CAS registry number: 394730-60-0 Boceprevir has the following chemical name: (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3- dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide. The molecular formula is C27H45N5O5 and its molecular weight is 519.7.

DESCRIPTION

VICTRELIS (boceprevir) is an inhibitor of the Hepatitis C Virus (HCV) non-structural protein 3 (NS3) serine protease. Boceprevir is manufactured as an approximately equal mixture of two diastereomers. Boceprevir is a white to off-white amorphous powder. It is freely soluble in methanol, ethanol and isopropanol and slightly soluble in water with a partition coefficient (logPoctanol/water) of 3.0. VICTRELIS 200 mg capsules are available as hard gelatin capsules for oral administration. Each capsule contains 200 mg of boceprevir and the following inactive ingredients: sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, pre- gelatinized starch, and magnesium stearate. The yellowish-brown opaque cap consists of gelatin, E172 Red Iron Oxide, E172 Yellow Iron Oxide and titanium dioxide. The off-white opaque body contains gelatin, titanium dioxide and E172 Yellow Iron Oxide. The capsule is printed in red ink (Red SB-1100). The red ink contains Shellac, Ph.Eur., Ethanol anhydrous, Ph.Eur., Isopropyl alcohol

PHARMACOLOGY

Pharmacodynamic Properties

VICTRELIS is an inhibitor of the HCV NS3 protease. VICTRELIS covalently, yet reversibly, binds to the NS3 protease active site serine (Ser139) through a (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells.

The antiviral activity of boceprevir was evaluated in a biochemical assay for slow binding inhibitors of NS3 protease and in the HCV replicon system. The IC50 and IC90 values for boceprevir were approximately 200 nM and 400 nM, respectively, in a 72-hour cell culture assay. Loss of replicon RNA appears to be first-order with respect to time of treatment. Treatment at IC90 for 72 hours resulted in a 1 log10 drop in replicon RNA. Prolonged exposure resulted in a 2 log10 decrease in RNA levels by Day 15. Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

Resistance to boceprevir was characterized in biochemical and HCV genotype 1b replicon assays. The activity of boceprevir against the HCV NS3/4A protease or genotype 1b replicon was reduced (2- to 10- fold) by the following amino acid substitutions in the NS3 protease domain: V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, V170A/T and M175L. A greater than 15-fold reduction in boceprevir anti-HCV activity was conferred by the substitutions T54C, R155G/I/T and A156S/T/V. The fold decrease in boceprevir anti-HCV activity conferred by double resistance-associated substitutions was approximately equal to the product of that for the individual substitutions. In cell-based protease assays, an NS3 Q80K substitution did not reduce HCV sensitivity to boceprevir. In addition, the decreased sensitivity to boceprevir observed with R155K was not further decreased when combined with either Q80K or Q80R. A loss of potency (> 50-fold) was observed with resistant-associated amino acid variant: A156T. Of note, replicons carrying the A156T variant are less fit than replicons carrying other RAVs.

An as-treated, pooled genotypic resistance analysis was conducted for patients who received four weeks of PegIntron/Rebetol followed by VICTRELIS 800 mg three times daily in combination with PegIntron/Rebetol in two Phase 3 studies, SPRINT-2 and RESPOND-2. Sustained Virologic Response (SVR) to treatment was defined as undetectable1 plasma HCV- RNA at follow-up week 24. Among VICTRELIS-treated patients who did not achieve a sustained virologic response, and for whom samples were analysed, 53% had one or more specific post- baseline, treatment-emergent NS3 protease domain amino acid substitutions detected by a population-based sequencing assay (Table 1). Nearly all of these substitutions have been shown to reduce boceprevir anti-HCV activity in cell culture or biochemical assays. Among VICTRELIS-treated patients who did not achieve SVR and for whom post-baseline samples were analysed, 31% of PegIntron/Rebetol-responsive patients, as defined by greater than or equal to 1 log10 decline in viral load at Treatment Week 4 (end of 4-week PegIntron /Rebetol lead-in period), had detectable treatment-emergent substitutions, compared to 69% of patients with less than 1 log10 decline in viral load at Treatment Week 4. Clear patterns of boceprevir

In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqMan(r) assay with a limit of detection of 9.3 IU/ml.

treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome were not observed.

Table 1: Pooled Analysis of Treatment-Emergent NS3 Protease Domain Amino Acid Substitutions Detected Among VICTRELIS-Treated Patients in SPRINT-2 and RESPOND-2 Who Did Not Achieve a Sustained Virologic Response (SVR)

Data from an ongoing, long-term follow-up study of patients who did not achieve SVR in Phase 2 trials with VICTRELIS, with a median duration of follow-up of approximately 2 years, indicate that HCV populations harbouring certain post-baseline, VICTRELIS-treatment-emergent substitutions may decline in relative abundance over time. However, among those patients with available data, one or more VICTRELIS-treatment-emergent substitutions remained detectable with a population-based sequencing assay in 25% of patients after 2.5 years of follow-up. The most common NS3 substitutions detected after 2.5 years of follow-up were T54S and R155K. The lack of detection of a substitution based on a population-based assay does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of boceprevir-resistance-associated substitutions is unknown. No data are available regarding the efficacy of VICTRELIS among patients who were previously exposed to VICTRELIS, or who previously failed treatment with a VICTRELIS-containing regimen.

A pooled analysis was conducted to explore the association between the detection of baseline NS3/4A amino acid polymorphisms and treatment outcome in the two Phase 3 studies, SPRINT-2 and RESPOND-2. Baseline resistance associated polymorphisms were detected in 7% of patients by a population- based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in patients treated with VICTRELIS. However, among patients with a relatively poor response to PegIntron/Rebetol during the 4-week lead-in period, the efficacy of VICTRELIS appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K detected at baseline. Patients with these baseline polymorphisms and reduced response to PegIntron/Rebetol represented approximately 1% of the total number of patients treated with VICTRELIS.

Many of the treatment-emergent NS3 amino acid substitutions detected in VICTRELIS-treated patients who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the anti-HCV activity of other HCV NS3/4A protease inhibitors. The impact of prior exposure to VICTRELIS or treatment failure on the efficacy of other HCV NS3/4A protease inhibitors has not been studied. The efficacy of VICTRELIS has not been established for patients with a history of exposure to other NS3/4A protease inhibitors. Cross-resistance is not expected between VICTRELIS and interferons, or VICTRELIS and ribavirin.

Pharmacokinetics

VICTRELIS capsules contain a 1:1 mixture of two diastereomers, SCH534128 and SCH534129. In plasma the diastereomer ratio changes to 2:1, favouring the active diastereomer, SCH534128. Plasma concentrations of boceprevir described below consist of both diastereomers SCH534128 and SCH534129, unless otherwise specified.

Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax and Cmin increased in a less-than dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1,200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing. In healthy individuals who received 800 mg three times daily alone, boceprevir medicine exposure was characterized by AUC(t) of 6,147 ng.hr/mL, Cmax of 1,913 ng/mL, and Cmin of 90 ng/mL. Pharmacokinetic results were similar between healthy individuals and HCV-infected individuals. The absolute bioavailability of boceprevir has not been studied.

VICTRELIS should be administered with food. Food enhanced the exposure of boceprevir by up to 60% at the 800 mg three times daily dose when administered with a meal relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, VICTRELIS may be taken without regard to either meal type or timing of the meal.

Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state. Human plasma protein binding is approximately 75% following a single dose of VICTRELIS 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers which rapidly interconvert in plasma. The predominant diastereomer is pharmacologically active and the other diastereomer is inactive.

Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo- ketoreductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800 mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diasteriomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.

Boceprevir is eliminated with a mean plasma half-life (t1/2) of approximately 3.4 hours. The two diastereomers, SCH534128 and SCH534129, had similar mean plasma half-life. Boceprevir has a mean total body clearance (CL/F) of approximately 161 L/hr. Following a single 800 mg oral dose of 14C-boceprevir, approximately 79% and 9% of the dose was excreted in faeces and urine, respectively, with approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in faeces and urine. The data indicate that boceprevir is eliminated primarily by the liver.

Special Populations

In a study of individuals with varying degrees of stable chronic liver impairment (mild, moderate and severe), no clinically significant differences in pharmacokinetic parameters were found, and no dose adjustment is recommended. VICTRELIS, in combination with peginterferon alpha and ribavirin, is contraindicated in cirrhotic patients with a Child-Pugh score > 6 (class B and C) (see CONTRAINDICATIONS).

No clinically significant differences in pharmacokinetic parameters were observed between individuals with end-stage renal disease (ESRD) and healthy individuals. No dose adjustment is required in patients with ESRD and in patients with any degree of renal impairment.

No gender-related pharmacokinetic differences have been observed in adult patients.

Population pharmacokinetic analysis of VICTRELIS indicated that race had no apparent effect on exposure.

Population pharmacokinetic analysis of VICTRELIS indicated that age had no apparent effect on exposure.

CLINICAL TRIALS

The efficacy of VICTRELIS as a treatment for Chronic Hepatitis C (genotype 1) infection was assessed in approximately 1,500 adult patients who were previously untreated (SPRINT-2) or who had failed previous therapy (RESPOND-2) in Phase III clinical studies. In both studies, the addition of VICTRELIS to the current standard of care (peginterferon alpha and ribavirin) significantly increased sustained virologic response (SVR) rates compared to the current standard of care alone.

