Data from FDA - Curated by EPG Health - Last updated 22 December 2016

Indication(s)

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime for Injection USP and Dextrose Injection USP and other antibacterial drugs, Cefepime for Injection USP and Dextrose Injection USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Cefepime for Injection USP and Dextrose Injection USP is a cephalosporin antibacterial indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms: Moderate to severe pneumonia (1.1); empiric therapy for febrile neutropenic patients (1.2); uncomplicated and complicated urinary tract infections (1.3); moderate to severe uncomplicated skin and skin structure infections (1.4); and complicated intra-abdominal infections (used in combination with metronidazole) (1.5).

1.1 Pneumonia Cefepime for Injection USP and Dextrose Injection USP is indicated for pneumonia (moderate to severe) caused by Streptococcus pneumoniae (including cases associated with concurrent bacteremia), Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.

1.2 Empiric Therapy for Febrile Neutropenic Patients Cefepime for Injection USP and Dextrose Injection USP 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 [see Clinical Studies (14.1)].

1.3 Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) Cefepime for Injection USP and Dextrose Injection USP is indicated for uncomplicated and complicated urinary tract infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.

1.4 Uncomplicated Skin and Skin Structure Infections Cefepime for Injection USP and Dextrose Injection USP is indicated for moderate to severe uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

1.5 Complicated Intra-abdominal Infections Cefepime for Injection USP and Dextrose Injection USP is indicated for complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis [see Clinical Studies (14.2)].

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Advisory information

contraindications

4 CONTRAINDICATIONS Hypersensitivity to cefepime or other cephalosporin class antibiotics, penicillins, or other beta-lactam antibiotics (4.1) Hypersensitivity to corn products (4.2) 4.1 Hypersensitivity to Cefepime or the Cephalosporin Class of Antibiotics, Penicillins, or Other Beta-lactam Antibiotics Cefepime for Injection USP and Dextrose Injection USP is contraindicated in patients who have a history of immediate hypersensitivity reactions (e.g., anaphylaxis, serious skin reactions) to cefepime or the cephalosporin class of antibiotics, penicillins, or other beta-lactam antibiotics [see Warnings and Precautions (5.1)].

4.2 Hypersensitivity to Corn Products Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products.

Adverse reactions

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hypersensitivity reactions [see Warnings and Precautions (5.1)] Renal Impairment [see W arnings and Precautions (5.2)] Neurotoxicity [see Warnings and Precautions (5.3)] Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.4)] Most common adverse reactions (incidence greater than 1 %): Local reactions (including phlebitis, pain and/or inflammation) and rash.

(6.1) At the highest dose (2 g every 8 hours), incidence of adverse reactions was equal to or greater than 1 % for rash, diarrhea, nausea, vomiting, pruritis, fever, and headache.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials using multiple doses of cefepime, 4137 patients were treated with the recommended dosages of cefepime (500 mg to 2 g intravenously every 12 hours).

There were no deaths or permanent disabilities thought related to drug toxicity.

Sixty-four (1.5 %) patients discontinued medication due to adverse reactions thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity.

Thirty-three (51 %) of these sixty-four patients who discontinued therapy did so because of rash.

The percentage of cefepime-treated patients who discontinued study drug because of drug-related adverse reactions was similar at daily doses of 500 mg, 1 g, and 2 g every 12 hours (0.8 %, 1.1 %, and 2.0 %, respectively).

However, the incidence of discontinuation due to rash increased with the higher recommended doses.

The following adverse reactions were thought to be probably related to cefepime during evaluation of the drug in clinical trials conducted in North America (n=3125 cefepime-treated patients).

Table 3: Adverse Clinical Reactions Cefepime Multiple-dose Dosing Regimens Clinical Trials - North America Incidence equal to or greater than 1 % Local reactionsLocal reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048).

(3.0 %), including phlebitis (1.3 %), pain and/or inflammation (0.6 %); rash (1.1 %) Incidence less than 1 % but greater than 0.1 % Colitis (including pseudomembranous colitis), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, anemia At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse reactions was higher among the 795 patients who received this dose of cefepime.

Reactions included rash (4 %), diarrhea (3 %), nausea (2 %), vomiting (1 %), pruritus (1 %), fever (1 %), and headache (1 %).

The following adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America.

Table 4: Adverse Laboratory Changes Cefepime Multiple-dose Dosing Regimens Clinical Trials - North America Incidence equal to or greater than 1 % Positive Coombs ' Test (without hemolysis) (16.2 %); decreased phosphorus (2.8 %); increased ALT/SGPT (2.8 %), AST/SGOT (2.4 %); eosinophils (1.7 %); abnormal PTT (1.6 %), PT (1.4 %) Incidence less than 1 % but greater than 0.1 % Increased alkaline phosphatase, BUN, calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calciumHypocalcemia was more common among elderly patients.

Clinical consequences from changes in either calcium or phosphorus were not reported., hematocrit, neutrophils, platelets, WBC 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of cefepime.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

Anaphylaxis (including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia) has been reported.

Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported.

Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of neurotoxicity occurred in patients receiving an appropriate dosage adjustment for their degree of renal impairment.

