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 events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. 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 events was very 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 events 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 10: Adverse Reactions Cefepime Multiple-Dose Dosing Regimens Clinical Trials—North America
|INCIDENCE EQUAL TO OR GREATER THAN 1%||Local 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, fever, headache, nausea, oral moniliasis,pruritus,urticaria, vaginitis, vomiting|
|* Local reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048).|
At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse events 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 adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America.
Table 11: 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 calcium*, hematocrit, neutrophils, platelets, WBC|
|* Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported.|
A similar safety profile was seen in clinical trials of pediatric patients (see PRECAUTIONS: Pediatric Use).
In addition to the events reported during North American clinical trials with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience.
Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), 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. (See WARNINGS).
As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported.
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 dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.