Patients who are previously untreated

SPRINT-2 (P05216) was a randomized, double blinded, placebo-controlled study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [peginterferon alfa-2b 1.5 ug/kg/week subcutaneously and weight-based dosing with ribavirin (600-1,400 mg/day orally divided twice daily)] to PR alone in adult patients who had Chronic Hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Patients (N=1,099) were randomized in a 1:1:1 ratio in two cohorts (Cohort 1/non-Black and Cohort 2/Black) and stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (<= 400,000 IU/mL vs. > 400,000 IU/mL) to one of the following three treatment arms: Peginterferon alfa-2b + ribavirin for 48 weeks (PR48). Peginterferon alfa-2b + ribavirin for 4 weeks followed by VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 24 weeks. The patients were then continued on different regimens based on Treatment Week (TW) 8 response-guided therapy (VICTRELIS-RGT). All patients in this treatment arm were limited to 24 weeks of therapy with VICTRELIS.

48 weeks. Peginterferon alfa-2b + ribavirin for four weeks followed by VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks (VICTRELIS-PR48). Mean age of patients randomised was 49 years. The racial distribution of patients was as follows: 82% White, 14% Black, and 4% others. The distribution of patients by gender was 60% men and 40% women. All patients with detectable HCV-RNA in plasma at TW 24 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectable plasma HCV- RNA at follow-up week 24. The addition of VICTRELIS to peginterferon alfa-2b and ribavirin significantly increased the SVR rates compared to peginterferon alfa-2b and ribavirin alone in the combined cohort (63% to 66% VICTRELIS-containing arms vs. 38% PR48 control) for randomized patients who received at least one dose of any study medication (Full Analysis Set population) and decreased the length of therapy to 28 weeks for early responders (see Table 2). SVR rates for Blacks who received the combination of VICTRELIS with peginterferon alfa-2b and ribavirin were 42% to 53%; these rates are approximately twofold higher than the SVR rate for the PR48 control (23%) (see Table 2). A secondary analysis of patients who received at least one dose of VICTRELIS or placebo after the four-week lead-in with peginterferon alfa-2b and ribavirin (Modified-Intent-to- Treat population) demonstrated SVR rates in the combined cohort of 67% to 68% VICTRELIS- containing arms vs. 40% PR48 control.

Table 2: Sustained Virologic Response (SVR) *, End of Treatment (EOT) and Relapse+ Rates for patients who are previously untreated

Interferon-responsiveness (as defined by >= 1 log10 decline in viral load at TW 4) was predictive of SVR. VICTRELIS-treated patients who demonstrated interferon responsiveness by TW 4 achieved SVR rates of 79-81%. In patients with < 1 log10 decline in viral load at TW 4 (poor interferon-responsiveness), treatment with the combination of VICTRELIS with peginterferon alfa-2b and ribavirin resulted in SVR rates of 28-38%, respectively, compared to 4% in patients treated with standard of care. Response-guided therapy based on TW 8 response is equally effective as adding VICTRELIS to the 48-week standard of care regimen. Fifty-seven percent (208/368) of patients in the VICTRELIS-RGT arm had undetectable HCV-RNA at TW 8 (early responders). After accounting for treatment discontinuations, 44% (162/368) of patients reached TW 24 and were assigned a short (28 weeks) treatment with VICTRELIS in combination with peginterferon alfa-2b and ribavirin in the VICTRELIS-RGT arm. These VICTRELIS-RGT early responders demonstrated similar SVR rates (156/162 or 96%) after 28 weeks of treatment compared with the matched population in the VICTRELIS-PR48 arm (e.g., those patients in the Victrelis-PR48 arm who also had undetectable HCV-RNA at TW 8 through TW 24) (155/161 or 96%) (see Table 3). Similarly, patients in the VICTRELIS-RGT arm with detectable HCV-RNA at any assay from TW 8 up to TW 24, but achieving undetectable HCV-RNA at TW 24 (82/368, 22%), were considered late responders and received an initial 4 weeks of peginterferon alfa-2b and ribavirin, then 24 weeks of VICTRELIS with peginterferon alfa-2b and ribavirin followed by 20 weeks of peginterferon alfa-2b and ribavirin alone in the VICTRELIS-RGT arm. These VICTRELIS-RGT late responders who were assigned to the VICTRELIS-RGT arm that received 48 weeks of treatment also had SVR rates (72%, 59/82) that were similar to those in the matched patients in the Victrelis-PR48 arm (75%, 55/73) (see Table 3). Patients in the VICTRELIS-RGT arm received a total of 48 weeks of therapy with peginterferon alfa-2b and ribavirin, but only 24 weeks of VICTRELIS (TW 4 to TW 28). While these late responders in the VICTRELIS-RGT arm continued on peginterferon alfa-2b and ribavirin alone (plus placebo) for the last 20 weeks of therapy, patients in the VICTRELIS-PR48 arm received VICTRELIS plus peginterferon alfa-2b and ribavirin for 44 weeks. These data support the concept that continued therapy with VICTRELIS in addition to peginterferon alfa-2b and ribavirin standard of care after TW 28 (as executed in the VICTRELIS-PR48 arm) does not improve SVR rates in late responders who receive a total of 48 weeks of peginterferon alfa-2b and ribavirin treatment.

Table 3: Sustained Virologic Response (SVR), End of Treatment (EOT) and Relapse Rates in experimental arms with undetectable or detectable HCV-RNA at TW 8 through TW 24 in patients who are previously untreated in the combined cohort

SVR rates in patients by demographics and baseline factors in the VICTRELIS-RGT and VICTRELIS-PR48 compared to patients receiving PR alone are presented in Table 4.

Table 4: Sustained Virologic Response (SVR) * by Demographics and Baseline Characteristics in Previously Untreated Patients in the combined cohort

Patients who have failed previous therapy: previous partial-responders and relapsers to interferon and ribavirin therapy

RESPOND-2 (P05101) was a randomized, parallel-group, double-blinded study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [peginterferon alfa-2b 1.5 ug/kg/week subcutaneously and weight-based ribavirin (600-1,400 mg BID) orally divided twice daily] compared to PR alone in adult patients with Chronic Hepatitis C (HCV) genotype 1 infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load >= 2 log10 by Week 12 or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma) and who failed prior treatment with peginterferon alpha and ribavirin. Patients (N=404) were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:

on different treatment regimens based on TW 8 response-guide therapy (VICTRELIS- RGT). All patients in this treatment arm were limited to 32 weeks of VICTRELIS.

Peginterferon alfa-2b + ribavirin for 4 weeks followed by VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks (VICTRELIS-PR48). RESPOND-2 enrolled patients who were partial responders or relapsers on prior therapy with peginterferon alfa and ribavirin. The trial did not enrol patients who had less than a 2 log10 HCV- RNA decline by treatment week 12 during prior therapy with peginterferon alpha and ribavirin (null responders). Mean age of patients randomised was 53 years. The racial distribution of patients was as follows: 85% White, 12% Black, and 3% others. The distribution of patients by gender was 67% men and 33% women. All patients with detectable HCV-RNA in plasma at TW 12 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectable plasma HCV- RNA at FW 24. The addition of VICTRELIS to the peginterferon alfa-2b and ribavirin therapy significantly increased the SVR rates compared to peginterferon alfa-2b and ribavirin therapy alone (59% to 66% VICTRELIS-containing arms vs. 21% PR48 control) for randomized patients who received at least one dose of any study medication (Full Analysis Set population) and decreased the length of therapy to 36 weeks for many previous treatment failures (see Table 5). A secondary analysis of patients who received at least one dose of VICTRELIS or placebo after the four week lead-in with peginterferon alfa-2b and ribavirin (Modified Intent to Treat population) demonstrated SVR rates of 61% to 67% in the VICTRELIS-containing arms compared to 22% PR48 control. Achievement of SVR was associated with the patient's response to peginterferon alfa-2b and ribavirin therapy, whether defined by classification of response to previous treatment, or by a decrease in HCV-RNA at TW 4 (see Table 5). The TW 4 response was a stronger predictor of SVR compared to response to previous treatment and allowed the determination of the patient's on-treatment interferon responsiveness.

Table 5: Sustained Virologic Response (SVR) *, End of Treatment (EOT), and Relapse * * Rates for patients who have failed previous therapy (previous partial responders and relapsers)

Response-guided therapy based on TW 8 response is equally effective as adding VICTRELIS to the 48-week standard of care regimen. Forty-six percent (74/162) of patients in the VICTRELIS- RGT arm and 52% (84/161) of patients in the VICTRELIS-PR48 arm were early responders (patients with undetectable HCV-RNA at TW 8). Of the patients that were early responders, 71 patients were undetectable at TW12 in the VICTRELIS-RGT arm and 81 patients were undetectable at TW 12 in VICTRELIS-PR48 arm. VICTRELIS-RGT early responders, who received 36 weeks of therapy (an initial 4 weeks of peginterferon alfa-2b and ribavirin followed by 32 weeks of VICTRELIS with peginterferon alfa-2b and ribavirin), had an SVR rate of 86% (64/74) compared with an SVR rate of 88% (74/84) in the matched population in the VICTRELIS-PR48 arm who received 48 weeks of therapy (an initial 4 weeks of peginterferon alfa-2b and ribavirin followed by 44 weeks of VICTRELIS with peginterferon alfa-2b and ribavirin) (see Table 6). In patients who were not early responders (patients with detectable HCV-RNA at TW 8), the SVR rate in the VICTRELIS-RGT arm was 40% (29/72) compared with an SVR rate of 43% (30/70) in the matched population in the VICTRELIS-PR48 arm (see Table 6). Thirty-eight patients in the VICTRELIS-RGT arm and 37 patients in the VICTRELIS-PR48 arm had detectable HCV-RNA at TW 8 but were subsequently undetectable at TW 12 (late responders). VICTRELIS-RGT late responders, who received an initial 4 weeks of peginterferon alfa-2b and ribavirin then 32 weeks of VICTRELIS with peginterferon alfa-2b and ribavirin followed by 12 weeks of peginterferon alfa-2b and ribavirin alone, had an SVR rate of 76% (29/38) compared with an SVR rate of 62% (23/37) in the matched population in the VICTRELIS-PR48 arm, who received 4 weeks of peginterferon alfa-2b and ribavirin followed by 44 weeks of VICTRELIS in addition to peginterferon alfa-2b and ribavirin. These data support that, in late responders, 36 weeks of VICTRELIS with peginterferon alfa-2b and ribavirin followed by 12 weeks of peginterferon alfa-2b and ribavirin is adequate and that treatment with VICTRELIS may be shortened to 32 weeks in patients who have received previous therapy.

Table 6: Sustained Virologic Response (SVR), End of Treatment (EOT), and Relapse Rates in the experimental arms with undetectable or detectable HCV-RNA at TW 8 in patients who have failed previous therapy (previous partial responders and relapsers)

The difference in the number of patients who achieved SVR between the VICTRELIS-RGT arm and the VICTRELIS-PR48 arm is explained by imbalances in treatment response observed while patients in each arm were receiving identical therapy prior to TW 36. SVR rates in patients by demographics and baseline factors in the VICTRELIS-RGT and VICTRELIS-PR48 compared to patients receiving PR alone are presented in Table 7.

Table 7: Sustained Virologic Response (SVR) * by Demographics and Baseline Characteristics in patients who have failed previous therapy (previous partial responders and relapsers)

Patients who have failed previous therapy: prior null responders, partial responders and relapsers to interferon and ribavirin therapy

PROVIDE was an open-label, single-arm study of boceprevir 800 mg orally three times daily in combination with PR (peginterferon alfa-2b 1.5 mg/kg/week subcutaneously and weight-based ribavirin [600 - 1,400 mg BID] orally, divided twice daily) in adults with chronic hepatitis C genotype 1 infection who did not achieve sustained viral response while in PR treated control arms of previous boceprevir combination therapy Phase 2 and 3 studies In the parent studies, null responders were defined as those who had less than 2 log10 HCV- RNA reduction at Treatment Week 12 of prior PR treatment; partial responders were defined as those who demonstrated >= 2 log10 reduction in HCV-RNA by Week 12 but had detectable HCV- RNA at EOT. Relapsers were defined as those who had undetectable plasma HCV RNA at end of prior treatment but detectable HCV RNA at end of follow-up. Patients who enrolled in PROVIDE within 2 weeks after the last dose of PR in the parent study received VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. Those who were not able to enrol in this study within 2 weeks received PR for 4 weeks followed by VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. The primary outcome, SVR, was defined as undetectable plasma HCV-RNA at FW 24. If other HCV-RNA values were available after FW 24 the last available values was used. If no result was available at and after FW 24, the FW 12 values were used. The SVR rates for participants who received at least one dose of any study medication (Intent- to-Treat population) are shown in Table 8. The SVR rates (95% CIs) for those who received at least one dose of boceprevir (i.e. excluding patients who discontinued during PR lead-in) were 41% (27%, 55%) for null responders, 67% (57%, 77%) for partial responders and 96% (90%, 100%) for relapsers.

Table 8: Sustained Virologic Response (SVR)a, Responseb at End of Treatment (EOT) and Relapsec Rate by Prior Treatment Resopnse and Overall (prior null responders, partial responders and relapsers to interferon and ribavirin therapy

Use with erythropoietin in Phase III trials

A randomised, parallel-arm, open-label study was conducted to compare use of erythropoietin to use of ribavirin dose reduction for management of anaemia in patients with chronic hepatitis C treated with peginterferon, ribavirin and boceprevir. The study enrolled 687 previously untreated patients with genotype 1 infection and with serum haemoglobin concentrations of less than or equal to 15 g/dL. Participants included 434 (63%) females and 254 (37%) males with mean age 49 years (range 19-73 years). Racial distribution was 77% white, 19% black and 4% others. Treatment of CHC consisted of 4 weeks of peginterferon alfa-2b 1.5 mg/kg/week subcutaneously and weight-based ribavirin (600 - 1,400 mg BID) orally divided twice daily followed by up to 44 weeks of boceprevir 800 mg three times daily plus peginterferon alfa-2b and ribavirin. Patients were randomised 1:1 to either ribavirin dose reduction (Arm 1) or erythropoietin treatment (Arm 2) at the time of development of anaemia defined as haemoglobin of approximately <= 10 g/dL. Treatment of anaemia consisted of either ribavirin dose reduction (N=249) or use of erythropoietin 40,000 units subcutaneously once weekly (N=251). If serum haemoglobin concentrations decreased to <= 8.5 g/dL, patients could be treated with secondary interventions including the addition of erythropoietin for those in the ribavirin dose reduction arm, or ribavirin dose reduction for those in the erythropoietin arm. A total of 18% of participants in Arm 1 had additional treatment with erythropoietin. Ribavirin dose reduction was reported for 37% of those in Arm 2. Packed red cell transfusions were administered to 10 patients (4%) in the ribavirin reduction arm and 5 patients (2%) in the erythropoietin arm. The SVR rate was 71.5% (178/249) in Arm 1 and 70.9% (178/251) in Arm 2. The difference (95% CI) was - 0.7% (-8.6%, 7.2%). The relapse rate in patients randomised to receive ribavirin dose reduction was 9.7% (19/196) and the relapse rate in patients randomised to receive erythropoietin was 9.6% (19/197). The overall frequency of adverse reactions was similar in patients randomised to receive ribavirin dose reduction compared to patients randomised to receive erythropoietin. The treatment discontinuation rate due to anaemia was 2% (5/249) in patients randomised to receive ribavirin dose reduction and 2% (6/251) in patients randomised to receive erythropoietin. In this trial, use of erythropoietin 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.

CONTRAINDICATIONS

VICTRELIS Capsules, in combination with peginterferon alpha and ribavirin, is contraindicated in:

Refer to the corresponding Product Information for peginterferon alpha and ribavirin for additional information regarding co-administration.

PRECAUTIONS

VICTRELIS must be administered in combination with peginterferon alpha and ribavirin. Dose reduction of VICTRELIS is not recommended. The Product Information of peginterferon alpha and ribavirin must be consulted prior to initiation of therapy with VICTRELIS.

Anaemia has been reported with peginterferon alpha/ribavirin therapy. The addition of VICTRELIS to peginterferon alpha and ribavirin is associated with an additional decrease in serum haemoglobin concentrations. In clinical trials, the median time to onset of haemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of VICTRELIS and peginterferon alfa-2b/ribavirin (71 days with a range of 15-337 days), compared to those who received peginterferon alfa-2b/ribavirin (71 days with a range of

8-337 days). Complete blood counts (with white blood differential count) should be obtained pre- treatment, and at Treatment Weeks 2, 4, 8, 12, and should be monitored closely at other time points, as clinically appropriate. If serum haemoglobin is < 10 g/dL, a decrease in dose or interruption of ribavirin and/or administration of erythropoietin (epoetin alfa) may be warranted. If permanent discontinuation of ribavirin is required, then peginterferon alfa and VICTRELIS must also be discontinued. Ribavirin dose reduction is the recommended strategy for the initial management of treatment- emergent anaemia. In a prospective randomized controlled trial, SVR rates were comparable with ribavirin dose reduction or administration of erythropoietin (see Clinical Trials). In this trial, use of erythropoietin was associated with an increased risk of thromboembolic events compared to ribavirin dose reduction alone (see Clinical Trials). Refer to the Product Information for ribavirin for statements regarding dose reduction and/or discontinuation.

In Phase 2 and 3 clinical trials, seven percent of patients receiving the combination of VICTRELIS with peginterferon alfa-2b/ribavirin had neutrophil counts of less than

0.5 x 109/L compared to 4% of patients receiving peginterferon alfa-2b/ribavirin alone. Three patients experienced severe or life-threatening infections associated with neutropenia, and two patients experienced life-threatening neutropenia while receiving the combination of VICTRELIS with peginterferon alfa-2b/ribavirin. Complete blood count must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained 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 of peginterferon alfa or discontinuation of therapy. If permanent discontinuation of peginterferon alfa is required, then ribavirin and VICTRELIS must also be discontinued. Refer to the Product Information for peginterferon alpha and ribavirin for statements regarding dose reduction and/or interruption.

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa, and ribavirin. If such reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted (see CONTRAINDICATIONS and ADVERSE EFFECTS).

Based on results of clinical studies, VICTRELIS must not be used alone due to the high probability of increased resistance without combination anti-HCV therapies. It is unknown what effect therapy with VICTRELIS will have on the activity of subsequently administered HCV protease inhibitors, including re-treatment with VICTRELIS.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The concomitant use of VICTRELIS with potent CYP3A4 inducers (rifampicin, carbamazepine, phenobarbital, phenytoin) is not recommended.

Caution should be exercised in patients taking drospirenone-containing medications with conditions that predispose them to hyperkalaemia or patients taking potassium-sparing diuretics. Alternative contraceptives should be considered (see Drug Interactions).

Co-administration of VICTRELIS with simvastatin may increase plasma levels of simvastatin, which could increase the risk of myopathy, including rhabdomyolysis.

Impairment on fertility

Ribavirin caused reversible testicular toxicity in animals; while peginterferon alfa may impair fertility in females. Extreme care must be taken to avoid pregnancy in partners of male patients taking ribavirin or female patients of childbearing potential. Please refer to Product Information for ribavirin and peginterferon alfa for additional information.

