Victrelis - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of boceprevir.

Excipient with known effect

Each capsule contains 56 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Each capsule has 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.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Victrelis is indicated for the treatment of chron combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Treatment with Victrelis should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.

Posology

Victrelis must be administered in combination with peginterferon alfa and ribavirin. The Summary of Product Characteristics of peginterferon alfa and ribavirin (PR) must be consulted prior to initiation of therapy with Victrelis.

The recommended dose of Victrelis is 800 mg administered orally three times daily (TID) with food al or light snack). Maximum daily dose of Victrelis is 2,400 mg. Administration without food be associated with a net loss of efficacy due to sub-optimal exposure.

Patients without cirrhosis who are previously untreated or who have failed previous therapy The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials (see section 5.1).

Table 1

Duration of therapy using Response-Guided Therapy (RGT) guidelines in patients without cirrhosis who are previously untreated or who have failed previous therapy to interferon and ribavirin therapy

If the patient has hepatitis C virus ribonucleic acid (HCV-RNA) results greater than or equal to 1,000 IU/mL at TW 8; then discontinue three-medicine regimen.

If the patient has HCV-RNA results greater than or equal to 100 IU/mL at TW 12; then discontinue three-medicine regimen.

If the patient has confirmed, detectable HCV-RNA at TW 24; then discontinue three-medicine regimen.

' In clinical trials, HCV-RNA in plasma was measured with the Roche COBAS Taqman 2.0 assay with a limit of detection of 9.3 lU/mL and a limit of quantification of 25 lU/mL.

*This regimen has only been tested in subjects who have failed previous therapy who were late responders (see section 5.1).

All cirrhotic patients and null responders

• –     Recommended treatment duration is 48 weeks: 4 weeks of bitherapy with peginterferon alfa+

ribavirin + 44 weeks of tritherapy with peginterferon alfa + ribavirin + Victrelis. (Refer to the stopping rule in Table 1 for all patients.)

o The duration of the tritherapy after the first 4 weeks of bitherapy should not be less than 32 weeks. Given the incremental risk of adverse events with Victrelis (anaemia notably); in case the patient cannot tolerate the treatment, consideration could be given to pursue with 12 weeks of bitherapy for the final 12 weeks of treatment instead of tritherapy (see sections 4.8 and 5.1). For additional information on use of Victrelis in patients with advanced liver disease, see section 4.4.

Poorly interferon-responsive patients

In poorly interferon responsive patients (defined as < 1-log10 decline in HCV-RNA at TW 4) t of triple therapy should be considered on a case by case basis, as the likelihood of achieving sustained virologic response (SVR) with triple therapy is lower in these patients (see section 5.1).

Missed doses

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 the missed dose with food and resume the normal dosing sc

Dose reduction

Dose reduction of Victrelis is not recommended.

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

Stopping ru!es

Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1,000 IU per mL at TW 8; or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW 12; or 3) confirmed, detectable HCV-RNA levels at TW 24.

;eprevir 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 older and younger patients (see section 5.2).

enal impairment

o dose adjustment of Victrelis is required in patients with any degree of renal impairment (see ction 5.2).

Hepatic impairment

No dose adjustment of Victrelis is required for patients with mild, moderate or severe hepatic impairment. Boceprevir has not been studied in patients with decompensated cirrhosis (see section 5.2). For additional information on use of Victrelis in patients with advanced liver disease, see section 4.4.

Paediatric population

The safety and efficacy of Victrelis in children aged below 18 years have not yet been established. No data are available.

Method of administration

To obtain the hard capsules the foil of the blister should be peeled off. Victrelis is to be taken orally with food (a meal or light snack).

4.3 Contraindications

• • Hypersensitivity to the active substance or any of the excipients listed in section 6.1. *
• • Patients with autoimmune hepatitis.
• • Co-administration 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 and triazolam, bepridil, pimozide, lurasidone, lumefantrine, halofantrine, tyrosine kinase inhibitors, simvastatin, lovastatin, quetiapine, alfuzosin, silodosin, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) (see section 4.5).

• • Pregnancy (see section 4.6).

Refer to the Summary of Product Characteristics for peginterferon information.

