warnings and cautions
5 WARNINGS AND PRECAUTIONS Use of VICTRELIS with Ribavirin and Peginterferon alfa: Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa): Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; use two or more forms of contraception, and have monthly pregnancy tests. ( 5.1 ) Anemia - The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone. ( 5.2 ) Neutropenia - The addition of VICTRELIS to peginterferon alfa and ribavirin may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. ( 5.3 ) Hypersensitivity – Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. ( 5.5 ) 5.1 Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa) Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Refer to the prescribing information for ribavirin for additional information. Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this time [see Contraindications (4) and Drug Interactions (7) ] . 5.2 Anemia (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 (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended [see Adverse Reactions (6.1) and Clinical Studies (14) ] . If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ] . Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation. In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per 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 per dL. In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of VICTRELIS and PegIntron/REBETOL (71 days with a range of 15-337 days), compared to those who received PegIntron/REBETOL (71 days with a range of 8-337 days). 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 (ESAs) 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 ESA was 43% in those treated with the combination of VICTRELIS with PegIntron/REBETOL compared to 24% in those treated with PegIntron/REBETOL alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of VICTRELIS with PegIntron/REBETOL compared to less than 1% in subjects who received PegIntron/REBETOL alone. Thromboembolic events have been associated with ESA 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 ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use. A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with VICTRELIS in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA. Ribavirin dose reduction is recommended for the initial management of anemia. 5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa) In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 × 10 9 per L compared to 4% of subjects receiving PegIntron/REBETOL alone (see Table 4 ). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ]. Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation. 5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa) Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters. 5.5 Hypersensitivity Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted [see Contraindications (4) and Adverse Reactions (6.2) ] . 5.6 Drug Interactions See Table 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity [see Contraindications (4) ]. Please refer to Table 5 for established and other potentially significant drug interactions [see Drug Interactions (7.3) ]. 5.7 Laboratory Tests HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result (reported as "Target Not Detected" or "HCV-RNA Not Detected"). Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements.