Cefepime (Page 3 of 7)

3 DOSAGE FORMS AND STRENGTHS

Cefepime for Injection, USP is a sterile white to pale yellow powder of cefepime in single-dose vials for reconstitution and it is available in the following strengths:

• 0.5 gram per vial

• 1 gram per vial

• 2 grams per vial

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Before therapy with Cefepime for Injection 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-lactams. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime for Injection occurs, discontinue the drug and institute appropriate supportive measures.

5.2 Neurotoxicity

Serious adverse reactions have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus [see Adverse Reactions (6.2)]. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. However, some cases of neurotoxicity occurred in patients receiving a dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with cefepime therapy occurs, discontinue cefepime and institute appropriate supportive measures.

5.3 Clostridioides difficile -Associated Diarrhea

Clostridioides difficile -Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefepime for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.4 Development of Drug-Resistant Bacteria

Prescribing Cefepime for Injection in the absence of a 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 Cefepime for Injection 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.

5.5 Drug/Laboratory Test Interactions

Urinary Glucose

The administration of cefepime may result in a false-positive reaction for glucose in the urine when using some methods (e.g. Clinitest™ tablets) [see Drug Interactions (7.1)].

Coombs’ Tests

Positive direct Coombs’ tests have been reported during treatment with Cefepime for Injection. In patients who develop hemolytic anemia, discontinue the drug and institute appropriate therapy. Positive Coombs’ test may be observed in newborns whose mothers have received cephalosporin antibacterial drugs before parturition.

Prothrombin Time

Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in the Warnings and Precautions section and below:

•Hypersensitivity Reactions [see Warnings and Precautions (5.1) ]

•Neurotoxicity [see Warnings and Precautions (5.2) ]

Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.3) ]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot 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 intravenous 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. Thirty-three (51%) of these 64 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%, respectively). However, the incidence of discontinuation due to rash increased with the higher recommended doses.

The following adverse reactions (Table 5) were identified in clinical trials conducted in North America (n=3125 cefepime-treated patients).

Table 5: Adverse Reactions in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America

Incidence equal to or greater than 1%

Local adverse reactions (3%), 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 adverse reactions was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%).

The following (Table 6) adverse laboratory changes, with cefepime, were seen during clinical trials conducted in North America.

Table 6: Adverse Laboratory Changes in Cefepime Multiple-Dose Dosing Regimens Clinical Trials in North America
*
Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported.

Incidence equal to or greater than 1%

Positive Coombs’ test (without hemolysis) (16.2%); decreased phosphorus (2.8%); increased Alanine Transaminase (ALT) (2.8%), Aspartate Transaminase (AST) (2.4%), eosinophils (1.7%); abnormal PTT (1.6%), Prothrombin Time (PT) (1.4%)

Incidence less than 1% but greater than 0.1%

Increased alkaline phosphatase, Blood Urea Nitrogen (BUN), calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium *, hematocrit, neutrophils, platelets, White Blood Cells (WBC)

A similar safety profile was seen in clinical trials of pediatric patients

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