No human data on the effect of VICTRELIS on fertility are available. Available pharmacodynamic/toxicological data in rats have shown effects of boceprevir/metabolites on fertility, which in females have been shown to be reversible. In rats, VICTRELIS induced reversible effects on fertility and early embryonic development in female rats with a no effect level (NEL) of 75 mg/kg. At this dose, the rat-to-human exposure multiple is 1.3-fold higher than the systemic human exposure at the recommended human therapeutic dose of 800 mg three times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration (NEL of 15 mg/kg which represents a rat-to-human exposure multiple of less than 1-fold the human exposure at the human therapeutic dose of 800 mg three times daily). Testicular degeneration has not been observed in mice or monkeys and therefore is considered species-specific to rats. Additionally, clinical monitoring of the surrogate marker inhibin B, as well as semen analysis, has revealed no evide nce that this finding is clinically relevant in human patients.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see CONTRAINDICATIONS and ribavirin Product Information). Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa Product Information).

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS. Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with VICTRELIS and concomitant ribavirin.

VICTRELIS must not be used as monotherapy (see INDICATIONS). There are no adequate and well-controlled studies with VICTRELIS in pregnant women. Fertile women should only be treated when they are using effective contraception during the treatment period.

No effects on fetal development with VICTRELIS alone have been observed in rats and rabbits. VICTRELIS, in combination with ribavirin and peginterferon alpha, is contraindicated in women who are pregnant (see CONTRAINDICATIONS). Please refer to the Product Information for ribavirin and peginterferon alpha for additional information.

It is not known whether peginterferon alfa, ribavirin or their metabolites are excreted in human milk.

Use in Lactation - VICTRELIS: Available pharmacodynamic/toxicological data in animals have shown excretion of boceprevir/metabolites in milk. Following a single, oral dose of 30 mg/kg 14C- boceprevir, drug-derived radiocarbon was transferred into the milk of lactating, 12-day postpartum rats. Peak systemic concentrations of drug-derived radiocarbon in nursing pups were over 100 *fold lower than in the mothers. Exposure to drug-derived materials in nursing human infants is estimated to be less than 1% of the dose. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment, taking into account the importance of the therapy to the mother.

The safety, efficacy and pharmacokinetic profile of VICTRELIS in paediatric patients below 18 years of age have not yet been established.

Clinical studies of VICTRELIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other clinical experience has not identified differences in responses between the elderly and younger patients.

Carcinogenesis and Mutagenesis - Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic in in vitro and in in vivo assays. There is no evidence for genotoxicity with interferon alfa. Ribavirin was not carcinogenic in mice and rats at doses less than the maximum recommended daily human dose. No carcinogenicity studies have been done with interferon alfa. Please refer to Product Information for ribavirin and peginterferon for additional information.

Two-year carcinogenicity studies in mice and rats were conducted with VICTRELIS. Mice were administered doses up to 650 mg/kg. Rats were administered doses of up to 125 mg/kg in males and 100 mg/kg in females. At the high dose of 650 mg/kg in female mice, the incidence of hepatocellular adenomas was increased at systemic exposures 5.7-fold higher than those in humans at the recommended

800 mg three times daily clinical dose; there was no increase in incidence at the next highest dose which corresponded to systemic exposure greater than the human exposure at the recommended 800 mg three times daily clinical dose. There were no increases in mortality or malignancy associated with the hepatocellular adenomas. Induction of CYP450 enzymes has been demonstrated previously in mice administered VICTRELIS, and liver tumours are a recognized sequelae with chronic exposure to an enzyme inducer. There were no increases in the incidence of tumours in male mice at any dose in the study. In rats, no adenomas or carcinomas occurred at systemic exposures higher than those in humans at the recommended 800 mg three times daily clinical dose. The clinical relevance of the hepatocellular adenomas observed in female mice, if any, is unknown. VICTRELIS was not mutagenic or genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, human peripheral blood lymphocyte and mouse micronucleus assays.

Interactions with other medicines

VICTRELIS is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may have increased exposure when administered with VICTRELIS, which could increase or prolong their therapeutic and adverse effects (see Table 8). VICTRELIS does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 in vitro. In addition, VICTRELIS does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4/5 in vitro. Boceprevir has been shown to be a P-gp substrate in vitro. In a drug interaction trial conducted with digoxin, VICTRELIS had limited p-glycoprotein (P-gp) inhibitory potential at clinically relevant concentrations (see Table 8). VICTRELIS is partly metabolized by CYP3A4/5. Co-administration of VICTRELIS with medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to VICTRELIS. VICTRELIS, in combination with peginterferon alpha and ribavirin, is contraindicated when co- administered with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events such as orally administered midazolam, triazolam, amiodarone, cisapride, alfuzosin, simvastatin, lovastatin, REVATIO (sildenafil) or tadalafil when used for the treatment of pulmonary arterial hypertension, and ergot derivatives (dihydroergotamine, ergotamine ) (see CONTRAINDICATIONS). Caution should be exercised with medicines known to prolong QT interval such as amiodarone, quinidine, methadone, pentamidine and some neuroleptics. Table 9 provides recommendations based on established or potentially clinically significant drug interactions.

Table 9: Pharmacokinetic interactions data in healthy individuals or HCV Positive Genotype-1 patients

No studies of the effects of VICTRELIS in combination with peginterferon alpha and ribavirin on the ability to drive and use machines have been performed. However, certain side effects that have been reported may affect some patients' ability to drive or operate machinery. Individual response to VICTRELIS in combination with peginterferon alpha and ribavirin may vary. Patients should be informed that fatigue and dizziness have been reported. Please see the Product Information for peginterferon alfa-2b and/or ribavirin for additional PRECAUTIONS.

ADVERSE EFFECTS

The safety profile represented by approximately 1,500 patients for the combination of VICTRELIS with peginterferon alfa-2b and ribavirin was based on pooled safety data in two clinical trials in patients who were previously untreated and one clinical trial in patients who had failed prior therapy. Patients with Chronic Hepatitis C received VICTRELIS 800 mg three times daily in combination with peginterferon alfa-2b and ribavirin. SPRINT-1 (P03523) evaluated the use of VICTRELIS in combination with peginterferon alfa-2b and ribavirin with or without a four week lead-in period with peginterferon alfa-2b and ribavirin compared to peginterferon alfa-2b and ribavirin alone in patients who were previously untreated. SPRINT-2 (P05216 patients who were previously untreated) and RESPOND-2 (P05101 - patients who had failed previous therapy) evaluated the use of VICTRELIS 800 mg three times daily in combination with peginterferon alfa-2b and ribavirin with a four-week lead-in period with peginterferon alfa-2b and ribavirin compared to peginterferon alfa-2b and ribavirin alone (see CLINICAL TRIALS). The population studied had a mean age of 49 years (2% of patients were > 65 years of age), 39% were female, and were 82% white and 15% black. Patients received VICTRELIS 800 mg three times daily in each study. Patients with Chronic Hepatitis C were randomized to receive VICTRELIS in the three studies for a median exposure of 201 days. The most frequently reported adverse reactions were similar across all study arms. The most frequently reported adverse reactions considered by investigators to be causally related to the combination of VICTRELIS with peginterferon alfa-2b and ribavirin in adult patients in clinical studies were: fatigue, anaemia (see PRECAUTIONS), nausea, headache, and dysgeusia. During the four-week lead-in period with peginterferon alfa-2b and ribavirin, 28/1,263 patients in the VICTRELIS-containing arms experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of patients who discontinued treatment due to adverse reactions was 13% for patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin and 12% for patients receiving peginterferon alfa-2b and ribavirin alone. Events resulting in discontinuation were similar to those seen in previous studies with peginterferon alfa-2b and ribavirin. Only anaemia and fatigue were reported as events that led to discontinuation in > 1% of patients in any arm. Adverse reactions that led to dose modifications of any medication occurred in 39% of patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin compared to 24% of patients receiving peginterferon alfa-2b and ribavirin alone. The most common reason for dose reduction was anaemia, which occurred more frequently in patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin than in patients receiving peginterferon alfa-2b and ribavirin alone. Adverse reactions considered by investigator to be causally related reported in >= 10% of patients who received the combination of VICTRELIS with peginterferon alfa-2b and ribavirin are listed in Table 10.

Table 10: Adverse reactions reported in >=10% of patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin reported during clinical trials

Adverse Reactions	Previously Untreated (SPRINT-1 & SPRINT-2)		Previous Treatment Failures (RESPOND-2)
	Percentage of Patients Reporting Adverse Reactions		Percentage of Patients Reporting Adverse Reactions
Body System Organ Class	VICTRELIS + peginterferon alfa-2b +ribavirin (N=1,225)	peginterferon alfa-2b +ribavirin (N=467)	VICTRELIS + peginterferon alfa-2b +ribavirin (N=323)	peginterferon alfa-2b +ribavirin (N=80)
Median Exposure (days)	197	216	253	104
Blood and Lymphatic System Disorders
Anaemia *	50	30	45	20
Neutropenia *	25	19	14	10
Gastrointestinal Disorders
Nausea *	45	40	41	38
Dysgeusia *	35	16	44	11
Diarrhea *	23	19	23	15
Vomiting *	19	12	15	8
Dry Mouth *	10	9	13	8
General Disorders and Administration Site Conditions
Fatigue *	58	58	55	50
Chills	33	29	33	30
Pyrexia *	32	32	28	21
Influenza Like Illness	22	25	23	25
Irritability	22	23	21	13
Asthenia *	15	18	21	16
Pain	10	8	7	4
Investigations
Weight decreased	11	12	11	9
Metabolism and Nutrition Disorders
Decreased Appetite *	25	24	25	16
Musculoskeletal and Connective Tissue Disorders
Myalgia	22	24	24	24
Adverse Reactions	Previously Untreated (SPRINT-1 & SPRINT-2)		Previous Treatment Failures (RESPOND-2)
	Percentage of Patients Reporting Adverse Reactions		Percentage of Patients Reporting Adverse Reactions
Body System Organ Class	VICTRELIS + peginterferon alfa-2b +ribavirin (N=1,225)	peginterferon alfa-2b +ribavirin (N=467)	VICTRELIS + peginterferon alfa-2b +ribavirin (N=323)	peginterferon alfa-2b +ribavirin (N=80)
Arthralgia	18	17	20	14
Nervous System Disorders
Headache *	45	42	40	48
Dizziness *	18	14	15	10
Psychiatric Disorders
Insomnia	33	33	29	20
Depression *	21	21	15	15
Anxiety *	12	12	12	6
Respiratory, Thoracic, and Mediastinal Disorders
Cough *	16	19	20	15
Dyspnea *	19	16	21	16
Dyspnea Exertional	8	8	11	5
Skin and Subcutaneous Tissue Disorders
Alopecia	27	27	22	16
Pruritus	22	24	19	18
Dry Skin	17	18	22	8
Rash	16	19	15	5
* Includes adverse reactions which may be serious as assessed by the investigator in clinical trial patients. + Since VICTRELIS is prescribed with peginterferon alpha and ribavirin, please also refer to the respective Product Information of peginterferon alpha and ribavirin. ++ Injection-site reactions have not been included since VICTRELIS is administered orally.