If neurotoxicity associated with cefepime therapy occurs, consider discontinuing cefepime or making appropriate dosage adjustments in patients with renal impairment.

6.3 Cephalosporin-class Adverse Reactions In addition to the adverse reactions listed above that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic impairment including cholestasis, and pancytopenia.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION For intravenous use only over approximately 30 minutes.

(2) Use this formulation of cefepime only in patients who require the entire 1 or 2 gram dose and not any fraction thereof.

(2.1) Recommended Dosing Schedule in Adult Patients with CrCL greater than 60 mL/min (2.1)Adjust dose in patients with CrCL less than or equal to 60 mL/min.

(2.2) Site and Type of Infection Dose Frequency Duration Moderate to severe pneumonia For Pseudomonas aeruginosa, use 2 g IV every 8 hours (2.1) 1 or 2 g IV Every 8-12 hours 10 days Empiric therapy for febrile neutropenic patients 2 g IV Every 8 hours 7 daysOr until resolution of neutropenia.

(2.1) Mild to moderate uncomplicated or complicated urinary tract infections 0.5 or 1 g IV Every 12 hours 7-10 days Severe uncomplicated or complicated urinary tract infections 2 g IV Every 12 hours 10 days Moderate to severe uncomplicated skin and skin structure infections 2 g IV Every 12 hours 10 days Complicated intra-abdominal infections (used in combination with metronidazole) 2 g IV Every 8-12 hours 7-10 days Pediatric Patients (2 months to 16 years) 50 mg per kg per dose every 12 hours (every 8 hours for febrile neutropenia).

(2.1) Use this formulation of cefepime only in pediatric patients who require the entire 1 or 2 gram dose and not any fraction thereof.

(2.1) 2.1 Adult and Pediatric Population Cefepime for Injection USP and Dextrose Injection USP in the DUPLEX® Container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof.

The recommended adult and pediatric dosages and routes of administration are outlined in Table 1.

Cefepime for Injection USP and Dextrose Injection USP should be administered intravenously (IV) over approximately 30 minutes.

Table 1: Recommended Dosing Schedule for Cefepime for Injection USP and Dextrose Injection USP in Patients with CrCL Greater Than 60 mL/min Adjust dose in patients with CrCL less than or equal to 60 mL/min (2.2) Site and Type of Infection Dose Frequency Duration (days) Adults Moderate to Severe Pneumonia due to S. pneumoniae Including cases associated with concurrent bacteremia, P. aeruginosa ForPseudomonas aeruginosa, use 2 g IV every 8 hours (50 mg per kg per dose in pediatric patients 2 months up to 16 years).

, K. pneumoniae, or Enterobacter species 1-2 g IV Every 8-12 hours 10 Empiric therapy for febrile neutropenic patients [see Indications and Usage (1) and Clinical Studies (14)] 2 g IV Every 8 hours 7Or 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.

Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli, K. pneumoniae, or P. mirabilis 0.5-1 g IV Every 12 hours 7-10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli or K.

pneumoniae 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes 2 g IV Every 12 hours 10 Complicated intra-abdominal infections (used in combination with metronidazole) caused by E. coli, viridans group streptococci, P. aeruginosa, K. pneumoniae, Enterobacter species, or B. fragilis.

[see Clinical Studies (14)] 2 g IV Every 8-12 hours 7-10 Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose.

The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given above.

Cefepime for Injection USP and Dextrose Injection

USP in the DUPLEX®

Container is designed to deliver a 1 g or 2 g dose of cefepime.

To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of cefepime.

2.2 Patients with Renal Impairment In patients with creatinine clearance less than or equal to 60 mL/min, the dose of Cefepime for Injection USP and Dextrose Injection USP should be adjusted to compensate for the slower rate of renal elimination.

The recommended initial dose of Cefepime for Injection USP and Dextrose Injection USP should be the same as in patients with normal renal function except in patients undergoing hemodialysis.

The recommended maintenance doses of Cefepime for Injection USP and Dextrose Injection USP in patients with renal impairment are presented in Table 2.

Cefepime for Injection USP and Dextrose Injection USP in the DUPLEX® Container should be used only in patients who require the entire 1 or 2 gram dose and not any fraction thereof.

When only serum creatinine is available, the following formula (Cockcroft and Gault equation)1 may be used to estimate creatinine clearance [see References (15)].

The serum creatinine should represent a steady state of renal function: Males: Creatinine Clearance (mL/min) = Weight (kg)?

(140-age) 72?

serum creatinine (mg/dL) Females: 0.85?

above value Table 2: Recommended Dosing Schedule for Cefepime for Injection USP and Dextrose Injection USP in Adult Patients (Normal Renal Function, Renal Impairment, and Hemodialysis) Creatinine Clearance (mL/min) Recommended Maintenance Schedule Greater than 60 (Normal recommended dosing schedule) 500 mg every 12 hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30-60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11-29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours Less than 11 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours CAPD 500 mg every 48 hours 1 g every 48 hours 2 g every 48 hours 2 g every 48 hours HemodialysisOn hemodialysis days

Cefepime for Injection USP and Dextrose Injection USP should be administered following hemodialysis.

