Maxipime (Cefepime HCl)

MAXIPIME™

Bristol-Myers Squibb

Cefepime HCl

Antibiotic

Action And Clinical Pharmacology: Cefepime is a semi-synthetic broad spectrum cephalosporin antibiotic intended for i.m. or i.v. administration. Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. It has a broad spectrum of activity against a wide range of gram-positive and gram-negative bacteria.

The average elimination half-life of cefepime is approximately 2 hours, and does not vary with respect to dose over the range of 250 mg to 2 g. There was no accumulation in healthy subjects receiving doses up to 2 g i.v. every 8 hours for a period of 9 days. Total body clearance averages 120 mL/minute. The average renal clearance of cefepime is 110 mL/minute, suggesting that the compound is eliminated almost exclusively by renal mechanisms, primarily glomerular filtration. Urinary recovery of unchanged cefepime represents approximately 85% of dose, resulting in high concentrations of cefepime in the urine. The serum protein binding of cefepime averages 16.4% and is independent of its concentration in the serum. The average steady-state volume of distribution is 18 L.

Following i.m. administration, cefepime is completely absorbed. The pharmacokinetics of cefepime administered i.m. are linear over the range of 500 mg to 2 g and do not vary with respect to treatment duration.

Children: Cefepime pharmacokinetics have been evaluated in pediatric patients following single and multiple 50 mg/kg doses on q8h (n=29) and q12h (n=13) schedules. The mean (±SD) age of the patients was 3.6 (±3.3) years, and ranged from 2.1 months to 11.2 years. Following a single i.v. dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1.0) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The overall mean elimination half-life was 1.7 (±0.4) hours. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and renal clearance was the primary pathway of elimination, averaging 2.0 (±1.1) mL/min/kg. There were no significant differences in the pharmacokinetics of cefepime among pediatric patients of various ages or between male (n=25) and female patients (n=17). There was no evidence of accumulation of cefepime in patients treated for up to 14 days with either regimen. The absolute bioavailability of cefepime after an i.m. dose of 50 mg/kg was 82.3 (±15.6)% in 8 patients. The exposure to cefepime, including minimum plasma concentrations at steady state, following a 50 mg/kg i.v dose in a pediatric patient is comparable to that in adults treated with a 2 g i.v. dose.

Indications And Clinical Uses: In the treatment of the following infections when caused by susceptible strains of the designated microorganisms: Adults: Lower respiratory tract infections: nosocomial and community acquired pneumonia caused by P. aeruginosa, S. aureus (methicillin-susceptible strains), S. pneumoniae, E. coli and H. influenzae.

Acute exacerbations of chronic bronchitis caused by S. pneumoniae and H. influenzae.

Uncomplicated and complicated urinary tract infections, including pyelonephritis caused by P. aeruginosa, E. coli, K. pneumoniae and P. mirabilis.

Due to the nature of the underlying conditions which usually predispose patients to Pseudomonas infections of the lower respiratory and urinary tracts, a good clinical response accompanied by bacterial eradication may not be achieved despite evidence of in vitro sensitivity.

Skin and skin structure infections caused by S. aureus (methicillin-susceptible strains), S. pyogenes (Group A streptococci) and P. aeruginosa.

Peritonitis due to gangrenous and perforated appendicitis caused by E. coli.

Bacterial septicemia caused by E. coli, S. pneumoniae and K. pneumoniae.

Empiric Therapy in 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. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.

Specimens for bacteriologic culture should be obtained prior to therapy in order to identify the causative organisms and to determine their susceptibilities to cefepime.

Treatment with cefepime may be instituted empirically before results of susceptibility studies are known; however, modification of the antibiotic treatment may be required once these results become available.

In patients who are at risk of infection due to an anaerobic organism, concurrent initial therapy with an antianaerobic agent such as metronidazole or clindamycin is recommended before the causative organism(s) is (are) known. When such concomitant treatment is appropriate, the recommended doses of both antibiotics should be given according to the severity of the infection and the patient’s condition.