Anaemia

: Anaemia was observed in 49% of patients treated with the combination of VICTRELIS with peginterferon alfa-2b and ribavirin compared with 29% of patients treated with peginterferon alfa-2b and ribavirin alone. VICTRELIS was associated with an additional decrease of approximately 1 g/dL in haemoglobin concentration. The mean decreases in haemoglobin values from baseline were larger in previously treated patients compared to patients who had never received prior therapy. Dose modifications due to anaemia/hemolytic anaemia occurred twice as often in patients treated with the combination of VICTRELIS with peginterferon alfa-2b and ribavirin (26%) compared to peginterferon alfa-2b and ribavirin alone (13%). In these clinical trials, proper management of anaemia was associated with continued

treatment and higher sustained virologic response, with the majority of the anaemic patients having received erythropoietin (see PRECAUTIONS). The proportion of patients who received a transfusion for the management of anaemia was 3% of patients in the VICTRELIS-containing arms compared to < 1% of patients receiving peginterferon alfa-2b and ribavirin alone. Neutrophils and Platelets: The proportion of patients with decreased neutrophil and platelet counts was higher in the VICTRELIS-containing arms compared to patients receiving only peginterferon alfa-2b and ribavirin. Seven percent of patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin had neutrophil counts of < 0.5 x 109 /L compared to 4% of patients receiving only peginterferon alfa-2b and ribavirin. Three percent of patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin had platelet counts of < 50 x 109 /L compared to 1% of patients receiving only peginterferon alfa-2b and ribavirin.

Post Marketing Adverse Events

The following additional adverse experiences have been reported in post-marketing experience without regard to causality.

Gastrointestinal disorders

: mouth ulceration, stomatitis

Skin and subcutaneous tissue disorders

: angioedema, urticaria (see PRECAUTIONS, Hypersensitivity) ; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma.

DOSAGE AND ADMINISTRATION

VICTRELIS must be administered in combination with peginterferon alpha and ribavirin. The Product Information of peginterferon alpha and ribavirin must be consulted prior to initiation of therapy with VICTRELIS.

Recommended Dose

The recommended dose of VICTRELIS is 800 mg administered orally three times daily (TID) (every 7-9 hours) with food (meal or light snack).

Initiate therapy with peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4). Add VICTRELIS 800 mg orally three times daily to peginterferon alpha and ribavirin regimen Treatment Week (TW) 5. Based on the patient's Hepatitis C Virus ribonucleic acid (HCV-RNA) levels at TW 8 and TW 24, use the following Response Guided Therapy (RGT) guidelines to determine duration of treatment (see Table 11).

Table 11: Duration of therapy using Response Guided Therapy (RGT) in patients without cirrhosis who are previously untreated

Patients without cirrhosis who have failed previous therapy (partial responders and relapsers)

Initiate therapy with peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1- 4). Add VICTERLIS 800 mg orally three times daily to peginterferon alpha and ribavirin regimen at Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 12, use the following Response Guided Therapy (RGT) guidelines to determine duration of treatment (see Table 12). If patient has detectable HCV-RNA at TW 24 discontinuation of therapy is recommended.

Table 12: Duration of therapy using Response Guided Therapy (RGT) in patients without cirrhosis who have failed previous therapy (partial responders and relapsers) *

Patients who had less than a 2 log10 HCV-RNA decline by treatment week 12, during prior therapy with peginterferon alpha and ribavirin (null responders), should receive 4 weeks of peginterferon alpha and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily in combination with peginterferon alpha and ribavirin. Discontinuation of therapy is recommended in patients with prior null response on previous therapy who have detectable HCV-RNA at TW12; if a patient has detectable HCV-RNA at TW24 discontinuation of therapy is recommended.

Patients with compensated cirrhosis should receive 4 weeks peginterferon alpha and ribavirin followed by 44 weeks Victrelis 800 mg orally three times daily in combination with peginterferon alpha and ribavirin. Discontinuation of therapy is recommended in previously untreated patients who have detectable HCV-RNA at TW24. Discontinuation of therapy is recommended in patients who failed therapy with detectable HCV-RNA at TW12; if a patient has detectable HCV- RNA at TW24, discontinuation of therapy is recommended.

Dose Interruption

If a patient misses a dose and it is less than 2 hours before the next dose is due, the missed dose should be skipped. If a patient misses a dose and it is 2 or more hours before the next dose is due, the patient should take the missed dose with food and resume the normal dosing schedule.

Dose Modification

Dose reduction of VICTRELIS is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alpha and/or ribavirin, the peginterferon alpha and/or ribavirin dose should be reduced. Refer to the Product Information for peginterferon alpha and ribavirin for additional information about how to reduce and/or discontinue the peginterferon alpha and/or ribavirin dose. VICTRELIS must not be administered in the absence of peginterferon alpha and ribavirin.

No dose adjustment of VICTRELIS is required in patients with any degree of renal impairment (see PHARMACOLOGY).

No dose adjustment of VICTRELIS is required for patients with mild, moderate or severe hepatic impairment. VICTRELIS, in combination with peginterferon alpha and ribavirin, is contraindicated in cirrhotic patients with a Child-Pugh score > 6 (class B and C) (see CONTRAINDICATIONS).

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alpha and ribavirin for the treatment of Chronic Hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied. For data regarding drug-drug interactions with immunosuppressants, see Interactions with Other Medicines.

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alpha and ribavirin for the treatment of Chronic Hepatitis C genotype 1 infection have not been established in patients co-infected with Human Immunodeficiency Virus (HIV) and HCV. For data regarding drug-drug interactions with antiretroviral agents , see Interactions with Other Medicines.

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alpha and ribavirin for the treatment of Chronic Hepatitis C genotype 1 infection in patients co-infected with Hepatitis B Virus (HBV) and HCV have not been studied.

The safety and efficacy of VICTRELIS alone or in combination with peginterferon alpha and ribavirin for the treatment of Chronic Hepatitis C genotypes other than genotype 1 infection have not been established.

OVERDOSAGE

Daily doses up to 3,600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects. There is no specific antidote for overdose with VICTRELIS Capsules. Ingestion of VICTRELIS at higher than recommended doses may potentially increase the risk of adverse events from drug-drug interactions associated with concomitantly administered medications that are metabolized via the CYP3A4 pathway. Treatment of overdose with VICTRELIS Capsules should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status.

PRESENTATION

VICTRELIS 200 mg Capsules are comprised of a yellowish-brown, opaque cap with an "MSD" logo imprinted in red ink and off-white, opaque body with the code "314" imprinted in red ink. The capsules are packaged in blisters. Each blister tray contains three pouches with each pouch containing four capsules. The available pack size is 336 capsules (four week pack).

STORAGE

Store VICTRELIS Capsules in a refrigerator at 2-8degC until dispensed to the patient. For patient use, VICTRELIS Capsules may be stored in the refrigerator until the expiration date printed on the label. VICTRELIS Capsules can also be stored below 30degC for up to 3 months. Store in the original container.

