5.2Anemia (Use with Ribavirin and Peginterferon Alfa)

Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Complete blood counts should be obtained pretreatment, and at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g/dL, a decrease in dosage or interruption of ribavirin is recommended; and if hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is recommended [see Adverse Reactions (6.1) and Clinical Studies (14)].

Refer to the Package Insert for ribavirin for additional information regarding dosage reduction and/or interruption.

In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL was higher in subjects treated with the combination of VICTRELIS with PegIntron®/REBETOL® than in those treated with PegIntron/REBETOL alone (see Table 4). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g/dL. Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of VICTRELIS with PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone [see Adverse Reactions (6.1)].

In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL (26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an erythropoiesis stimulating agent was 43% in the VICTRELIS-containing arms compared to 24% in the PegIntron/REBETOL arms. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects in the VICTRELIS-containing arms compared to less than 1% in subjects who received PegIntron/REBETOL alone.

Thromboembolic events have been associated with erythropoiesis stimulating agent use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of erythropoiesis stimulating agent use. No definite causality assessment or benefit risk assessment can be made for these events due to the presence of confounding factors and lack of randomization of erythropoiesis stimulating agent use.

5.3Neutropenia (Use with Ribavirin and Peginterferon Alfa)

In Phase 2 and 3 clinical trials,