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of 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 reactions (see Table 2). Victrelis does not inhibit or induce the other enzymes of the CYP450.

Boceprevir has been shown to be a p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) substrate in vitro. There is potential for inhibitors of these transporters to increase concentrations of boceprevir; the clinical implications of these interactions are not known. A clinical drug interaction study with digoxin demonstrated that boceprevir is a mild P-gp inhibitor in vivo , increasing digoxin exposure by 19%. An increase in plasma concentrations of substrates of the P-gp efflux transporter, such as digoxin or dabigatran, should be anticipated (see table 2).

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 (see section 4.4). Victrelis, in combination with peginterferon alfa and ribavirin, is contraindicated when coadministered 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 and triazolam, bepridil, pimozide, lurasidone, lumefantrine, halofantrine, tyrosine kinase inhibitors, simvastatin, lovastatin, quetiapine, alfuzosin, silodosin, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) (see section 4.3).

Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a nically significant extent. Victrelis may be co-administered with AKR inhibitors.

e concomitant use of Victrelis with rifampicin or anticonvulsants (such as phenytoin, phenobarbital carbamazepine) may significantly reduce the plasma exposure of boceprevir. No data are available;

therefore, the combination of boceprevir with these medicines is not-recommended (see section 4.4).

The concomitant use of Victrelis with doxazosin or tamsulosin may increase plasma concentrations of these medicines. The combination of boceprevir with these medicines is not recommended (see section 4.4).

Caution should be exercised with medicines known to prolong QT interval such as amiodarone, quinidine, methadone, pentamidine and some neuroleptics.

As liver function may change during treatment with Victrelis, a close monitoring of International Normalised Ratio (INR) values is recommended in patients treated with vitamin K antagonists.

Table 2 provides dosing recommendations as a result of drug interactions with Victrelis. These recommendations are based on either drug interaction studies (indicated with ) or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy.

The percent change and arrows (t = increase, ^ = decrease, ^ = no change) are used to show the magnitude and direction of change in mean ratio estimate for each pharmacokinetic parameter.

Table 2

Pharmacokinetic interactions data

Breast-feeding

Boceprevir/me­tabolites are excreted in rat milk (see section 5.3). It is not known whether boceprevir is excreted in human breast milk.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy with Victrelis taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of Victrelis on fertility are available. Effects on fertility and Sertoli cells have been observed in rats but not in mice and monkeys. Clinical data (semen analyses and inhibin B levels – [a glycoprotein produced by Sertoli cells – used as a surrogate marker of testicdar function]) showed no evidence of altered testicular function. Available pharmacodynamic/to­xicological data in rats have shown effects of boceprevir/me­tabolites on fertility, which in females have been shown to be reversible (see section 5.3).

4.7 Effects on ability to drive and use machines

Combination therapy of Victrelis, peginterferon alfa and ribavirin may influence some patients’ ability to drive and use machines. Patients should be informed that fatigue, dizziness, syncope, blood pressure fluctuations and blurred vision have been reported (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

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: one in patients who were previously untreated, and one in patients who had failed prior therapy (see section 5.1).

The most frequently reported adverse reactions were fatigue, anaemia (see section 4.4), nausea, headache, and dysgeusia.

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.

Tabu lated list of adverse reactions

Adverse reactions are listed by System Organ Class (see Table 3). Within each system organ class, adverse reactions are listed under headings of frequency using the categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data).

Table 3

Adverse reactions in combination with Victrelis with peginterferon alfa-2b and ribavirin reported during clinical trials ^ and*

Description of selected adverse reactions

Anaemia (see section 4.4)

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 (see section 4.4). 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/haemolytic 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 clinical trials, the proportion of subjects who received erythropoietin for the management of anaemia was 43% (667/1,548) of subjects in the Victrelis-containing arms compared to 24% (131/547) of subjects receiving peginterferon alfa-2b and ribavirin alone. The majority of the anaemia subjects received erythropoietin when haemoglobin levels were <10 g/dL (or 6.2 mmol/L). 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.