Whenever possible, Cefepime for Injection USP and Dextrose Injection USP should be administered at the same time each day.

1 g on day 1, then 500 mg every 24 hours thereafter 1 g every 24 hours In patients undergoing continuous ambulatory peritoneal dialysis, Cefepime for Injection USP and Dextrose Injection USP may be administered at normally recommended doses at a dosage interval of every 48 hours (see Table 2).

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 for Injection USP and Dextrose Injection USP for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours.

Cefepime for Injection USP and Dextrose Injection USP should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 2).

2.3 Preparation for Use of Cefepime for Injection USP and Dextrose Injection USP in DUPLEX® Container This reconstituted solution is for intravenous use only.

Do not use plastic containers in series connections.

Such use would result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Use only if solution is clear and container and seals are intact.

DUPLEX® Container Storage To avoid inadvertent activation, the DUPLEX® Container should remain in the folded position until activation is intended.

Patient Labeling and Drug Powder/Diluent Inspection Apply patient-specific label on foil side of container.

Use care to avoid activation.

Do not cover any portion of foil strip with patient label.

Unlatch side tab and unfold DUPLEX® Container (see Diagram 1).

Visually inspect diluent chamber for particulate matter.

Use only if container and seals are intact.

To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2).

Protect from light after removal of foil strip.

Note:

If foil strip is removed, the container should be re-folded and the side tab latched until ready to activate.

The product must then be used within 7 days, but not beyond the labeled expiration date.

Diagram 1 Diagram 2 Reconstitution (Activation) Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use.

Unfold the DUPLEX® container and point the set port in a downward direction.

Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold.

To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3).

Agitate the liquid-powder mixture until the drug powder is completely dissolved.

Note:

Following reconstitution (activation), product must be used within 12 hours if stored at room temperature or within 5 days if stored under refrigeration.

Diagram 3 Administration Visually inspect the reconstituted solution for particulate matter.

Point the set port in a downwards direction.

Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold.

Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4).

Prior to attaching the IV set, check for minute leaks by squeezing container firmly.

If leaks are found, discard container and solution as sterility may be compromised.

Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5).

Refer to directions for use accompanying the administration set.

Diagram 4 Diagram 5 Important Administration Instructions Do not use in series connections.

Do not introduce additives into the DUPLEX® Container.

Administer Cefepime for Injection USP and Dextrose Injection USP intravenously over approximately 30 minutes.

Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions.

However, during infusion of Cefepime for Injection USP and Dextrose Injection USP, it is advisable to discontinue the other solution.

Solutions of cefepime 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, netilimicin sulfate or aminophylline because of potential interaction.

However, if concurrent therapy with cefepime is indicated, each of these antibiotics can be administered separately.

Use in special populations

8 USE IN SPECIFIC POPULATIONS Geriatric use: Serious adverse reactions have occurred in geriatric patients with renal impairment given unadjusted doses of cefepime (5.2, 8.5) Pediatric use: Safety and efficacy not established in patients less than 2 months of age or for use in any pediatric patients with complicated intra-abdominal infections.

(8.4) 8.1 Pregnancy 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 (1.6 times the recommended maximum human dose calculated on a mg/ m2 basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/ m2 basis) or to rabbits at a dose level of 100 mg/kg (0.3 times 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.

8.2 Labor and Delivery Cefepime has not been studied for use during labor and delivery.

Treatment should only be given if clearly indicated.

8.3 Nursing Mothers Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL) [see Clinical Pharmacology (12.3)].

Caution should be exercised when cefepime is administered to a nursing woman.

8.4 Pediatric Use 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 for Injection USP and Dextrose Injection USP 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 Clinical Pharmacology (12.3)].

Safety and efficacy in pediatric patients for the treatment of complicated intra-abdominal infections have not been established.

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 for Injection USP and Dextrose Injection USP 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. Cefepime for Injection USP and Dextrose Injection USP in the DUPLEX® Container should be used only in pediatric patients who require the entire 1 or 2 gram dose and not any fraction thereof.

8.5 Geriatric Use Of the more than 6400 adults treated with cefepime 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 reactions have occurred in geriatric patients with renal impairment given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions (6.2)].

Cefepime 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

Pregnancy and lactation
8.3 Nursing Mothers Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL) [see Clinical Pharmacology (12.3) ]. Caution should be exercised when cefepime is administered to a nursing woman.

Interactions

7 DRUG INTERACTIONS Aminoglycosides: Increased potential of nephrotoxicity and ototoxicity.

(7.1) Diuretics: Nephrotoxicity has been reported with concomitant administration of cephalosporins with potent diuretics such as furosemide.

(7.2) 7.1 Aminoglycosides Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Cefepime for Injection USP and Dextrose Injection USP because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

7.2 Diuretics Nephrotoxicity has been reported following concomitant administration of cephalosporins with potent diuretics such as furosemide.

More information

Category Value
Authorisation number NDA050821
Orphan designation No
Product NDC 0264-3195,0264-3193
Date Last Revised 05-11-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1665093
Marketing authorisation holder B. Braun Medical Inc.