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

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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-log drop in replicon RNA. Prolonged exposure resulted in a 2-log 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 subjects 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. Among VICTRELIS-treated subjects who did not achieve a sustained virologic response, and for whom samples were analyzed, 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 subjects who did not achieve SVR and for whom post-baseline samples were analyzed, 31% of PegIntron/REBETOL-responsive subjects, 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 subjects with less than 1-log10 decline in viral load at Treatment Week 4. Clear patterns of boceprevir treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome were not observed.

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Pooled Analysis of Treatment-Emergent NS3 Protease Domain Amino Acid Substitutions Detected Among VICTRELIS-Treated Subjects 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 subjects 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 harboring certain post-baseline, VICTRELIS-treatment-emergent substitutions may decline in relative abundance over time. However, among those subjects with available data, one or more VICTRELIS-treatment-emergent substitutions remained detectable with a population- based sequencing assay in 25% of subjects 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 subjects 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 subjects by a population- based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in subjects treated with VICTRELIS. However, among subjects 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. Subjects with these baseline polymorphisms and reduced response to PegIntron/REBETOL represented approximately 1% of the total number of subjects treated with VICTRELIS.

Many of the treatment-emergent NS3 amino acid substitutions detected in VICTRELIS-treated subjects 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.

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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 subjects 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 subjects and HCV-infected subjects. 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 4fold 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.

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Special Populations

In a study of patients 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 patients with end-stage renal disease (ESRD) and healthy subjects. No dose adjustment is required in these patients and in patients with any degree of renal impairment.

No gender-related pharmacokinetic differences have been observed in adult patients. Race 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 subjects 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 subjects who had Chronic Hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects (N=1099) 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 subjects 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.

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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 subjects randomised was 49 years. The racial distribution of subjects was as follows: 82% White, 14% Black, and 4% others. The distribution of subjects by gender was 60% men and 40% women. All subjects with detectable HCV-RNA in plasma at TW 24 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectable1 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 subjects 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 two-fold higher than the SVR rate for the PR48 control (23%) (see Table 2). A secondary analysis of subjects 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

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.

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Interferon-responsiveness (as defined by >= 1-log10 decline in viral load at TW 4) was predictive of SVR. VICTRELIS -treated subjects who demonstrated interferon responsiveness by TW 4 achieved SVR rates of 79-81%. In subjects 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 2838%, 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 subjects in the VICTRELIS -RGT arm had undetectable HCV-RNA at TW 8 (early responders). After accounting for treatment discontinuations, 44% (162/368) of subjects 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 subjects 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, subjects 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 subjects in the Victrelis-PR48 arm (75%, 55/73) (see Table 3). Subjects 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, subjects 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.

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

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

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Patients who have failed previous 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 subjects 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. Subjects (N=404) were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. non-responders) and by HCV subtype (1a vs. 1b) to one of the following 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 32 weeks. The subjects were then continued 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 subjects randomised was 53 years. The racial distribution of subjects was as follows: 85% White, 12% Black, and 3% others. The distribution of subjects by gender was 67% men and 33% women.

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All subjects with detectable HCV-RNA in plasma at TW 12 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectable2 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 subjects 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 subjects 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 subject'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 subject'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

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.

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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 subjects in the VICTRELIS- RGT arm and 52% (84/161) of subjects in the VICTRELIS -PR48 arm were early responders (subjects with undetectable HCV-RNA at TW 8). Of the subjects that were early responders, 71 subjects were undetectable at TW12 in the VICTRELIS-RGT arm and 81 subjects 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 subjects who were not early responders (subjects 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 subjects in the VICTRELIS-RGT arm and 37 subjects 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.

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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

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

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The use of erythropoietin was permitted with or without ribavirin dose reduction in the clinical trials in subjects who are previously untreated and subjects who have failed previous therapy as a supportive therapy for the management of anaemia (see PRECAUTIONS).

CONTRAINDICATIONS

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

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Refer to the corresponding Data Sheet 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 Data Sheet of peginterferon alpha and ribavirin must be consulted prior to initiation of therapy with VICTRELIS.

Anaemia:

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. Complete blood counts should be obtained pretreatment, Treatment Week 4, Treatment Week 8, and thereafter, 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. Refer to the Data Sheet for ribavirin for statements regarding dose reduction and/or interruption.

