During the clinical development of fidaxomicin, 728 subjects received fidaxomicin: 116 healthy adult volunteers in phase 1 studies and 612 adults with CDI in phase 2A and 3 studies. In the phase 1 and 2A studies, subjects were exposed to doses of fidaxomicin ranging 100–450 mg. No significant dose-related adverse events (AEs) were observed [14
The safety and efficacy of fidaxomicin were compared with oral vancomycin in 2 randomized, double-blinded pivotal phase 3 studies. One was performed in North America [12
], and the other was performed in both North America and Europe [13
]. In both phase 3 studies, fidaxomicin was administered orally at 200 mg every 12 hours for 10 days, and vancomycin was administered orally at 125 mg every 6 hours for 10 days (the currently recommended dose for nonfulminant disease). In these studies, 564 subjects with CDI were treated with fidaxomicin and 583 were treated with vancomycin, respectively. Overall, 86.7% of subjects completed a full course of treatment.
Of the 1147 subjects evaluable for the pooled phase 3 safety analysis, 567 (49.4%) were aged ≥65 years (272 treated with fidaxomicin and 295 treated with vancomycin), reflecting that the elderly are disproportionately affected by CDI. Subjects were mainly white (90%), female (58%), and in-patients (64%). Many subjects enrolled in the phase 3 program were acutely ill, with concomitant acute and chronic medical conditions in addition to CDI.
In these clinical studies, the safety profile of fidaxomicin was comparable with that of the active comparator vancomycin. For example, the total number of deaths in the phase 3 trials was similar for fidaxomicin (36 of 564; 6.4%) and vancomycin (38 of 583; 6.5%; P = not significant). None of these deaths was believed to be due to study drug toxicity, but they were attributed to the subject's significant underlying morbidities. Nine of the deaths were deemed possibly related to progression of the underlying CDI: 5 for fidaxomicin and 4 for vancomycin (5 men, 4 women; mean days on therapy, 6.78). In terms of any serious AEs (SAEs) or general AEs, the overall rates also were similar (Table ). The vast majority of all events were rated as not related to study drug by the investigators.
Adverse Events in Phase 3 Trials
Rates for discontinuation of dosing due to an AE were also comparable for both drugs in the phase 3 trials. There were 33 of 564 (5.9%) and 40 of 583 (6.9%) subjects in the fidaxomicin and vancomycin arms, respectively, who stopped their treatment due to an AE (P
= .48). Vomiting was the most frequent AE leading to study drug discontinuation. This occurred for 0.5% of subjects in both treatment groups [16
Because the majority of fidaxomicin remains in the intestinal lumen and exerts its activity there, GI AEs in the fidaxomicin phase 3 studies were evaluated closely. In the phase 3 studies, the number of overall GI AEs and SAEs was similar between the fidaxomicin and vancomycin groups. Slightly more GI AEs led to discontinuation from the study in the fidaxomicin group than in the vancomycin group (2.3% vs 1.4%; P = .24), but deaths due to a GI AE tended to occur less frequently in the fidaxomicin group than the vancomycin group (0.5% vs 1.0%; P = .51).
Some form of GI bleeding occurred in 23 fidaxomicin-treated patients (23 of 564; 4.1%) and 18 vancomycin-treated patients (18 of 583; 3.1%; P = .37). All GI bleeding events in fidaxomicin subjects were deemed not related or unlikely related to the drug by the investigators. Also, many of these subjects had other risk factors for GI bleeding, such as recent bowel surgery, coagulopathies, or concomitant medications with anticoagulant properties. For fidaxomicin subjects, the early GI bleeding events tended to be mild self-limited events (such as a single bloody bowel movement or intermittent bleeding from preexisting rectal hemorrhoids) not requiring intervention. Fidaxomicin was not associated with an increase in bleeding events in other (non-GI) organ systems.
Three patients in the fidaxomicin arm developed megacolon, an unfortunate complication of CDI. One subject received only 2 doses before his condition worsened. For the 2 other subjects, megacolon was diagnosed with a treatment failure on days 3 and 6 of therapy, respectively. One vancomycin subject presented with a large-intestine perforation on day 31 and was found to have toxic megacolon during colectomy.
