1 INDICATIONS AND USAGE

VICTRELIS™ (boceprevir) is indicated for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy [see Clinical Studies (14)].

The following points should be considered when initiating VICTRELIS for treatment of chronic hepatitis C infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2-log10 HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included subjects who were poorly interferon responsive. Subjects with less than 0.5-log10 HCV-RNA decline in viral load at Treatment Week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than 2-log10 viral load decline at Treatment Week 12) to peginterferon alfa and ribavirin therapy [see Clinical Studies (14)].
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin [see Microbiology (12.4) and Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. The dose of VICTRELIS is 800 mg (four 200-mg capsules) three times daily (every 7–9 hours) with food [a meal or light snack] (see Table 1). Refer to the peginterferon alfa and ribavirin Package Inserts for instructions on dosing.

The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials [see Clinical Studies (14)]. Response-Guided Therapy (RGT) is recommended for most individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).

2.1VICTRELIS Combination Therapy: Patients Without Cirrhosis Who Are Previously Untreated or Who Are Previous Partial Responders or Relapsers to Interferon and Ribavirin Therapy

• Initiate therapy with peginterferon alfa and ribavirin for 4 weeks (Treatment Weeks 1–4).
• Add VICTRELIS 800 mg (four 200-mg capsules) orally three times daily (every 7–9 hours) to peginterferon alfa and ribavirin regimen after 4 weeks of treatment. Based on the patient's HCV-RNA levels at Treatment Week (TW) 8, TW12 and TW24, use the following Response-Guided Therapy (RGT) guidelines to determine duration of treatment (see Table 1).

Response-Guided Therapy was not studied in subjects who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin. If considered for treatment, these subjects should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin. In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW 4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin in order to maximize rates of SVR [see Clinical Studies (14)].

2.2VICTRELIS Combination Therapy: Patients with Cirrhosis

Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks VICTRELIS 800 mg (four 200-mg capsules) three times daily (every 7–9 hours) in combination with peginterferon alfa and ribavirin.

2.3 Dose Modification

Dose reduction of VICTRELIS is not recommended.

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin Package Inserts for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

2.4Discontinuation of Dosing Based on Treatment Futility

Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 100 IU/mL at TW 12; or 2) confirmed detectable HCV-RNA levels at TW24.

3 DOSAGE FORMS AND STRENGTHS

VICTRELIS 200 mg Capsules, red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink.

4 CONTRAINDICATIONS

Contraindications to peginterferon alfa and ribavirin also apply to VICTRELIS combination treatment.

VICTRELIS combination treatment is contraindicated in:

• Pregnant women and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
• Coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events, including those in Table 2 [see also Drug Interactions (7)].
• Coadministration with potent CYP3A4/5 inducers, where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy, including those in Table 2 [see also Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1Pregnancy (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. 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. Routine monthly pregnancy tests must be performed during this time. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS. Two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with VICTRELIS and concomitant ribavirin.

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, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 × 109/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 count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained at Treatment Weeks 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.

Refer to Package Inserts for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation for peginterferon alfa and ribavirin.

5.4Drug 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)].

5.5Laboratory 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/mL, and a limit of HCV-RNA detection of approximately 10–15 IU/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.

Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained at Treatment Weeks 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

Refer to the Package Inserts for peginterferon alfa and ribavirin, including pregnancy testing requirements.

6 ADVERSE REACTIONS

See peginterferon alfa and ribavirin Package Inserts for description of adverse reactions associated with their use.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VICTRELIS cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling: Anemia and neutropenia [see Warnings and Precautions (5.2, 5.3)].

The most commonly reported adverse reactions (>35% of subjects regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL.

The safety of the combination of VICTRELIS 800 mg three times daily with PegIntron/REBETOL was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) eva luated the use of VICTRELIS in combination with PegIntron/REBETOL with or without a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) eva luated the use of VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL with a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone [see Clinical Studies (14)]. The population studied had a mean age of 49 years (3% of subjects were >65 years of age), 39% were female, 82% were white and 15% were black.

During the four week lead-in period with PegIntron/REBETOL in the VICTRELIS-containing arms, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and 12% for subjects receiving PegIntron/REBETOL alone. Events resulting in discontinuation were similar to those seen in previous studies with PegIntron/REBETOL. Only anemia and fatigue were reported as events that led to discontinuation in >1% of subjects in any arm.

Adverse reactions that led to dose modifications of any drug (primarily PegIntron and REBETOL) occurred in 39% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL compared to 24% of subjects receiving PegIntron/REBETOL alone. The most common reason for dose reduction was anemia, which occurred more frequently in subjects receiving the combination of VICTRELIS with PegIntron/REBETOL than in subjects receiving PegIntron/REBETOL alone.

Serious adverse events were reported in 11% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and in 8% of subjects receiving PegIntron/REBETOL.

Adverse events (regardless of investigator's causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and reported at a rate of greater than or equal to 5% than PegIntron/REBETOL alone in SPRINT-1, SPRINT-2, and RESPOND-2 are presented in Table 3.

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