Neutrophils (see section 4.4)

The proportion of subjects with decreased neutrophils was higher in the Victrelis-containing arms compared to subjects receiving only peginterferon alfa-2b and ribavirin. The percentage of patients with Grades 3–4 neutropenia (neutrophil counts < 0.75 × 109/L) was higher in boceprevir-treated patients (29%) than in placebo-treated patients (17%), in combination with 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 × 109/L (Grade 4 neutropenia) compared to 4% of subjects receiving only peginterferon alfa-2b and ribavirin.

Combined use with peginterferon alfa-2a see specific section in section 4.4.

Platelets

Platelet counts were decreased for subjects in the Victrelis containing-arms (3%) compared to subjects receiving peginterferon alfa-2b and ribavirin alone (1%). In both treatment arms, patients with cirrhosis were at a higher risk to experience Grade 3–4 thrombocytopenia compared with non cirrhotic patients.

Other laboratory findings

The addition of Victrelis to peginterferon alfa-2b and nbav:rin was associated to higher incidences of increase in uric acid, triglycerides and cholesterol total compared to peginterferon alfa-2b and ribavirin only.

Patients with HIV co-infection

The safety profile of Victrelis in HCV/HIV-1 co-infected patients (n=64) was overall similar to the safety profile in mono-infected HCV patients.

Reporting of suspected adverse reacti ons

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Daily doses of 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. Treatment of overdose with Victrelis should consist of general supportive measures, including monitoring of vital signs, and observation of the patient’s clinical status.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE12

Mechanism of action

Boceprevir is an inhibitor of the HCV NS3 protease. Boceprevir 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.

Antiviral activity in cell culture

The antiviral activity of boceprevir was evaluated in a biochemical assay for slow binding inhibitors of NS3 protease and in the genotype 1a and 1b HCV replicon system. The IC50 and IC90 values for boceprevir against different genotype 1b replicons ranged from 200 to 600 nM and 400 to 900 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 R Prolonged exposure resulted in a 2-log decrease in RNA levels by Day 15. In a genotype 1a replicon, the IC50 and IC90 values for boceprevir were 900 nM and 1,400 nM, respectively.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that prod suppression of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

Resistance

The activity of boceprevir against the HCV genotype 1a replicon was reduced (2– to 6-fold) by the following amino acid substitutions in the NS3 protease domain: V36A/L/M, Q41R, T54A/S, V55A, R155K and V158I. A greater than 10-fold reduction in boceprevir susceptibility was conferred by the amino acid substitutions R155T and A156S. The V55I and D168N single substitutions did not reduce sensitivity to boceprevir. The following double amino acid substitutions conferred more than 10-fold reduced sensitivity to boceprevir: V55A+I170V, T54S+R155K, R155K+D168N, R155T+D168N and V36M+R155K.

type 1b replicon was reduced (2– to 8-fold) by the

following amino acid substitutions in the NS3 protease domain: V36A/M, F43S, T54A/G/S, V55A, R155K/G, V158I, V170M and M175L. A greater than 10-fold reduction in boceprevir susceptibility was conferred by the amino acid substitutions A156S/T/V, V170A, R155W+A156G and V36M+R155K. The D168V single substitution did not reduce sensitivity to boceprevir.

In a pooled analysis of subjects who were previously untreated and subjects who have failed previous therapy who received four weeks of peginterferon alfa-2b and ribavirin followed by boceprevir 800 mg three times daily in combination with peginterferon alfa-2b and ribavirin in two Phase III studies, post-baseline RAVs were detected in 15% of all subjects. In boceprevir-treated subjects who did not attain sustained virologic response (SVR) for whom samples were analysed, 53% had postbaselines detected.

The most frequently (> 25% of subjects) detected post-baseline RAVs in these subjects were amino acid substitutions V36M (61%) and R155K (68%) in subjects infected with genotype 1a viruses and T54A (42%), T54S (37%), A156S (26%) and V170A (32%) in subjects infected with genotype 1b viruses.

In subjects treated with boceprevir, interferon responsiveness (as defined by > 1-logi0 decline in viral load at Treatment Week 4) was associated with detection of fewer RAVs, with 6% of these subjects having RAVs compared to 4i% of subjects with < i-logi0 decline in viral load at Treatment Week 4 (poorly interferon responsive).

In subjects treated with boceprevir who did not achieve SVR and with post-baseline samples analysed for RAVs, interferon responsiveness was associated with detection of fewer RAVs, with 31% of these subjects having post-baseline RAVs compared to 69% of subjects with < 1-log10 decline in viral load at Treatment Week 4.