Children: In pediatric patients for the treatment of infections listed below when caused by susceptible bacteria:

Lower respiratory tract infections: nosocomial and community acquired pneumonia caused by P. aeruginosa, S. aureus (methicillin-susceptible strains), S. pneumoniae, E. coli, and H. influenzae.

Uncomplicated and complicated urinary tract infections, including pyelonephritis caused by P. aeruginosa, E. coli, K. pneumoniae, and P. mirabilis.

Skin and skin structure infections caused by S. aureus (methicillin-susceptible strains), S. pyogenes (Group A streptococci), and P. aeruginosa.

Empiric Therapy in 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. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.

Specimens for bacteriologic culture should be obtained prior to therapy in order to identify the causative organisms and to determine their susceptibilities to cefepime.

Treatment with cefepime may be instituted empirically before results of susceptibility studies are known; however, modification of the antibiotic treatment may be required once these results become available.

Contra-Indications: In patients who have had previous hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Manufacturers’ Warnings In Clinical States: Before therapy with cefepime is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins or other beta-lactam antibiotics. Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. If an allergic reaction to cefepime occurs, discontinue the drug and institute supportive treatment as appropriate (e.g., maintenance of ventilation, pressor amines, antihistamines, corticosteroids). Serious immediate hypersensitivity reactions may require epinephrine and other supportive therapy.

Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics including cefepime; therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with the use of antibiotics.

Treatment with broad-spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. 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 may respond to drug discontinuation alone. In moderate to severe cases, management should include fluids and electrolytes and protein supplementation. When colitis does not improve after drug discontinuation or when it is severe, it should be treated with an antibiotic clinically effective against C. difficile. Other causes of colitis should also be considered.

Precautions: General: As with other antibiotics, prolonged use of cefepime may result in overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Cefepime should be used with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Drug Interactions: The combination of cefepime with an aminoglycoside has been shown to be synergistic in vitro. Although there is no evidence that cefepime adversely affects renal function at normal therapeutic doses, the usual precautions with respect to combining a cephalosporin with an aminoglycoside should be applied.

Pregnancy: There are no adequate and well-controlled studies in pregnant women.

Reproduction studies performed in mice and rats showed no evidence of fetal damage at dose levels equivalent to (mouse) or slightly greater (rat) than the maximum human daily dose when the daily doses are compared to those in man on a mg/mbasis. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk.

Lactation: Cefepime is excreted in human breast milk in very low concentrations. Although less than 0.01% of a 1 g i.v. dose is excreted in milk, caution should be used when cefepime is administered to a nursing woman.

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 (nosocomial and community acquired), and as empiric therapy in febrile neutropenic patients, have been established in the age groups 2 months up to 12 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 (see Pharmacology and Adverse Effects).

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.

Geriatrics: Healthy elderly male and female volunteers (³65 years old) who received a single 1 g i.v. dose of cefepime had higher area under the curve (AUC) and lower renal clearance values when compared to younger subjects. However, this appeared to be a function of the decrease in creatinine clearance with increasing age. In patients with age-normalized renal function, a dosage adjustment of cefepime is not necessary.

In clinical studies, the safety and efficacy of cefepime were comparable in elderly patients and nonelderly adult patients receiving the usual recommended adult dose.

Hepatic Impairment: The pharmacokinetics of cefepime were unaltered in patients with impaired hepatic function who received a single 1 g dose. Therefore, dosage adjustments are not required in patients with hepatic impairment.

Renal Impairment: Elimination half-life is prolonged in patients with various degrees of renal insufficiency, with a linear relationship between total body clearance and creatinine clearance. This serves as the basis for dosage adjustment recommendations in this group of patients (see Dosage). The average half-life is 13 hours in patients with severe renal impairment requiring hemodialysis and 19 hours in those requiring continuous ambulatory peritoneal dialysis.

Cystic Fibrosis: The pharmacokinetics of cefepime do not change to a clinically significant degree in patients with cystic fibrosis. It is not necessary to alter the dosage of cefepime in this patient population.

Adverse Reactions: Cefepime is generally well tolerated. In clinical trials (N=5 598) the most common adverse events were gastrointestinal symptoms and hypersensitivity reactions. Adverse events considered to be of probable relationship to cefepime are listed below.

