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)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)] The most common adverse reactions (incidence ≥ 1%) were local reactions, positive Coombs' test, decreased phosphorous, increased ALT and AST, increased PT and PTT and rash. (6.1) At the highest dose (2 g every 8 hours), incidence of adverse reactions was ≥1% for rash, diarrhea, nausea, vomiting, pruritis, fever, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at-1-800-706-5575 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 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 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 calciumHypocalcemia was more common among elderly patients. Clinical consequences from changes in either calcium or phosphorus were not reported., hematocrit, neutrophils, platelets, White Blood Cells (WBC) A similar safety profile was seen in clinical trials of pediatric patients 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cefepime. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to the adverse reactions reported during the North American clinical trials with cefepime, the following adverse reactions have been reported during worldwide postmarketing experience. Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus have been reported. [see Warnings and Precautions (5.2 )] Anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia, have been reported. 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 antibacterial drugs: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.