NAME AND ADDRESS OF THE SPONSOR

Merck Sharp & Dohme (Australia) Pty Limited 54-68 Ferndell Street, South Granville, NSW 2142 Australia

POISON SCHEDULE OF THE MEDICINE

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG)

9 January 2012 DATE OF MOST RECENT AMENDMENT: 17 September 2013 Date of most recent safety-related change: 9 January 2013

	Patients Infected with HCV Genotype 1a	Patients Infected with HCV Genotype 1b
>10% of VICTRELIS treated patients who did not achieve SVR	V36M, T54S, R155K	T54A, T54S, V55A, A156S, I/V170A
<1% to 10% of VICTRELIS treated patients who did not achieve SVR	V36A, T54A, V55A, V55I, V107I, R155T, A156S, A156T, V158I, D168N, I/V170T, I/V170F	V36A, V36M, T54C, T54G, V107I, R155K, A156T, A156V, V158I, I/V170T, M175L

Study Cohorts	VICTRELIS- RGT	VICTRELIS- PR48	PR48
Cohort 1 Plus Cohort 2	n=368	n=366	n=363
SVR ++ %	63	66	38
EOT(Undetectable HCV-RNA) %	71	76	53
Relapse + % (n/N)	9 (24/257)	9 (24/265)	22 (39/176)
Cohort 1 (non-Black)	n=316	n=311	n=311
SVR ++ %	67	68	40
EOT(Undetectable HCV-RNA) %	74	77	57
Relapse + % (n/N)	9 (21/232)	8 (18/230)	23 (37/162)
Cohort 2 (Black)	n=52	n=55	n=52
SVR ++ %	42	53	23
EOT (Undetectable HCV-RNA) %	50	65	29
Relapse + % (n/N)	12 (3/25)	17 (6/35)	14 (2/14)
* The Full Analysis Set (FAS) consisted of all randomized patients who received at least one dose of any study medication (N=1,097) (peginterferon alfa-2b, ribavirin, or VICTRELIS). + Relapse rate was the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among patients who were undetectable at EOT and not missing End of Follow-up (EOF) data. ++ SVR: defined as undetectable plasma HCV-RNA at Follow-up Week (FW) 24. If other HCV-RNA values were available after FW 24, the last available value in the period after FW 24 was used. If there were no such values at and after FW 24, the FW 12 value was used. SVR rates with "missing=failure" approach were nearly identical to those in the table. Cohort 1: 39% for PR48; 66% for VICTRELIS- RGT, 68% for VICTRELIS-PR48. Cohort 2: 21% for PR48, 42% for VICTRELIS-RGT, 51% for VICTRELIS-PR48. Cohort 1+ Cohort 2: 37% for Control; 62% for VICTRELIS-RGT, 65% for VICTRELIS-PR48.

	Undetectable HCV-RNA at TW 8 *		Detectable HCV-RNA at TW 8 *
	VICTRELIS-RGT +	VICTRELIS- PR48	VICTRELIS- RGT +	VICTRELIS- PR48
SVR ++ % (n/N)	96 (156/162)	96 (155/161)	72 (59/82)	75 (55/73)
EOT (Undetectable HCV-RNA), % (n/N)	100 (162/162)	99 (159/161)	80 (66/82)	90 (66/73)
Relapse ++++ % (n/N)	3 (5/161)	1 (2/157)	11 (7/66)	14 (9/64)
* Per the study design, patients with undetectable HCV-RNA at TW 8 and all subsequent assays through TW 24 ended treatment at TW 28 (treatment duration assigned by Interactive Voice Response System (IVRS). + VICTRELIS-RGT - Patients received peginterferon alfa-2b and ribavirin for 4 weeks, then VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin as follows: VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin for 24 weeks (patients with undetectable HCV-RNA at TW 8 (early responders) and all subsequent assays through TW 24) or VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin for 24 weeks followed by placebo + peginterferon alfa-2b and ribavirin for 20 weeks (patients with detectable HCV-RNA at TW 8 up to TW 24; but achieving undetectable HCV-RNA at TW 24). ++ SVR: defined as undetectable plasma HCV-RNA at Follow-up Week (FW) 24. If other HCV-RNA values were available after FW 24, the last available value in the period after FW 24 was used. If there were no such values at and after FW 24, the FW 12 value was used. ++++ Relapse rate was the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among patients who were undetectable at EOT and not missing End of Follow-up (EOF) data.

Demographics/Baseline Characteristic		VICTRELIS-RGT	VICTRELIS-PR48	PR48
Age (years)	< 40, % (n/N)	73 (35/48)	70 (37/53)	53 (30/57)
	>= 40-< 65, % (n/N)	63 (193/308)	66 (201/306)	35 (103/291)
	>= 65, % (n/N)	42 (5/12)	57 (4/7)	27 (4/15)
	>= 75, % (n/N)	64 (151/237)	68 (159/235)	32 (70/217)
Body Mass Index (BMI)	<= 25, % (n/N)	58 (59/101)	68 (83/123)	47 (60/129)
	>25-30, % (n/N)	75 (129/173)	65 (90/138)	33 (49/148)
	> 30, % (n/N)	48 (45/94)	66 (69/105)	33 (28/86)
Baseline Viral Load: (IU/mL)	<= 400,000, % (n/N)	78 (25/32)	88 (22/25)	81 (21/26)
Baseline Viral Load: (IU/mL)	> 400,000, % (n/N)	62 (208/336)	65 (220/341)	34 (116/337)
HCV-1 Subtype:	1a, % (n/N)	59 (139/234)	62 (147/237)	34 (78/227)
HCV-1 Subtype:	1b, % (n/N)	71 (88/124)	73 (85/117)	39 (48/121)
Baseline Fibrosis	Metavir Fibrosis Score (F0/1/2), % (n/N)	67 (213/319)	67 (211/313)	38 (123/328)
Baseline Fibrosis	Metavir Fibrosis Score (F3/4), % (n/N)	41 (14/34)	52 (22/42)	38 (9/24)
Baseline Platelet Count (10 9 /L)	<150, % (n/N)	55 (18/33)	53 (20/38)	30 (8/27)
Baseline Platelet Count (10 9 /L)	>=150, % (n/N)	64 (215/335)	68 (222/328)	38 (129/336)
* The Full Analysis Set (FAS) consisted of all randomized patients who received at least one dose of any study medication (N=1,097) (peginterferon alfa-2b, ribavirin, or VICTRELIS). Mean age of patients randomized was 49.1 years. The race distribution of patients was as follows: 82% White, 14% Black, 2% Asian, 1% multiracial, 1% American Indian or Alaskan Native. The distribution of patients by gender was 60% men and 40% women.

	Overall	Previous Treatment Response		Lead-In Response ++ (Viral Load Reduction)
	Overall	Previous Partial Responders * * *	Previous Relapsers +	< 1 log 10 decline	>= 1 log 10 decline
PR48 (N=80)
SVR ++++ , % (n/N)	21 (17/80)	7 (2/29)	29 (15/51)	0 (0/12)	25 (17/67)
Relapse * * , % (n/N)	32 (8/25)	33 (1/3)	32 (7/22)	0 (0/0)	32 (8/25)
EOT, % (n/N)	31 (25/80)	10 (3/29)	43 (22/51)	0 (0/12)	37 (25/67)
Victrelis-RGT (N=162)
SVR ++++ , % (n/N)	59 (95/162)	40 (23/57)	69 (72/105)	33 (15/46)	73 (80/110)
Relapse * * , % (n/N)	15 (17/111)	18 (5/28)	14 (12/83)	12 (2/17)	16 (15/94)
EOT, % (n/N)	70 (114/162)	54 (31/57)	79 (83/105)	41 (19/46)	86 (95/110)
Victrelis-PR48 (N=161)
SVR ++++ , % (n/N)	66 (107/161)	52 (30/58)	75 (77/103)	34 (15/44)	79 (90/114)
Relapse * * , % (n/N)	12 (14/121)	14 (5/35)	10 (9/86)	25 (5/20)	9 (9/99)
EOT, % (n/N)	77 (124/161)	60 (35/58)	86 (89/103)	48 (21/44)	89 (101/114)
* The Full Analysis Set (FAS) consisted of all randomized patients who received at least one dose of any study medication (N=403) (peginterferon alfa-2b, ribavirin, or VICTRELIS). * * Relapse rate was the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among patients who were undetectable at EOT and not missing End of Follow-up (EOF) data. * * * Previous Partial Responder - patient who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin, but demonstrated >= 2 log 10 reduction in HCV-RNA by Week 12 and had detectable HCV-RNA at the end of follow-up. + Previous Relapser - patient who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin with undetectable HCV-RNA at the end of treatment, but had detectable HCV-RNA at the end of follow-up. ++ Eleven patients were missing TW 4 assessment (HCV-RNA) and were not included in the Lead-In response results. ++++ SVR: defined as undetectable plasma HCV-RNA at FW 24. If other HCV-RNA values were available after FW 24, the last available value in the period after FW 24 was used. If there were no such values at and after FW 24, the FW 12 value was used. SVR rates with "missing=failure" approach 17/80 [21.3%] for PR48, 94/162 [58.0] for Victrelis-RGT, 106/161 [65.8%] for Victrelis-PR48.

	Undetectable HCV-RNA at TW 8		Detectable HCV-RNA at TW 8
	VICTRELIS-RGT +	VICTRELIS- PR48	VICTRELIS-RGT +SS	VICTRELIS- PR48
SVR * , % (n/N)	86 (64/74)	88 (74/84)	40 (29/72)	43 (30/70)
EOT (Undetectable HCV-RNA), % (n/N)	97 (72/74)	95 (81/84)	56 (40/72)	57 (40/70)
Relapse ++++ , % (n/N)	11 (8/71)	8 (6/80)	24 (9/38)	21 (8/38)
* SVR: defined as undetectable plasma HCV-RNA at Follow-up Week (FW) 24. If other HCV-RNA values were available after FW 24, the last available value in the period after FW 24 was used. If there were no such values at and after FW 24, the FW 12 value was used. + VICTRELIS-RGT - Patients received peginterferon alfa-2b and ribavirin for 4 weeks, then VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin as follows: VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin for 32 weeks (patients with undetectable HCV-RNA at TW 8 (early responders) and TW 12) or VICTRELIS 800 mg three times daily + peginterferon alfa-2b and ribavirin for 32 weeks followed by placebo + peginterferon alfa-2b and ribavirin for 12 weeks (patients detectable HCV-RNA at TW 8 but subsequently negative by TW 12). ++++ Relapse rate was the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among patients who were undetectable at EOT and not missing End of Follow-up (EOF) data. SS Includes all patients with detectable HCV-RNA at TW 8. Late responders represent a subset of this group, patients with a detectable HCV-RNA at TW 8 but subsequently undetectable at TW 12. In late responders, the SVR rate was 76% (29/38) in VICTRELIS-RGT arm and 62% (23/37) in the VICTRELIS-PR48.