Events that occurred at an incidence of >0.1 to 1% (except where noted) were:

Hypersensitivity: rash (1.8%), pruritus, urticaria.

Gastrointestinal: nausea, vomiting, oral moniliasis, diarrhea (1.2%), colitis (including pseudomembranous colitis).

CNS: headache.

Other: fever, erythema.

Events that occurred between 0.05 to 0.1% were: abdominal pain, constipation, vasodilation, dyspnea, dizziness, paresthesia, genital pruritus, taste perversion, chills, unspecified moniliasis, vaginal moniliasis, urogenital infection and vaginitis.

Local reactions at the site of i.v. infusion occurred in 5.2% of patients; these included phlebitis (2.9%) and inflammation (0.1%). I.M. administration of cefepime was very well tolerated with 2.6% of patients experiencing pain or inflammation at the injection site.

At the higher dose of 2 g q8h in febrile neutropenia, the incidence of probably related adverse events was higher among 1 048 patients who received this dose of cefepime in clinical trials. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%) and headache (1%).

Laboratory test abnormalities that developed during clinical trials in patients with normal baseline values were transient. Those that occurred at a frequency between 1 and 2% (unless noted) were: elevations in ALT (3.6%), AST (2.5%), alkaline phosphatase, total bilirubin, prothrombin time, and partial thromboplastin time (2.8%); anemia, eosinophilia and positive Coombs’ test without hemolysis (18.7%) also occurred. Additionally, increased phosphorous, decreased phosphorous (2.8%), increased calcium, decreased calcium (which was more common in elderly patients) and increased potassium were observed.

As with some other cephalosporins, transient elevations of blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in 0.5 to 1% of patients. Transient leukopenia and neutropenia were also seen.

Renal insufficiency and hepatic failure have been reported in conjunction with cefepime treatment. However, a causative relationship to cefepime therapy has not been determined. During postmarketing experience, encephalopathy has been reported in patients with renal impairment who received unadjusted doses of cefepime.

The following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, false positive test for urinary glucose and pancytopenia.

A similar safety profile has been experienced in infants and children relative to the adult population. No specific concerns have been identified.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Cefepime is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will aid in the removal of cefepime from the body. Peritoneal dialysis is of no value.

Dosage And Administration: Can be administered either i.v. or i.m. The dosage and route of administration should be determined according to the susceptibility of the causative organisms, the severity of the infection, and the condition and renal function of the patient.

Pediatrics (aged 2 months up to 12 years with normal renal function): Usual Recommended Dosages: Empiric treatment of febrile neutropenia: Patients >2 months of age with body weight 40 kg: 50 mg/kg i.v q8h for 7 to 10 days.

Pneumonia, urinary tract infections, skin and skin structure infections: Patients >2 months of age with body weight 40 kg: 50 mg/kg i.v q12h for 10 days.

For pediatric patients with body weights >40 kg, adult dosing recommendations apply. For patients older than 12 years who are 40 kg, the dosage recommendations for younger patients 40 kg should be used. Dosage in pediatric patients should not exceed the maximum recommended dosage in adults (2 g q8h). Experience with i.m. administration in pediatric patients is limited.

Infection: The usual duration of therapy is 7 to 10 days; however, more severe infections may require longer treatment.

Impaired Hepatic Function: No adjustment is necessary for patients with impaired hepatic function.

Impaired Renal Function: There is no need to adjust dosage in the elderly unless renal impairment is present.

Cefepime is excreted by the kidneys almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (creatinine clearance 50 mL/min), the dose of cefepime should be adjusted to compensate for the slower rate of renal elimination. The initial dose of cefepime is the same as in patients with normal renal function. An estimate of creatinine clearance should be made to determine the appropriate maintenance dose.

Children With Impaired Renal Function: Since urinary excretion is the primary route of elimination of cefepime in pediatric patients (see Pharmacology), an adjustment of the dosage of cefepime should also be considered.

A dose of 50 mg/kg in patients aged 2 months up to 12 years is comparable to a dose of 2 g in an adult.