Neutropenia:

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 x 109/L compared to 4% of subjects receiving PegIntron/REBETOL alone. 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 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 the Data Sheet for peginterferon alpha and ribavirin for statements regarding dose reduction and/or interruption.

HCV protease monotherapy:

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.

Use in patients with rare hereditary disorders:

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

Potent CYP3A4 inducers:

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

Drospirenone-containing medications:

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).

Simvastatin:

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

Impairment on fertility

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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 the Data Sheet 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 evidence that this finding is clinically relevant in human subjects.

Use in Pregnancy: Category (X) - Use with Ribavirin and Peginterferon alfa

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 Data Sheet).

Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa Data Sheet). 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.

Use in Pregnancy: Boceprevir( Category B2) -

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 Data Sheet for ribavirin and peginterferon alpha for additional information.

Use in Lactation Use with ribavirin and peginterferon alfa:

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

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must be made whether to discontinue nursing or discontinue treatment, taking into account the importance of the therapy to the mother.

Patients under the age of 18 years:

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

Elderly patients 65 years of age:

Clinical studies of VICTRELIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 Data Sheet for ribavirin and peginterferon for additional information.

Carcinogenesis and Mutagenesis: Use with VICTRELIS:

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.

Drug Interaction

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 is a potential inhibitor of p-glycoprotein (P-gp) based on in vitro studies. The potential for a drug interaction with sensitive substrates of p-glycoprotein (e.g., digoxin) has not been evaluated in a clinical trial. 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,

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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.

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Effects on ability to drive and use machines

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 Data Sheet for PEG-INTRON, PEGATRON Combination Therapy or REBETOL Capsules for additional PRECAUTIONS.

ADVERSE REACTIONS

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 subjects who were previously untreated. SPRINT-2 (P05216 subjects who were previously untreated) and RESPOND-2 (P05101 - subjects 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. Subjects 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 subjects 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 subjects in the VICTRELIS-containing arms 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 peginterferon alfa-2b and ribavirin and 12% for subjects receiving peginterferon alfa-2b and ribavirin alone. Events resulting in discontinuation were similar to those seen in previous studies

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with peginterferon alfa-2b and ribavirin. Only anaemia 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 medication occurred in 39% of subjects receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin compared to 24% of subjects receiving peginterferon alfa-2b and ribavirin alone. The most common reason for dose reduction was anaemia, which occurred more frequently in subjects receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin than in subjects receiving peginterferon alfa-2b and ribavirin alone. Adverse reactions considered by investigator to be causally related reported in >=10% of subjects who received the combination of VICTRELIS with peginterferon alfa-2b and ribavirin are listed in Table 9.

Table 9

Adverse reactions reported in >=10% of subjects 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 Subjects Reporting Adverse Reactions		Percentage of Subjects Reporting Adverse Reactions
Body System Organ Class	VICTRELIS + peginterferon alfa-2b +ribavirin (n=1225)	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
Anemia *	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

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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
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 subjects.

Since VICTRELIS is prescribed with peginterferon alpha and ribavirin, please also refer to the respective Data Sheet for peginterferon alpha and ribavirin.

Injection-site reactions have not been included since VICTRELIS is administered orally.

Anaemia

: Anaemia was observed in 49% of subjects treated with the combination of VICTRELIS with peginterferon alfa-2b and ribavirin compared with 29% of subjects 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 subjects having received erythropoietin (see PRECAUTIONS). The proportion of subjects who received a transfusion for the management of anaemia was 3% of subjects in the VICTRELIS -containing arms compared to < 1% of subjects receiving peginterferon alfa-2b and ribavirin alone.

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Neutrophils and Platelets: The proportion of subjects with decreased neutrophil and platelet counts was higher in the VICTRELIS-containing arms compared to subjects receiving only peginterferon alfa-2b and ribavirin. Seven percent of subjects receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin had neutrophil counts of < 0.5 x 109 /l compared to 4% of subjects receiving only peginterferon alfa-2b and ribavirin. Three percent of subjects receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin had platelet counts of < 50 x 109 /l compared to 1% of subjects receiving only peginterferon alfa-2b and ribavirin.

DOSAGE AND ADMINISTRATION

VICTRELIS must be administered in combination with peginterferon alpha and ribavirin. The Data Sheet 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 10).

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 11). If patient has detectable HCV-RNA at TW 24 discontinuation of therapy is recommended.

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

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Response-Guided Therapy was not studied in 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). If considered for treatment, these subjects 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 Data Sheet 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. Renal impairment No dose adjustment of VICTRELIS is required in patients with any degree of renal impairment (see PHARMACOLOGY).

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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).

Organ transplant recipients:

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.

Patients co-infected with HCV/HIV:

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.

Patients co-infected with HCV/HBV:

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.

Patients having HCV genotypes other than genotype 1:

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 (NZ) Ltd PO Box 99 851 Newmarket Auckland 1149 Tel: 0800 500 673

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MEDICAL CLASSIFICATION

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	Subjects Infected with HCV Genotype 1a	Subjects Infected with HCV Genotype 1b
>10% of VICTRELIS treated subjects who did not achieve SVR	V36M, T54S, R155K	T54A, T54S, V55A, A156S, I/V170A
<1% to 10% of VICTRELIS treated subjects 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 + %	9	9	22
(n/N)	(24/257)	(24/265)	(39/176)
Cohort 1 (non-Black)	n=316	n=311	n=311
SVR ++ %	67	68	40
EOT(Undetectable HCV-RNA) %	74	77	57
Relapse + %	9	8	23
(n/N)	(21/232)	(18/230)	(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 subjects 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 subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data. ++ SVR: The last available value in the period at or after Follow-up Week (FW) 24. If there is no such value, the FW 12 value is carried forward. SVR24 rates (SVR with "missing=failure" approach) were nearly identical. Cohort 1: 39% PR48; 66% VICTRELIS -RGT, 68% VICTRELIS -PR48. Cohort 2: 21% PR48, 42% VICTRELIS -RGT, 51% VICTRELIS -PR48. Cohort 1+ Cohort 2: 37% Control; 62% VICTRELIS -RGT, 65% VICTRELIS -PR48.

	Undetectable HCV-RNA at TW 8 *		Detectable HCV-RNA at TW 8 *
	VICTRELIS-RGT +	VICTRELIS- PR48	VICTRELIS-RGT +	VICTRELIS- PR48
SVR ++ %	96	96	72	75
	(156/162)	(155/161)	(59/82)	(55/73)
(n/N)
EOT (Undetectable HCV-	100	99	80	90
RNA), % (n/N)	(162/162)	(159/161)	(66/82)	(66/73)
Relapse ++++ %	3	1	11	14
	(5/161)	(2/157)	(7/66)	(9/64)
(n/N)
* Per the study design, subjects 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 - Subjects 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 (subjects 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 (subjects with detectable HCV-RNA at TW 8 up to TW 24; but achieving undetectable HCV-RNA at TW 24). ++ Sustained Virologic Response (SVR): The last available value in the period at and after Follow-up Week (FW) 24. If there is no such value, the FW 12 value was carried forward. ++++ Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV- RNA at End of Follow-up (EOF) among subjects 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,	73 (35/48)	70 (37/53)	53 (30/57)
	>=40-<65,	63 (193/308)	66 (201/306)	35 (103/291)
	>=65,	42 (5/12)	57 (4/7)	27 (4/15)
	>=75,	64 (151/237)	68 (159/235)	32 (70/217)
Body Mass Index (BMI)	<=25,	58 (59/101)	68 (83/123)	47 (60/129)
	>25-30,	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)

	Metavir Fibrosis Score (F3/4), % (n/N)	41 (14/34)	52 (22/42)	38 (9/24)
Baseline Platelet Count (10 9 /L)	<150	55 (18/33)	53 (20/38)	30 (8/27)
Baseline Platelet Count (10 9 /L)	>=150	64 (215/335)	68 (222/328)	38 (129/336)
* The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of any study medication (N=1,097) (peginterferon alfa-2b, ribavirin, or VICTRELIS). Mean age of subjects randomized was 49.1 years. The race distribution of subjects was as follows: 82% White, 14% Black, 2% Asian, 1% multiracial, 1% American Indian or Alaskan Native. The distribution of subjects by gender was 60% men and 40% women.

	Overall	Previous Treatment Response		Lead-In Response ++ (Viral Load Reduction)
	Overall	Previous Non- Responders * * *	Previous Relapsers +	< 1-log 10 decline	>= 1-log 10 decline
PR48 (N=80)
SVR ++++ %	21	7	29	0	25
(n/N)	(17/80)	(2/29)	(15/51)	(0/12)	(17/67)
Relapse * * % (n/N)	32	33	32	0	32
	(8/25)		(7/22)
	(8/25)	(1/3)	(7/22)	(0/0)	(8/25)
EOT %	31	10	43	0	37
(n/N)	(25/80)	(3/29)	(22/51)	(0/12)	(25/67)
Victrelis-RGT (N=162)
SVR ++++ %	59	40	69	33	73
(n/N)	(95/162)	(23/57)	(72/105)	(15/46)	(80/110)
Relapse * * % (n/N)	15	18	14	12	16
	(17/111)		(12/83)
	(17/111)	(5/28)	(12/83)	(2/17)	(15/94)
EOT % (n/N)	70	54	79	41	86

	(114/162)	(31/57)	(83/105)	(19/46)	(95/110)
Victrelis-PR48 (N=161)
SVR ++++ %	66	52	75	34		79
(n/N)	(107/161)	(30/58)	(77/103)	(15/44)		(90/114)
Relapse * * % (n/N)	12	14	10	25		9
	(14/121)		(9/86)
	(14/121)	(5/35)	(9/86)	(5/20)		(9/99)
EOT %	77	60	86	48		89
(n/N)	(124/161)	(35/58)	(89/103)	(21/44)		(101/114)
* The Full Analysis Set (FAS) consisted of all randomized subjects who received at least one dose of any study medication (N=403) (peginterferon alfa-2b, ribavirin, or VICTRELIS). * * Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data. * * * Previous Non-Responder = subject who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin, but demonstrated a >= 2 log 10 reduction in HCV-RNA by Week 12. + Previous Relapser = subject who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin, but had undetectable HCV-RNA at the end of treatment. ++ Eleven subjects were missing TW 4 assessment (HCV-RNA) and were not included in the Lead-In response results. ++++ Sustained Virologic Response (SVR): The last available value in the period at and after Follow-up Week (FW) 24. If there is no such value, the FW 12 value was carried forward. SVR rates (SVR with "missing=failure" approach) 17/80 [21.3%] PR48, 94/162 [58.0] Victrelis-RGT, 106/161 [65.8%] Victrelis-PR48.

	Undetectable HCV-RNA at TW 8		Detectable HCV-RNA at TW 8
	VICTRELIS-RGT +	VICTRELIS-PR48	VICTRELIS-RGT + and SS	VICTRELIS- PR48
SVR * %,	86	88	40	43
(n/N)
(n/N)	(64/74)	(74/84)	(29/72)	(30/70)
EOT (Undetectable	97	95	56	57
HCV-RNA) % (n/N)
HCV-RNA) % (n/N)	(72/74)	(81/84)	(40/72)	(40/70)
Relapse ++++ %	11	8	24	21
(n/N)	(8/71)	(6/80)	(9/38)	(8/38)
* Sustained Virologic Response (SVR): The last available value in the period at and after Follow-up Week (FW) 24. If there is no such value, the FW 12 value was carried forward. + VICTRELIS-RGT - Subjects 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 (subjects 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 (subjects detectable HCV-RNA at TW 8 but subsequently negative by TW 12). ++++ Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV- RNA at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data. SS Includes all subjects with detectable HCV-RNA at TW 8. Late responders represent a subset of this group, subjects 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.

Baseline Viral Load: (IU/mL)	<= 400,000, , % (n/N)	100 (7/7)	71 (5/7)	50 (3/6)
Baseline Viral Load: (IU/mL)	> 400,000, % (n/N)	57 (88/155)	66 (102/154)	19 (14/74)
HCV-1 Subtype:	1a, % (n/N)	53 (50/94)	64 (61/96)	24 (11/46)
HCV-1 Subtype:	1b, % (n/N)	67 (44/66)	71 (43/61)	18 (6/34)
Baseline Fibrosis	Metavir Fibrosis Score (F0/1/2) , % (n/N)	66 (77/117)	68 (81/119)	23 (14/61)
Baseline Fibrosis	Metavir Fibrosis Score (F3/4), % (n/N)	44 (14/32)	68 (21/31)	13 (2/15)
Baseline Platelet Count (10 9 /L)	<150	20 (2/10)	68 (13/19)	38 (8/21)
Baseline Platelet Count (10 9 /L)	>=150	21 (15/70)	66 (94/142)	62 (87/141)
Previous Treatment Response	Relapser	29 (15/51)	75 (77/103)	69 (72/105)
Previous Treatment Response	Nonresponder	40 (23/57)	52 (30/58)	7 (2/29)
* The Full Analysis Set (FAS) consisted of all randomized subjects (N=403) who received at least one dose of any study medication (peginterferon alfa-2b, ribavirin, or VICTRELIS). Mean age of subjects randomized was 52.7 years. The race distribution of subjects was as follows: 85% White, 12% Black, 1% Asian, < 1% multiracial, < 1% Native Hawaiian or Other Pacific Islander. The distribution of subjects by gender was 67% men and 33% women.

Medicinal products by therapeutic areas	Interaction * (postulated mechanism of action, if known)	Recommendations concerning co-administration
ANTI-INFECTIVES
Antiviral
Peginterferon alfa-2b (peginterferon alfa-2b 1.5 mcg/kg subcutaneous (SC) weekly + Victrelis 400 mg three times daily)	Victrelis AUC * * - Victrelis C max - 12% Victrelis C min N/A peginterferon alfa-2b AUC - 1% + ++ and peginterferon alfa-2b C max N/A	No dose adjustment required for Victrelis or peginterferon alfa- 2b.
Antibiotic
Clarithromycin (in combination with diflunisal) (clarithromycin: 500 mg three times daily + diflunisal 500 mg two to three times daily + Victrelis 400 mg two times daily)	Victrelis AUC - 21% Victrelis C max \| 36% Victrelis C min - 15%	No dose adjustment is required with Victrelis in combination with clarithromycin, or Victrelis in combination with clarithromycin and diflunisal.
Antifungals
Ketoconazole (ketoconazole 400 mg two times daily + Victrelis 400 mg single dose)	Victrelis AUC \| 131% Victrelis C max \| 41% Victrelis C min N/A	No dose adjustment required for Victrelis or ketoconazole.
Antiretroviral
Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Tenofovir (tenofovir 300 mg daily + Victrelis 800 mg three times daily)	Victrelis AUC - 8% * * Victrelis C max - 5% Victrelis C min - 8% tenofovir AUC - 5% tenofovir C max \| 32%	No dose adjustment required for Victrelis or tenofovir.
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz (efavirenz 600 mg daily + Victrelis 800 mg three times daily)	Victrelis AUC - 19% * * Victrelis C max - 8% Victrelis C min \| 44% efavirenz AUC - 20% efavirenz C max - 11%	Plasma trough concentrations of Victrelis were decreased when administered with efavirenz. The clinical outcome of this observed reduction of Victrelis trough concentrations has not been directly assessed.
HIV Protease Inhibitor (PI)

ASSESSMENT (HCV-RNA Results *)		ACTION
At Treatment Week 8	At Treatment Week 24	ACTION
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.

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.

Demographics/Baseline Characteristic		VICTRELIS-RGT	VICTRELIS-PR48	PR48
Race	White/Other,	58 (84/144)	68 (97/142)	24 (16/68)
Race	Black,	61 (11/18)	53 (10/19)	8 (1/12)
Age (years)	<40,	60 (3/5)	71 (5/7)	0 (0/4)
	>=40-<65,	58 (84/146)	65 (95/146)	23 (16/70)
	>=65,	73 (8/11)	88 (7/8)	17 (1/6)
Body Mass Index (BMI)	<=25,	60 (21/35)	68 (30/44)	20 (4/20)
	>25-30,	60 (41/68)	67 (44/66)	26 (11/42)
	>30,% (n/N)	56 (33/59)	65 (33/51)	11 (2/18)

NAME OF THE MEDICINE