FDA label 18bf4c29-e238-45aa-b976-d2d600fb0609

WARNINGS Hypersensitivity Reactions to Cefepime, Cephalosporins, Penicillins, or Other Drugs 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 drugs. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibiotics 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. Use in Patients with Renal Impairment In patients with creatinine clearance less than or equal to 60 mL/min, adjust the dose of cefepime for injection to compensate for the slower rate of renal elimination [see DOSAGE AND ADMINISTRATION ]. Because high and prolonged serum cefepime concentrations can occur from usual dosages in patients with renal impairment, the cefepime dosage should be reduced when it is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms. Neurotoxicity During postmarketing surveillance, 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), myoclonus, seizures, and non-convulsive status epilepticus (see ADVERSE REACTIONS: Postmarketing Experience ). 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, consider discontinuing cefepime or making appropriate dosage adjustments in patients with renal impairment. Clostridium difficile Associated Diarrhea Clostridium 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

ADVERSE REACTIONS Clinical Trials 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 (Table 8) 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 8: 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%) Local reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048). ; 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 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 (Table 9) adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America. Table 9: 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 Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported. , hematocrit, neutrophils, platelets, WBC A similar safety profile was seen in clinical trials of pediatric patients (see PRECAUTIONS: Pediatric Use ). Postmarketing Experience 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 non-convulsive 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.

<table ID="_RefIDC64DBC6D9AC6499CAF399215E3553BD1"> <caption>Table 8: Adverse Reactions Cefepime Multiple-Dose Dosing Regimens Clinical Trials &#x2013; North America</caption> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>INCIDENCE EQUAL TO OR GREATER THAN 1%</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Local reactions (3%), including phlebitis (1.3%), pain and/or inflammation (0.6%)<footnote ID="_RefID14E3F6055695474F9291C986810D3C5A">Local reactions, irrespective of relationship to cefepime in those patients who received intravenous infusion (n=3048).</footnote>; rash (1.1%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>INCIDENCE LESS THAN 1% BUT GREATER THAN 0.1% </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Colitis (including pseudomembranous colitis), diarrhea, erythema, fever, headache, nausea, oral moniliasis, pruritus, urticaria, vaginitis, vomiting, anemia</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID4AA721A368F9443EA4A50CB26717A6B8"> <caption>Table 9: Adverse Laboratory Changes Cefepime Multiple-Dose Dosing Regimens Clinical Trials &#x2013; North America</caption> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>INCIDENCE EQUAL TO OR GREATER THAN 1%</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Positive Coombs&#x2019; 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%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>INCIDENCE LESS THAN 1% BUT GREATER THAN 0.1%</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Increased alkaline phosphatase, BUN, calcium, creatinine, phosphorus, potassium, total bilirubin; decreased calcium<footnote ID="_RefIDB936AE9EF8E5497ABEEC1144EE24640D">Hypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported.</footnote>, hematocrit, neutrophils, platelets, WBC</paragraph> </td> </tr> </tbody> </table>