Dialysis Patients: 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, cefepime may be administered at the same doses recommended for patients with normal renal function, i.e., 500 mg, 1 g or 2 g (depending on the severity of the infection) at a dosage interval of every 48 hours.

Route of Administration: I.V.: The i.v. route of administration is preferable for patients with severe or life-threatening infections, particularly if the possibility of shock is present.

For direct i.v. injection, the solution reconstituted as recommended (see Reconstitution and Compatibility) should be slowly injected directly into the vein over a period of 3 to 5 minutes. Alternatively, the injection can be made into the tubing of an administration set while the patient is receiving a compatible i.v. fluid.

For continuous i.v. infusion, reconstitute the 1 or 2 g vial as recommended (see Reconstitution and Compatibility) and add an appropriate quantity of the resulting solution to one of the compatible i.v. fluids in an i.v. administration set. The resulting solution should be administered over a period of approximately 30 minutes.

For intermittent i.v. infusion, a Y-tube administration set can be used with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

I.M.: Reconstituted as recommended (see Reconstitution and Compatibility) to a final concentration of 280 mg/mL and given by deep i.m. injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus).

Although cefepime can be constituted with 0.5 or 1% lidocaine HCl, it is usually not required since cefepime causes little or no pain upon i.m. administration.

Reconstitution: I.M. Injection: The following diluents may be used for constituting cefepime for i.m. injection: sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, bacteriostatic water for injection with paraben(s), bacteriostatic water for injection with benzyl alcohol, 0.5 or 1% lidocaine HCl.

Direct I.V. Injection: Constitute cefepime with 10 mL of sterile water for injection, 5% dextrose injection or 0.9% sodium chloride injection.

I.V. Infusion: Constitute the 1 g or 2 g vial as recommended and add an appropriate quantity of the resulting solution to one of the compatible i.v. fluids in an i.v. administration set.

At concentrations between 1 and 40 mg/mL, cefepime is compatible with the following i.v. infusion fluids: 0.9% sodium chloride injection, 5% or 10% dextrose injection, M/6 sodium lactate injection, 5% dextrose and 0.9% sodium chloride injection, Lactated Ringers and 5% dextrose injection and Normosol-R and Normosol-M in 5% dextrose injection.

Compatibility: Cefepime, prepared in 0.9% sodium chloride or 5% dextrose injection at a concentration of 4 mg of cefepime/mL, is stable for 72 hours under refrigeration (2 to 8°C) when admixed with: heparin (10 or 50 U/mL), potassium chloride (10 or 40 mEq/mL), theophylline (0.8 mg/mL in 5% dextrose injection).

Cefepime at a concentration of 40 mg/mL in 0.9% sodium chloride solution or 5% dextrose injection was found to be compatible with amikacin (6 mg/mL).

Solutions of cefepime, like solutions of most beta-lactam antibiotics, should not be added to solutions of ampicillin, metronidazole, vancomycin, gentamicin, tobramycin sulfate or netilmicin sulfate because of physical or chemical incompatibility. However, if concurrent therapy with cefepime is indicated, each of these antibiotics can be administered separately to the same patient.

As with all parenteral products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration whenever solution and container permit.

Stability and Storage: Store dry powder at room temperature (15 to 30°C) and protect from light. The dry powder may also be stored in the refrigerator (2 to 8°C), protected from light.

Solutions for i.m. or i.v. use reconstituted as well as diluted as recommended with sterile water for injection, 0.9% sodium chloride injection or 5% dextrose injection are stable for 72 hours when stored under refrigeration (2 to 8°C) and protected from light. Solutions reconstituted as well as diluted with diluents other than those listed above should be used immediately after reconstitution.

Note: Parenteral drugs should be inspected visually for particulate matter before administration, and not used if particulate matter is present.

As with other cephalosporins, the color of reconstituted solutions of cefepime may darken (colorless to amber) on storage, nevertheless, the product potency is not adversely affected.

Availability And Storage: Each single use vial of dry powder contains: cefepime HCl equivalent to 1 g and 2 g of cefepime activity. Nonmedicinal ingredients: L-arginine 725 mg per g of cefepime.

MAXIPIME™ Bristol-Myers Squibb Cefepime HCl Antibiotic

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