RAVs were detected in 8% of patients at baseline by population sequencing. Overall, the presence of baseline RAVs did not appear to have a notable association with treatment response in subjects receiving the combination of boceprevir with peginterferon alfa-2b and ribavirin.

However, among poorly interferon-responsive patients to peginterferon alfa-2b/ribavirin during the 4-week lead-in period, the efficacy of boceprevir appeared to be reduced for those who had variants V36M, T54S, V55A or R155K detected at baseline. Subjects with these baseline variants and reduced response to peginterferon alfa-2b/ribavirin represented approximately 1% of the total number of subjects treated with boceprevir.

Follow-up analysis of boceprevir-treated subjects who did not achieve SVR showed that the population of wild-type virus increased and the majority of boceprevir-resistant variants became undetectable over time after the end of boceprevir treatment. Of 314 treatment-naive a.d previously treated subjects who did not achieve SVR from Phase 2/3 studies (P03523, P03659, P05216, and P05101) in whom boceprevir-resistant variants had emerged during treatment, 73% (228/314) of subjects no longer had any RAVs detected at the boceprevir-resistance associated loci by population sequencing within 3 years post-therapy. Among the variants, 91% of V36M, 98% of T54A, 71% of

T54S, 78% of V55A, 76% of R155K, 92% of A156S, 96% of I/V170A, 77% of R155K+T54S and 95% of R155K+V36M were undetectable by population sequencing. The median time for all RAVs to become undetectable was 1.11 years.

Among the 314 subjects, 230 were infected with genotype 1a HCV and 84 were infected with genotype 1b HCV. Seventy percent (70%) (162/230) of genotype 1a subjects no longer had any RAVs detected at the boceprevir-resistance associated loci by population sequencing. The median time for all RAVs to become undetectable was 1.17 years for genotype 1a. The median times for the most relevant boceprevir-resistant variants observed in genotype 1a patients (> 10%) to become undetectable were as follows: R155K+V36M, 0.69 years; V36M, 0.89 years; R155K+T54S, 1.05 years; R155K, 1.08 years; and T54S, 1.14 years. In comparison, 79% (66/84) of genotype 1b subjects no longer had any RAVs detected at the boceprevir-resistance associated loci by population sequencing. The median time for all RAVs to become undetectable was 1.04 years for genotype 1b. The median times for the most relevant boceprevir-resistant variants observed in genotype 1b patients (> 10%) to become undetectable were as follows: I/V170A, 0.46 years; T54A, 0.47 years; V55A,

0.83 years; A156S, 0.89 years; and

Efficacy

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 alfa and ribavirin) significantly increased sustained virologic response (SVR) rates compared to the current standard of care alone. It should be noted that retrospective analyses bridging the data between the two pivotal studies have led to a recommended posology that differs from the regimen studied in some patient subgroups.

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 ^g/kg/week subcutaneously and weight-based dosing with ribavirin (6001,400 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 were randomized in a 1:1:1 ratio in two cohorts (Cohort 1 N=

938/non-Black and Cohort 2 /Black N=159) and stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (< 400,000 lU/mL vs. > 400,000 lU/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.

o Subjects with undetectable HCV-RNA at TW 8 (early responders) and who also had undetectable HCV-RNA through TW 24 discontinued therapy and entered follow-up at the TW 28 visit.

o Subjects with detectable HCV-RNA at TW 8 or any subsequent treatment week but subsequently undetectable at TW 24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with peginterferon alfa-2b + ribavirin for an additional 20 weeks, for a total treatment duration of 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-P 48).

All subjects with detectable HCV-RNA in plasma at TW 24 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectableplasma 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 medicine (Full-Analysis-Set population) and decreased the length of therapy to 28 weeks for early responders (see Table 4). 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-

Table 4

Sustained Virologie Response (SVR) , End of Treatment (EOT) and Relapse Rates for patients who are previously untreated

• * The Full Analysis Set (FAS) consisted of all randomized subjects (N=1,097) who received at least one dose of any study medicine (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.

• * 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 EOF data.