	Null responders d in parent study	Partial responders e in parent study	Relapsers f in the parent study	All g
	N = 52	N = 85	N = 29	N = 168
SVR % (n/N) 95% CI (%)	38 (20/52) (25, 52)	67 (57/85) (57, 77)	93 (27/29) (84, 100)	63 (106/168) (56, 70)
EOT % (n/N)	44 (23/52)	82 (70/85)	97 (28/29)	73 (123/168)
Relapse c % (n/N)	13 (3/23)	15 (10/67)	0 (0/27)	(13/119)
a SVR: defined as undetectable HCV-RNA at FW 24. If other HCV-RNA values were available after FW24, the last available value was used. If no result was available at and after FW24, the FW12 value was used. b Response at End of Treatment (EOT): defined as undetectable HCV-RNA at EOT. c Relapse Rate: the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) who had detectable HCV-RNA at End of Follow-up (EOF). The calculation was based on patients who were undetectable at EOT and not missing EOF data. d Prior Null Responder = patient who had less than a 2-log10 HCV-RNA reduction at Treatment Week (TW) 12 of prior PR treatment. e Prior Partial Responder = patient who demonstrated a >= 2 log10 reduction in HCV-RNA by TW 12 but had detectable HCV-RNA at EOT of prior PR treatment. f Prior Relapsers = patient who had undetectable plasma HCV RNA at end of prior treatment but detectable HCV RNA at end of follow-up. g All: The Intent to Treat (ITT) population consisted of all subjects (N=168) who received at least one dose of any study medication (peginterferon alfa-2b, ribavirin, or VICTRELIS). The race distribution of subjects was as follows: 84% white, 13% Black, 2% Asian, and 1% others. The distribution of subjects by gender was 67% men and 33% women. The ITT population included 2 subjects that had undetectable HCV-RNA at EOT and end of follow-up (SVR) in a prior PR study.

Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
ANTI-ARRHYTHMICS
Digoxin (0.25 mg digoxin single dose + boceprevir 800 mg three times daily x 10 days)	digoxin AUC 1.19 (1.12 - 1.27) digoxin C max 1.18 (1.07 - 1.31)	No dose adjustment of digoxin or boceprevir is recommended. Measure serum digoxin concentrations before initiating boceprevir. Continue monitoring digoxin concentrations during co- administration.
ANTI-INFECTIVES
Antiviral
Peginterferon alfa-2b (peginterferon alfa-2b 1.5 mcg/kg subcutaneous (SC) weekly x 2 weeks + boceprevir 200 or 400 mg three times daily x 1 week)	boceprevir AUC (0-8h) 1.00 (0.89 - 1.13) boceprevir C max 0.88 (0.66 - 1.18) boceprevir C min Not available peginterferon alfa-2b AUC (0-168h) 0.99 (0.83-1.17) (Reported AUC is 200 mg and 400 mg cohorts combined) peginterferon alfa-2b C max not available	No dose adjustment required for boceprevir or peginterferon alfa-2b.
Antibiotic
Clarithromycin (in combination with diflunisal) (clarithromycin: 500 mg three times daily x 5 days + diflunisal 500 mg two to three times daily x 11 days + boceprevir 400 mg two times daily x 10 days)	boceprevir AUC 1.21 (1.06 - 1.38) boceprevir C max 1.36 (1.04 - 1.78) boceprevir C min 0.85 (0.61 - 1.19)	No dose adjustment is required with boceprevir in combination with clarithromycin, or boceprevir in combination with clarithromycin and diflunisal.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Antifungals
Ketoconazole (ketoconazole 400 mg two times daily x 6 days + boceprevir 400 mg single dose)	boceprevir AUC 2.31 (2.00-2.67) boceprevir C max 1.41 (1.00-1.97) boceprevir C min not available (CYP 3A4/5 inhibition and/or P-gp inhibition)	No dose adjustment required for boceprevir or ketoconazole.
Antiretroviral
HIV Integrase Inhibitor
Raltegravir (raltegravir 400 mg single dose + boceprevir 800mg three times daily x 10 days)	raltegravir AUC 1.04 (0-12h) (0.88-1.22) raltegravir C max 1.11 (0.91-1.36) raltegravir C 12h 0.75 (0.45-1.23)	No dose adjustment required for boceprevir or raltegravir.
HIV Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Tenofovir (tenofovir 300 mg daily x 7days + boceprevir 800 mg three times daily x 7 days)	boceprevir AUC 1.08 (0-8h) (1.02-1.14) boceprevir C max 1.05 (0.98-1.12) boceprevir C min 1.08 (0.97-1.20 tenofovir AUC 1.05 (1.01-1.09) tenofovir C max 1.32 (1.19-1.45)	No dose adjustment required for boceprevir or tenofovir.
HIV Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz (efavirenz 600 mg daily x 16 days + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC (0-8h) 0.81 (0.75-0.89) boceprevir C max 0.92 (0.78-1.08) boceprevir C min 0.56 ((0.42-0.74) efavirenz AUC 1.20 (1.15-1.26) efavirenz C max 1.11 (1.02-1.20) (CYP 3A4 induction - effect on boceprevir)	Plasma trough concentrations of boceprevir were decreased when administered with efavirenz. The clinical outcome of this observed reduction of boceprevir trough concentrations has not been directly assessed.
Etravirine (etravirine 200 mg every 12 hours x 11-14 days + boceprevir 800 mg three times daily x 11-14 days)	boceprevir AUC 1.10 (0.94-1.28) boceprevir C max 1.10 (0.94-1.29) boceprevir C 8h 0.88 (0.66-1.17) etravirine AUC 0.77 (0.66-0.91) etravirine C max 0.76 (0.68-0.85) etravirine C min 0.71 (0.54-0.95)	The clinical significance of the reductions in etravirine pharmacokinetic parameters and boceprevir C min in the setting of combination therapy with HIV antiretroviral medicines, which also affect the pharmacokinetics of etravirine and/or boceprevir, has not been directly assessed. Increased clinical and laboratory monitoring for HIV and HCV suppression is recommended.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
HIV Protease Inhibitor (PI)
Atazanavir/Ritonavir (atazanavir 300 mg daily x 22 days + ritonavir 100 mg daily x 22 days + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC 0.95 (0.87-1.05) boceprevir C max 0.93 (0.80-1.08) boceprevir C min 0.82 (0.68-0.98) atazanavir AUC 0.65 (0.55-0.78) atazanavir C max 0.75 (0.64-0.88) atazanavir C min 0.51 (0.44-0.61) ritonavir AUC 0.64 (0.58-0.72) ritonavir C max 0.73 (0.64-0.83) ritonavir C min 0.55 (0.45-0.67)	It is not recommended to co-administer atazanavir/ritonavir and boceprevir
Darunavir/Ritonavir (darunavir 600 mg two times daily x 22 days + ritonavir 100 mg two times daily x 22 days + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC 0.68 (0.65-0.72) boceprevir C max 0.75 (0.67-0.85) boceprevir C min 0.65 (0.56-0.76) darunavir AUC 0.56 (0.51-0.61) darunavir C max 0.64 (0.58-0.71) darunavir C min 0.41 (0.38-0.45) ritonavir AUC 0.73 (0.68-0.79) ritonavir C max 0.87 (0.76-1.00) ritonavir C min 0.55 (0.52-0.59)	It is not recommended to co-administer darunavir/ritonavir and boceprevir
Lopinavir/Ritonavir (lopinavir 400 mg two times daily x 22 days + ritonavir 100 mg two times daily x 22 days + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC 0.55 (0.49-0.61) boceprevir C max 0.50 (0.45-0.55) boceprevir C min 0.43 (0.36-0.53) lopinavir AUC 0.66 (0.60-0.72) lopinavir C max 0.70 (0.65-0.77) lopinavir C min 0.57 (0.49-0.65) ritonavir AUC 0.78 (0.71-0.87) ritonavir C max 0.88 (0.72-1.07) ritonavir C min 0.58 (0.52-0.65)	It is not recommended to co-administer lopinavir/ritonavir and boceprevir.
Ritonavir (ritonavir 100 mg daily x 12 days + boceprevir 400 mg three times daily x 15 days)	boceprevir AUC 0.81 (0.73-0.91) boceprevir C max 0.73 (0.57-0.93) boceprevir C min 1.04 (0.62-1.75) (CYP 3A4/5 inhibition)	When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Narcotic analgesic/opiod dependence
Buprenorphine/Naloxone (buprenorphine/naloxone 8/2 - 24/6 mg daily x 6 days + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC 0.88 (0.76-1.02) boceprevir C max 0.82 (0.71-0.94) boceprevir C min 0.95 (0.70-1.28) (Boceprevir AUC, C max and C min are compared to historical controls) buprenorphine AUC 1.19 (0.91-1.57) buprenorphine C max 1.18 (0.93-1.50) buprenorphine C min 1.31 (0.95-1.79) naloxone AUC 1.33 (0.90-1.98) naloxone C max 1.09 (0.79-1.51)	No dose adjustment of buprenorphine/naloxone or boceprevir is recommended.
Methadone (methadone 20-150 mg daily + boceprevir 800mg three times daily)	boecprevir AUC 0.80 (0.69-0.93) boceprevir C max 0.62 (0.53-0.72) boceprevir C min 1.03 (0.75-1.42) (Boceprevir AUC, C max and C min are compared to historical controls) R-methadone AUC 0.85 (0.74-0.96) R-methadone C max 0.90 (0.71-1.13) methadone C min 0.81 (0.66-1.00) methadone AUC 0.78 (0.66-0.93) S-methadone C max 0.83 (0.64-1.09) S-methadone C min 0.74 (0.58-0.95) (CYP 3A4/5 inhibition)	No dose adjustment of boceprevir is recommended. Individual patients may require additional titration of their methadone dosage when boceprevir is started or stopped to ensure clinical effect of methadone.
Non-steriodal anti-inflammatories (NSAIDs)
Diflunisal (diflunisal 250 mg two times daily x 7 days + boceprevir 800 mg two to three times daily x 12 days)	boceprevir AUC 0.96 (0.79-1.17) boceprevir C max 0.86 (0.56-1.32) boceprevir C min 1.31 (1.04-1.65)	No dose adjustment required for boceprevir or diflunisal.
Ibuprofen (ibuprofen 600 mg three times daily x 6 days + boceprevir 400 mg single dose)	boceprevir AUC 1.04 (0.90-1.20) boceprevir C max 0.94 (0.67-1.32) boceprevir C min Not available	No dose adjustment required for boceprevir or ibuprofen.
Antidepressants
Escitalopram (escitalopram 10 mg single dose + boceprevir 800 mg three times daily x 11 days)	boceprevir AUC 0.91 (0.81-1.02) boceprevir C max 1.02 (0.96-1.08) escitalopram AUC 0.79 (0.71-0.87) escitalopram C max 0.81 (0.76-0.87)	Exposure of escitalopram was decreased when co- administered with boceprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with boceprevir.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Corticosteroids
Prednisone (prednisone 40 mg single dose + boceprevir 800 mg three times daily x 6 days)	prednisone AUC 1.22 (1.16-1.28) prednisone C max 0.99 (0.94-1.04) prednisolone AUC 1.37 (1.31-1.44) prednisolone C max 1.16 (1.09-1.24)	No dose adjustment is necessary when co- administered with boceprevir. Patients receiving prednisone and boceprevir should be appropriately monitored for side-effects associated with chronic corticosteroid therapy.
HMG CoA reductase inhibitors
Atorvastatin (atorvastatin 40 mg single dose + boceprevir 800 mg three times daily x 7 days)	boceprevir AUC 0.95 (0.90-1.01) boceprevir C max 1.04 (0.89-1.21) atorvastatin AUC 2.30 (1.84-2.88) atorvastatin C max 2.66 (1.81-3.90) (CYP 3A4/4 and OATPB1 inhibition)	Exposure to atorvastatin was increased when administered with boceprevir. Use the lowest possible effective dose of atorvastatin, but do not exceed a daily dose of 20 mg when co-administered with boceprevir.
Pravastatin (pravastatin 40 mg single dose + boceprevir 800 mg three times daily x 6 days)	boceprevir AUC 0.94 (0.88-1.01) boceprevir C max 0.93 (0.83-1.04) pravastatin AUC 1.63 (1.01-2.62) pravastatin C max 1.49 (1.03-2.14) (OATPB1 inhibition)	Concomitant administration of pravastatin with boceprevir increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when co-administered with boceprevir. Close clinical monitoring for pravastatin side-effects is warranted.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Immunosuppressants
Cyclosporine (cyclosporine 100 mg single dose + boceprevir 800 mg single dose) (cyclosporine 100 mg single dose + boceprevir 800 mg three times daily multiple dose)	boceprevir AUC 1.16 (1.06-1.26) boceprevir C max 1.08 (0.97-1.20) cyclosporine AUC 2.68 (2.38-3.03) cyclosporine C max 2.01 (1.69-2.40) (CYP 3A4/5 inhibition - effect on cyclosporine)	The mean half-life for cyclosporine increased from 11.2 hours (administered alone) to 15.5 hours (co- administered with boceprevir) and the mean clearance (CL/F) decreased by approximately 2-fold from 58.8 L/hr(administered alone) to 21.2 L/hr (co- administered with boceprevir). The mean C min measured at 48 hours following a single 100 mg dose of cyclosporine increased from 5.20 ng/mL (administered alone) to 15.0 ng/mL (co-administered with boceprevir). Dose adjustment of cyclosporine should be anticipated when administered with boceprevir and should be guided by close monitoring of cyclosporine blood concentrations, frequent assessments of renal function and cyclosporine- related side effects.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Tacrolimus (tacrolimus 0.5 mg single dose + boceprevir 800 mg single dose) (tacrolimus 0.5 mg single dose + boceprevir 800 mg three times daily x 7 days)	boceprevir AUC 1.00 (0.95-1.06) boceprevir C max 0.97 (0.84-1.13) tacrolimus AUC 17.1 (14.0-20.8) tacrolimus C max 9.90 (7.96-12.3) (CYP 3A4/5 inhibition - effect on tacrolimus)	The mean half-life for cyclosporine increased from 11.2 hours (administered alone) to 15.5 hours (co- administered with boceprevir) and the mean clearance (CL/F) decreased by approximately 2-fold from 58.8 L/hr(administered alone) to 21.2 L/hr (co- administered with boceprevir). The mean C min measured at 48 hours following a single 100 mg dose of cyclosporine increased from 5.20 ng/mL (administered alone)to 15.0 ng/mL (co-administered with boceprevir). Concomitant administration of boceprevir with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessment of renal function and tacrolimus-related side effects. Patients should be monitored for compliance with the dosing regimen as serious adverse reactions including graft rejection, or other adverse reactions could be a consequence of either under- or over- exposure to tacrolimus. (see Product Information for tacrolimus).
Sirolimus	Interaction not studied	Blood concentrations of sirolimus are expected to increase significantly when administered with boceprevir. Close monitoring of sirolimus blood concentrations is recommended.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Oral Contraceptives
Drospirenone/Ethinyl estradiol : (drospirenone 3 mg daily + ethinyl estradiol 0.02 mg daily x 14 days + boceprevir 800 mg three times daily x 7 days)	drospirenone AUC 1.99 (1.87-2.11) drospirenone C max 1.57 (1.46-1.70) ethinyl estradiol AUC 0.76 (0.73-0.79) ethinyl estradiol C max 1.00 (0.91-1.10) (drospirenone - CYP3A4/5 inhibition)	Caution should be exercised in patients with conditions that predispose them to hyperkalaemia or patients taking potassium- sparing diuretics. Alternative contraceptives should be considered.
Norethisterone/ethinyl estradiol : (norethisterone 1 mg daily + ethinyl estradiol 0.035 mg daily x 21 days + boceprevir 800 mg three times daily x 28 days)	norethisterone AUC (0-24h) 0.96 (0.87- 1.06) norethisterone C max 0.83 (0.76-0.90) ethinyl estradiol AUC 0-24h 0.74 (0.68- 0.80) ethinyl estradiol C max 0.79 (0.75 -0.84)	Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels indicate that ovulation was suppressed during co- administration of ethinyl estradiol 0.035 mg/norethindrone 1 mg with boceprevir. Coadministration of boceprevir with combined oral contraceptives containing ethinyl estradiol and at least 1 mg of norethindrone is unlikely to alter the contraceptive effectiveness. (see Pregnancy and Lactation). The ovulation suppression activity of oral contraceptives containing lower doses of norethindrone and of other forms of hormonal contraception during coadministration with boceprevir has not been established. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
Medicinal products by therapeutic areas	Interaction * (Ratio Estimate of PK Parameters in Combination vs. Alone with 90% CI) (postulated mechanism of action, if known)	Recommendations concerning co- administration
Proton pump inhibitor
Omeprazole: (omeprazole 40 mg daily x 5 days + boceprevir 800 mg three times daily x 5 days)	boceprevir AUC (0-8h) 0.92 (0.87-0.97) boceprevir C max 0.94 (0.86-1.02) boceprevir C 8h 1.17 (0.97-1.42) omeprazole AUC (0-8h) 1.06 (0.90-1.25) omeprazole C max 1.03 (0.85-1.26) omeprazole C 8h 1.12 (0.75-1.67)	No dose adjustment of omeprazole or boceprevir is recommended.
SEDATIVES
Midazolam (oral administration) (4 mg single oral dose + boceprevir 800 mg three times daily x 6 days)	midazolam AUC 5.30 (4.66-6.03) midazolam C max 2.77 (2.36-3.25) (CYP3A4/5 inhibition)	Co-administration with boceprevir is contraindicated.
Alprazolam, midazolam, triazolam (intravenous administration)	Interaction not studied (CYP3A4/5 inhibition)	Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of boceprevir with intravenous benzodiazepines (alprazolam, midazolam, triazolam). Dose adjustment of the benzodiazepine should be considered.
* Interaction of boceprevir with other medicinal products (change in mean ratio estimate of boceprevir in combination with co-administered medicine/boceprevir alone with 90% CI) .

ASSESSMENT (HCV-RNA Results *)		ACTION
At Treatment Week 8	At Treatment Week 24
Undetectable	Undetectable	Complete three medicines regimen at Treatment Week 28.
Detectable	Undetectable
Any Result	Detectable	Discontinue three medicines regimen.
* In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS (r) TaqMan (r) assay with a limit of detection of 9.3 IU/ml.

ASSESSMENT (HCV-RNA Results +	)	ACTION
At Treatment Week 8	At Treatment Week 12
Undetectable	Undetectable	Continue three medicines regimen until completion through Treatment Week 36.
Detectable	Undetectable	Continue all three medications until Treatment Week 36, and then Administer peginterferon alpha and ribavirin until Treatment Week 48.
Any Result	Detectable	Discontinue three medicines regimen.
* Previous Partial responders - Patients with a decrease in HCV-RNA viral load >= 2 log10 by Week 12 but never achieved SVR Relapsers -Patients with undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma. + In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqMan (r) assay with a limit of detection of 9.3 IU/ml.

VICTRELIS (BOCEPREVIR) CAPSULES NAME OF THE MEDICINE