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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serious Skin Reactions/Rash: Fatal and non-fatal serious skin reactions (including SJS, DRESS, and TEN) have been reported. Patients with mild to moderate rash should be monitored for progression. If rash progresses and becomes severe, INCIVEK should be discontinued. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Consider discontinuing other medications known to be associated with serious skin reactions. ( 5.1 ) Anemia: Monitor hemoglobin prior to and at regular intervals during INCIVEK combination treatment. Follow dose modifications for ribavirin; discontinue INCIVEK if required. ( 5.2 ) Pregnancy: 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 initiating therapy, use at least 2 effective methods of contraception, and undergo monthly pregnancy tests. ( 5.3 , 8.1 ) 5.1 Serious Skin Reactions/Rash Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care. In clinical trials, serious skin reactions, including DRESS and SJS were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all subjects recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips). TEN and Erythema Multiforme (EM) have been observed in post-marketing experience [see also Boxed Warning and Adverse Reactions (6.2) ]. Rash events (all grades) developed in 56% of subjects who received INCIVEK combination treatment [see Adverse Reactions (6.1) ] and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during INCIVEK combination treatment. Rash events led to discontinuation of INCIVEK alone in 6% of subjects and discontinuation of INCIVEK combination treatment in 1% of subjects. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component. Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered [see also Boxed Warning ] . Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended [see Drug Interactions (7) ] . 5.2 Anemia Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of INCIVEK to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with lowest values reached at the end of INCIVEK dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after INCIVEK dosing was completed. Hemoglobin values less than or equal to 10 g per dL were observed in 36% of subjects who received INCIVEK combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. In clinical trials, the median time to onset of hemoglobin less than or equal to 10 g per dL was faster among subjects treated with INCIVEK combination treatment compared to those who received peginterferon alfa and ribavirin: 56 days (range 8-365 days) versus 63 days (range 13-341 days), respectively. Hemoglobin values less than 8.5 g per dL were observed in 14% of subjects who received INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin. In subjects receiving INCIVEK combination treatment, 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia, 6% received a blood transfusion, 4% discontinued INCIVEK, and 1% discontinued INCIVEK combination treatment. In subjects treated with peginterferon alfa and ribavirin alone, 12% underwent ribavirin dose modification due to anemia, 1% received a blood transfusion, and fewer than 1% discontinued treatment. Anemia requiring ribavirin dose reduction, blood transfusion, and/or erythropoiesis stimulating agent (ESA) has been reported to occur as soon as 10 days following initiation of INCIVEK combination treatment. Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate. Earlier and more frequent monitoring for some patients should be considered. For the management of anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of anemia, INCIVEK must also be permanently discontinued. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of INCIVEK must not be reduced and INCIVEK must not be restarted if discontinued. 5.3 Pregnancy: 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. Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see Contraindications (4) and Use in Specific Populations (8.1) ] . Refer also to the prescribing information for ribavirin. Female Patients Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK [see Drug Interactions (7) ]. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs) [see also Use in Specific Populations (8.1) ] . Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. 5.4 Drug Interactions See Table 3 for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening adverse events or potential loss of therapeutic effect to INCIVEK [see Contraindications (4) ] . Refer to Table 5 for established and other potentially significant drug-drug interactions [see Drug Interactions (7) ] . 5.5 Laboratory Tests HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV RNA levels during treatment is recommended. The assay should have a lower limit of HCV RNA quantification equal to or less than 25 IU per mL and a limit of HCV RNA detection of approximately 10-15 IU per mL. For the purpose of assessing response-guided therapy eligibility, an "undetectable" HCV RNA (Target Not Detected) result is required; 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"). Hematology evaluations (including hemoglobin, white cell differential, and platelet count) are recommended prior to and at weeks 2, 4, 8 and 12 and as clinically appropriate. Chemistry evaluations (including electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as frequently as hematology evaluations or as clinically appropriate [see Adverse Reactions (6.1) ] . Refer to the prescribing information for peginterferon alfa and ribavirin, including pregnancy testing requirements. 5.6 General INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK. There are no clinical data on re-treating patients who have failed an HCV NS3/4A protease inhibitor-based treatment , nor are there data on repeated courses of INCIVEK [see Microbiology (12.4) ] . 5.7 Hepatic Impairment INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients with decompensated liver disease. Refer to prescribing information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK [see Use in Specific Populations (8.6) ] .