• * SVR: defined as undetectableplasma 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: 37% for Control, 62% for Victrelis-RGT, 65% for Victrelis-PR48.

• § The number of subjects with cirrhosis is limited (where 40 subjects were treated with Victrelis of the total of 53 subjects).

Interferon-responsiveness (as defined by > 1-log, decline in viral load at TW 4) was predictive of SVR. In subjects who demonstrated interferon responsiveness by TW 4, treatment with the combination of Victrelis with peginterferon alfa-2b and ribavirin resulted in SVR rates of 79–81%, compared to 51% in subjects treated with standard of care. 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 28–38%, respectively, compared to 4% in subjects treated with standard of care.

Sustained Virologi c Resp onse (SVR) in patients receiving similar therapy up to treatment week 28

Table 5 presents sustained virologic response per treatment arm in previously untreated patients who were early responders and late responders and that received similar therapy up to treatment week 28. Fifty-seven percent (208/368) of subjects in the Victrelis-RGT arm and 56% (204/366) of subjects in the Victrelis-PR48 arm had undetectable HCV-RNA at TW 8 compared with 17% (60/363) of subjects in the PR arm.

Table 5

Sustained Virologie Response (SVR), End of Treatment (EOT), and Relapse in previously untreated patients (early and late responders)

As a conservative measure in view of the limitations of the data, in treatment naïve patients-late

responders, the treatment duration of the tritherapy is recommended to be prolonged to 32 weeks as

compared to the tested 24 weeks duration of the tritherapy, for a total treatment duration of 48 weeks.

Patients with HIV co-infection

\O

P05411 was a phase II randomized, double-blind, placebo-controlled study comparing Victrelis

800 mg orally three times daily in combination with pR [peginterferon alfa-2b 1.5 ^g/kg/week subcutaneously and weight-based dosing with ribavirin (600–1,400 mg/day orally)] to PR alone in subjects co-infected with HIV and HCV genotype 1 who were previously untreated for chronic HCV infection. Subjects were treated with 4 weeks of PR followed by 44 weeks of Victrelis or placebo with PR. Subjects were on an antiretroviral regimen with stable HIV disease (HIV-1 viral load < 50 copies/mL and CD4 count > 200 ce’ls/^L). The majority of subjects (87%; 85/98) were taking a ritonavir-boosted HIV protease inhibitor (PI) combined with HIV nucleoside reverse transcriptase inhibitors (NRTIs). The most common HIV PI taken was atazanavir followed by lopinavir and darunavir. Subjects were randomized in a2:1 ratio and stratified based on cirrhosis/fibrosis and baseline HCV-RNA (< 800,000 IU/mL vs. > 800,000 IU/mL).

The SVR rate was 62.5% (40/64) in subjects treated with Victrelis in combination with PR and 29.4% (10/34) in subjects treated with PR alone (see Table 6).

In the limited number of co-infected subjects who did not achieve SVR and for whom population sequencing was performed, the prevalence of post-baseline RAVs was higher than that in monoinfected subjects in study SPRINT-2.

Table 6

Sustained Virologie Response (SVR), End of Treatment (EOT) and HCV Relapse Rates * in previously untreated subjects with HIV co-infection

• * The Full Analysis Set (FAS) consisted of all randomized subjects (N=98) who received at least one dose of any study medicine (peginterferon alfa-2b, ribavirin, or Victrelis). Mean age of subjects randomized was 43.6 years. The race distribution of subjects was as follows: 82% White, 18% Non-White, 14% Black, 3% Asian, and 1% Multiracial. The distribution of subjects by gen was 69% men and 31% women. The study included 5 subjects with cirrhosis and 4 were in the Victrelis arm.

  
  

• * HCV 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 EOF data.

• * SVR: defined as undetectableplasma HCV-RNA at Follow-up Week (FW) 24. The last available value in the period at and after FW 24. If there is no such value, the FW 12 value was carried forward.

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 ^g/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 alfa and ribavirin. Null responders (as defined historically by a decrease in HCV-RNA viral load < 2 log10 by Week 12 to prior therapy) were excluded. Subjects 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:

• • Peginterferon af –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.

o Subjects with undetectable HCV-RNA at TW 8 (early responders) and TW 12 completed therapy at TW 36 visit.

o Subjects with a detectable HCV-RNA at TW 8 but subsequently undetectable at TW 12 (late responders) were changed in a blinded fashion to placebo at the TW 36 visit and continued treatment with peginterferon alfa-2b + ribavirin for an additional 12 weeks, for a total treatment duration of 48 weeks.