Anemia was reported in 2% of both fidaxomicin and vancomycin subjects. Leukopenia (eg, decreases in white blood cell counts or neutrophils) were observed in 14 of 564 (2.5%) fidaxomicin subjects and 6 of 583 (1.0%) vancomycin subjects (P
= .06). There was no apparent explanation for this finding except that more patients received antineoplastic or immunomodulating agents in the fidaxomicin group (11.9% vs 8.2%; P
= .04) [13
]. Nearly all these reported events of leukopenia occurred in subjects with underlying hematologic malignancies, recent bone marrow transplant, and/or recent chemotherapy. No specific bone marrow toxicity was observed with fidaxomicin in the nonclinical studies [13
]. The main clinical concern regarding leukopenia is that it could lead to an increased incidence of serious infections. However, it should also be noted that no overall increased incidence of infections with fidaxomicin vs vancomycin was observed in the phase 3 studies (22.9% vs 20.8%, respectively). The incidence of infections resulting in death was 2.0% for fidaxomicin subjects and 1.9% for vancomycin subjects. No adverse effect on platelet counts was observed in nonclinical or clinical studies.
Electrocardiograms (ECGs) were obtained before the first dose and at the end of therapy. No significant changes in ECGs were observed during the study period. There were no significant corrected QT (QTc) interval modifications for either group in the phase 3 studies (Table ). There was no association between QTc interval prolongation and increased fidaxomicin level. One patient receiving oral vancomycin in a phase 3 trial developed torsades de pointes. Deaths due to cardiac events occurred in 0.4% of fidaxomicin subjects and 1.2% of vancomycin subjects (P = .18). In a subgroup analysis with high plasma levels (fidaxomicin plus OP–1118 levels ≥150 ng/mL), there was no association between QTc interval prolongation and drug levels.
Summary of 12-Lead Electrocardiogram Corrected QT Interval Results (Bazett's and Fridericia's corrections): Phase 3 Studies
In the phase 3 clinical studies, the incidence of AEs involving abnormal liver function test (LFT) results was similar between fidaxomicin and vancomycin (3.2% vs 2.6%; P = .53). No significant changes in mean LFT results were observed in either group (Table ). The numbers of subjects with normal LFT results at baseline but a later LFT result at least 3 times the upper limit of normal (ULN) were 6 for fidaxomicin and 5 for vancomycin. No subject in either group had an increase in aspartate or alanine aminotransferase level to >3 times ULN with an increase in bilirubin level >2 times ULN. Adverse events were also examined for subjects with and without abnormal LFT results at baseline. The overall incidence of AEs was similar for fidaxomicin- and vancomycin-treated subjects with and without these abnormal laboratory parameters.
Summary Statistics for Changes in Liver Function Parameters Between Baseline and End of Therapy: Phase 3 Studies
Use in Renal Impairment
No specific safety studies have been carried out to date with fidaxomicin in subjects with renal or hepatic impairment. However, 48% of subjects in the phase 3 studies had renal insufficiency at baseline, and the safety of fidaxomicin was examined in subgroups of subjects who had varying degrees of renal insufficiency based on estimated creatinine clearance and characterized as either mild (51–79 mL/min), moderate (31–50 mL/min), or severe (≤30 mL/min). No clinically significant differences in the incidence of AEs between fidaxomicin and vancomycin subjects were observed within subpopulations with mild, moderate, or severe renal insufficiency.
Use in Pregnancy
To date, there are no meaningful data available for fidaxomicin use during pregnancy in humans. One woman with B-cell lymphoma in a phase 3 study receiving fidaxomicin and also receiving numerous other agents (including methotrexate and vincristine) had a multiple-birth pregnancy. Her pregnancy test was negative at enrollment and became positive on day 25. She delivered 3 live and 1 dead fetuses; 1 female fetus was found to have a cleft palate.