 24h	1g q 24h

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. A repeat dose, equivalent to the initial dose, should be given at the completion of each dialysis session
 
In patients undergoing continuous ambulatory peritoneal dialysis, ACEPIME may be administered at normally recommended doses at a dosage interval of every 48 hours.

-  Administration
- For Intravenous Use: For IV administration, the vials 500mg, 1g, or 2g should be constituted by adding the appropriate volumes, as shown below, of one of the following IV fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection , sodium lactate injection, 5% Dextrose and 0.9% sodium chloride injection, Lactated Ringers and 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20˚- 30˚ C or 7 days in a refrigerator 2˚- 8˚ C.
THE RESULTING SOLUTION SHOULD BE ADMINISTERED OVER APPROXIMATELY 30 MINUTES.
- Intramuscular Administration : For IM administration, ACEPIME (Cefepime dihydrochloride monohydrate) should be reconstituted, as shown below, with one of the following diluents: Sterile Water for Injection, 0.9% sodium chloride, 5% dextrose injection, 0.5% or 1.0% lidocaine hydrochloride, or sterile bacteriostatic water for injection with parabens or benzyl alcohol. The resulting solutions are stable for 24 hours at controlled room temperature 20˚-25˚ C or for 7 days in a refrigerator 2˚- 8˚ C.

Preparation of Solutions of ACEPIME:

Single Dose Vials for Intravenous / Intramuscular Administration	Amount of Diluent to be Added (ml)	Approximate Available Volume (ml)	Approximate Cefepime Concentration (mg/ml)
500mg (IV)	5.0	5.6	100
500mg (IM)	1.3	1.8	280
1g (IV)	10.0	11.3	100
1g (IM)	2.4	3.6	280
2g (IV)	10.0	12.5	160