• • Peginterferon alfa-2b + ribavirin for 4 weeks followed by Victrelis 800 mg three times

daily + peginterferon alfa-2b + ribavirin for 44 weeks (Victrelis-PR48).

All subjects with detectable HCV-RNA in plasma at TW 12 were discontinued from treatment. Sustained Virologic Response (SVR) to treatment was defined as undetectableplasma 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 medicine (Full-Analysis-Set population) and decreased the length of therapy to 36 weeks for many previous treatment failures (see Table 7). 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 7). 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.

The Full Analysis Set (FAS) consisted of all randomized subjects (N=403) who received at least

one dose of any study medicine (peginterferon alfa-2b, ribavirin, or Victrelis). Mean age of subjects randomized was 52.7 years. The race distribution of subjects was as follows: 85% 12% Black, 1% Asian, < 1% multiracial, < 1% Native Hawaiian or Other Pacific Islander distribution of subjects by gender was 67% men and 33% women.

Relapse rate was the proportion of subjects with undetectable HCV-RNA at End (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among subjects wh undetectable at EOT and not missing EOF data.

Previous Partial Responder = subject who failed to achieve SVR after previous treatment with peginterferon alfa and ribavirin, but demonstra

HCV-RNA by Week 12 and had detectable HCV-RNA at End of Treatment (EOT).

• 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.

• * * SVR: defined as

  p 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 17/80 [21.3%] for PR48, 94/162 [58.0%] for Victrelis-RGT, 106/161 [65.8%] for Victrelis-PR48.

§ The number of subjects with cirrhosis is limited (where 39 subjects were treated with Victrelis of the total of 49 subjects). j

Sustained Virologic Response (SVR) in patients receiving similar therapy up to treatment week 36

Table 8 presents sustained virologic response per treatment arm in patients who had failed previous

ders and late responders and that received similar therapy up to

Table 8

Sustained Virologie Response (SVR), End of Treatment (EOT) and Relapse in patients who had failed previous therapy (early and late responders)

As a conservative measure in view of limitations of the data, in treatment experienced patients early

responders, the total treatment duration is recommended to be prolonged to 48 weeks as compared to the tested 36 weeks total treatment duration (tested RGT), with a 12 weeks of peginterferon ribavirin consolidation phase after the end of the tritherapy at week 36.

A study with peginterferon alfa-2a in treatment experienced patients gave consistent results as compared to the study P05101 (see section 4.4).

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

PROVIDE (P05514) was an open-label, single-arm study of Victrelis 800 mg orally three times daily in combination with PR [peginterferon afa-2b 1.5 ^g/kg/week subcutaneously and weight-based ribavirin (600 – 1,400 mg BID) orally divided twice daily] in adult subjects with chronic hepatitis C (HCV) genotype 1 infection who did not achieve SVR while in the PR control arms of previous Phase 2 and 3 studies of combination therapy with Victrelis. Subjects who enrolled in PROVIDE within 2 weeks after the last dose of PR in the parent study received Victrelis 800 mg three times daily + PR for 44 weeks. Subjects 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 + PR for 44 weeks.

The subjects included 62% (104/168) genotype 1a and 38% (63/168) genotype 1b. Ten percent of subjects (17/168) were cirrhotic, including 3 (6%) prior null responders, 2 (7%) prior relapsers, and 12 (14%) prior partial responders.

The SVR rates for subjects who received at least one dose of any study medication (Intent-to-Treat population) are shown in Table 9. The SVR rates for those who received at least one dose of Victrelis (i.e. excluding patients who discontinued during PR lead-in) are 41% for null responders, 67% for partial responders and 96% for relapsers.

Table 9

Sustained Virologie Response (SVR), End of Treatment (EOT) and Relapse Rates for subjects who

failed previous therapy

The Intent-to-Treat (ITT) population consisted of all subjects (N=168) who received at least one dose of any study medicine (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.

