Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D

Disclosures

Am J Health Syst Pharm. 2012;69(11):933-943. 

In This Article

Safety

Safety information for fidaxomicin is based on data from a Phase I study, a Phase III clinical trial comparing fidaxomicin with vancomycin, and a briefing document submitted to FDA by Optimer Pharmaceuticals.[29,48,49]

A two-phase, double-blind, randomized, placebo-controlled, dose-escalation study was conducted to evaluate the safety and pharmacokinetics of single oral doses of fidaxomicin.[29] Sixteen healthy subjects were enrolled in the Phase IA (single-dose) study, and 24 healthy subjects were enrolled in the Phase IB (multidose) study. Study subjects were monitored for adverse events and abnormal laboratory test values throughout the treatment period and at follow-up.

No clinically meaningful changes were observed in electrocardiograms, laboratory reports, or vital signs in either Phase I study. In the Phase IA study, five mild adverse effects were reported (headache, rhinorrhea, open wound in the left upper leg, elevated serum lipase concentration [value not reported], and elevated serum amylase concentration [value not reported]). The abnormalities in amylase and lipase values reported in a single subject were noted in baseline laboratory test values. In the Phase IB study, eight adverse events were reported among the subjects enrolled in the fidaxomicin group (headache [two reports], weakness, difficulty swallowing, pharyngitis, conjunctivitis, eosinophilia, and upper-respiratory-tract infection). All adverse effects were not considered to be treatment related.

In the Phase III trial reported by Louie et al.,[48] the safety of fidaxomicin 200 mg twice daily was compared with vancomycin 125 mg four times daily. Safety records of subjects in the fidaxomicin (n = 300) and vancomycin (n = 323) groups were reviewed. The frequency of adverse effects was similar between groups (Table 4). Approximately 60% of subjects in each group reported a treatment-emergent adverse effect (62.3% in the fidaxomicin group versus 60.4% in the vancomycin group). In the fidaxomicin and vancomycin groups, adverse gastrointestinal effects were the most common adverse effects reported (25% versus 22.3%, respectively), followed by general disorders (fevers, chills, edema, and fatigue) (15.3% versus 16.7%, respectively) and infections (urinary tract infection and pneumonia) (21.3% versus 19.5%, respectively). Serious adverse effects were reported by 25% of subjects in the fidaxomicin group versus 24.1% of subjects in the vancomycin group). These events included gastrointestinal disorders (4.3% versus 3.4%, respectively); infections (C. difficile, pneumonia, sepsis, and bacteremia) (7% versus 9.3%, respectively); hypokalemia, hyperglycemia, hyponatremia, hypophosphatemia, and hypoglycemia (3% in both groups); and renal failure (1.6% versus 1.2%, respectively).

A recent safety analysis included pooled results from the Louie et al.[48] Phase III trial and another Phase III trial.[49] The second Phase III trial enrolled patients from April 2007 through December 2009 in the United States, Canada, and the European Union. The overall frequency of treatment-emergent adverse events in the pooled Phase III studies showed there were no clinically relevant differences between subjects in the vancomycin group (n = 583) and the fidaxomicin group (n = 564). The number of subjects who experienced gastrointestinal bleeding treatment-emergent adverse events was higher in the fidaxomicin group (n = 20, 3.5%) than in the vancomycin group (n = 10, 1.7%). Diarrhea hemorrhage (0.9% versus 0%) and gastrointestinal hemorrhage (0.9% versus 0.2%) were also more common in the fidaxomicin group. However, the median time to gastrointestinal bleeding treatment-emergent adverse events was 14 days (range, 2–46 days), with the most serious occurring weeks after the subjects had received the study drug.

There was a higher frequency of reduced WBC counts in the fidaxomicin group than in the vancomycin group (23 subjects versus 11 subjects). Leukopenia was the most frequently reported hematologic and lymphatic system disorder (8 subjects in the fidaxomicin group versus 4 subjects in the vancomycin group). However, a higher frequency of subjects with preexisting active hematologic and lymphatic disorders were enrolled in the fidaxomicin group (38.7% versus 32.6% in the vancomycin group). In addition, more subjects in the fidaxomicin group were receiving concomitant treatment with an antineoplastic or immunomodulatory agent compared with the vancomycin group (67 versus 48).

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