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 EOF data.

• * ** Null responder: subject who had less than a 2-log10 HCV-RNA decline by treatment week 12 with peginterferon alfa-2b and ribavirin.

• ** ** Partial Responder: subject who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa-2b and ribavirin, but demonstrated a L 2 iog10 reduction in HCV-RNA by Week 12 and had detectable HCV-RNA at End of Treatment (EOT).

• ^R elapser: subject who failed to achieve SVR after at least 12 weeks oc previous treatment with peginterferon alfa-2b and ribavirin, but had undetectable HCV-RNA at the end of treatment.

• § SVR: defined as undetectableplasma 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.

  Long-term efficacy data

  
  
  
  

A 3-year follow-up study of subjects who achieved SVR with a Victrelis-based regimen showed that > 99% (693/696) of patients maintained their SVR (no relapse) through the available follow-up period (median duration of 3.4 years).

Exploratory pharmacogenom.i: analysis of IL28B in phase 3 studies of Victrelis

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon alfa-2b/ribavirm. IL28B rs12979860 was genotyped in 653 of 1,048 (62%) subjects in SPRINT-2 (previously untreated) and 259 of 394 (66%) subjects in RESPOND-2 (previous treatment failure) [see section 5.1 for the clinical trial descriptions]. The results of this retrospective subgroup analysis should be viewed with caution because of the small sample size and potential differences of the sub-study population relative to the overall trial population.

The degree of added value of Victrelis on top of the bitherapy in C/C patients will depend on the likelihood of achieving SVR with the bitherapy only. In C/C patients receiving tritherapy 89% in treatment naive were HCV-RNA undetectable by TW 8 and eligible for shorter duration of therapy as compared to 52% in treatment naïve non C/C.

In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS Taqman assay with a limit of detection of 9.3 IU/mL and a limit of quantification of 25 IU/mL.

Table 10

Sustained Virologie Response (SVR) rates by IL28B rs12979860 genotype

Please see section 5.1 clinical trial descriptions for each treatment arm.

Whether on treatment early viral response and/or IL28B genotype could reliably identify those patients who are unlikely to retrieve significant benefit of boceprevir (higher SVR rates or short course treatment duration) on top of the bitherapy is currently under investigation.

Use of ribavirin dose reduction versus erythropoietin in the managem ent of anaemia in previously untreated subjects

A randomized, parallel-arm, open-label study (P06086) was conducted to compare two strategies for the management of anaemia (use of erythropoietin versus ribavirin dose reduction) in 687 subjects including 60 cirrhotic patients with previously untreated CHC genotype 1 infection who became anaemic during therapy with Victrelis 800 mg orally three times daily in combination with PR [peginterferon alfa-2b 1.5 ^g/kg/week subcutaneously and weight-based ribavirin (600 – 1,400 mg BID) orally divided twice daily].

If serum haemoglobin concentrations continued to decrease to < 8.5 g/dL, subjects could be treated with additional anaemia interventions, including the use of erythropoietin or ribavirin dose reduction.

The SVR rates in subjects randomized to receive ribavirin dose reduction and randomized to receive erythropoietin were comparable.

Table 11

Sustained Virologic Response (SVR) * and Relapse Rates for using ribavirin dose reduction versus erythropoietin in the management of anaemia in previously untreated subjects

• * The Full Analysis Set (FAS) consisted of all subjects who became anaemic (serum haemoglobin of approximately <10 g/dL within the treatment period) and were randomized to using either ribavirin dose reduction or erythropoietin (N=500). Mean age of subjects randomized was 49 years. The race distribution of subjects was as follows: 77% White, 19% Black, and 4% others. The distribution of subjects by genders was 37% men and 63% women.

• * 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 EOF data.

• * SVR: defined as undetectableplasma 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 FW24 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 similar to those in the table: 69.9% (174/249) for subjects randomized to receive ribavirin dose reduction; 68.5% (172/251) for subjects randomized to receive erythropoietin.

There were 77 subjects who received > 5 steps ribavirin dose reduction for the management of anaemia. For most of these subjects (n=54), the lowest dose of ribavirin received for at least 14 days was > 600mg/day. A limited number of subjects (n=12) received < 200mg/day of ribavirin for at least 14 days.

The treatment discontinuation rate due to anaemia was 2% (5/249) in subjects randomized to receive ribavirin dose reduction and 2% (6/251) in subjects randomized to receive erythropoietin. The transfusion rate was 4% (10/249) in subjects randomized to receive ribavirin dose reduction and 2% (5/251) in subjects randomized to receive erythropoietin.

The use of erythropoesis stimulating agents was associated with an increased risk of thromboembolic

events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis.

Paediatric populati

The European Medicines Agency has deferred the obligation to submit the results of studies with Victrelis in one or more subsets of the paediatric population in chronic viral hepatitis C (see section 4.2 for information on paediatric use).

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 Victrelis has not been studied.

Effects of food on oral absorption

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 is 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.

Distribution

Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 7

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. At steady-state, the exposure ratio for the two diastereomers is

approximately 2:1, with the predominant diastereomer being pharmacologica­lly active

Biotransformation

Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldoketoreductase (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.

Elimination

Boceprevir is eliminated with a mean plasma half-life (t'/z) of approximately 3.4 hours. 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 popula tions

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. For additional information on use of Victrelis in patients with advanced liver disease, see section 4.4.

Renal impairment

No clinically significant differences in pharmacokinetic parameters were observed between patients with end-stage renal disease (ESRD) and healthy subjects. Boceprevir is not eliminated by dialysis. No dose adjustment is required in these patients and in patients with any degree of renal impairment.

Gender

No gender-related pharmacokinetic differences in the phase III studies have been observed in adult patients.

Race

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

Age

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

5.3 Preclinical safety data

In an in vitro dog Purkinje fiber study, boceprevir prolonged the action potential duration with inver frequency dependence; the clinical relevance remains uncertain.                           ­♦ c

In repeat-dose toxicity studies boceprevir showed testicular degeneration in rats at systemic exposures lower than those in humans at the recommended human therapeutic dose. This is not observed in mice or monkeys.

Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, human peripheral blood lymphocyte and mouse micronucleus assays.

In 2-year carcinogenicity studies, no carcinogenicity was observed, but there was an increased incidence of hepatocellular adenomas in mice, which was not statistically significant, at systemic exposures 5.7-fold higher than those in humans at the recommended therapeutic dose. No carcinomas or adenomas were observed in rats. The hepatocellular tumours are considered due to enzyme induction and therefore not relevant for humans.

Boceprevir/medicine derived material was shown to be transferred into the milk of lactating rats.

Exposure to boceprevir in nursing human infants is estimated to be less than 1% of the dose.

In rats, boceprevir induced reversible effects on fertility and early embryonic development in female rats at exposures 1.2-fold the human exposure at the recommended therapeutic dose. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration (no testicular degeneration has been observed in mice or monkeys). Boceprevir was shown to be devoid of embryonic or teratogenic potential in both rats and rabbits at maternotoxic dose levels.

Data obtained in juvenile rats suggest that the pharmacokinetic profile of boceprevir may be different than in adult rats, possibly due to immaturity of some metabolic pathways. No clinical paediatric exposure data is available (see section 4.2).

6.1 List of excipients

Capsule contents:

Sodium lauryl sulfate Microcrystalline cellulose Lactose monohydrate Croscarmellose sodium Pre-gelatinized starch Magnesium stearate

Capsule shell:

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172) Red iron oxide (E172)

Red printing ink containing:

Shellac

Red iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Storage by the pharmacist

Store in a refrigerator (2°C – 8°C).

Storage by the patient

• • Store in a refrigerator (2°C – 8°C) until expiry.

OR

• • Store outside of the refrigerator at or below 30°C for a period of not more than 3 months until

6.5 Nature and contents of container

Clear polychlorotri­fluoroethylene /PVC/aluminium blisters containing 4 hard capsules per blister cavity. Each blister cavity is heat sealed closed with the peelable lidding in a configuration of 3 blister cavities per blister card and packaged.

Pack sizes: carton of 84 hard capsules and multipack containing 336 (4 packs of 84) hard capsules. Not all pack sizes may be marketed.

nal product or waste material should be disposed of in accordance with local

k Sharp & Dohme Ltd

Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/704/001

EU/1/11/704/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION