Merck and Roche Establish Strategic Agreements in Fight Against Chronic Hepatitis C

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May 17, 2011 10:30 am ET

Agreements Focused on Improving Diagnosis, Awareness and Treatment of Chronic Hepatitis C and the Co-Promotion of VICTRELIS™ (boceprevir)

Merck (NYSE: MRK), known as MSD outside the United States, announced
today that it has entered into agreements with Roche (SIX: RO, ROG;
OTCQX: RHHBY), through their respective subsidiaries, to improve
treatment, diagnosis and awareness of chronic hepatitis C (HCV)
infection in developed and emerging markets.

In addition, researchers affiliated with both companies will collaborate
to examine novel combinations of marketed and investigational medicines
from both organizations to expedite the availability of potential new
treatment regimens for patients with HCV.

Under the terms of the non-exclusive agreements, Roche will promote
VICTRELIS™ (boceprevir) to physicians as part of a triple combination
therapy regimen, starting with the United States, and Merck and Roche
will work together to educate physicians and patients about hepatitis C,
including diagnosis. The companies are also working together to extend
the agreement to other developed and emerging markets globally.

“These agreements are consistent with both companies’ goal of improving
healthcare outcomes for patients with chronic hepatitis C,” said Adam H.
Schechter, executive vice president and president, Global Human Health,
Merck. “Hepatitis C often goes undetected for many years. By working
together we will be able to provide physicians, nurses and patients with
education about the disease, its diagnosis and treatment options
including the appropriate use of VICTRELIS.”

“Triple combination therapy for hepatitis C marks a major change in the
way this disease is treated,” said Pascal Soriot, Roche Pharmaceuticals
Division, Chief Operating Officer. “The use of these medicines in
combination offers better treatment outcomes for patients. Roche will
work with Merck to provide health care professionals and patients with
education about the management of hepatitis C. Both companies will also
collaborate to develop improved therapies for this serious disease.”

Important information about VICTRELIS, including safety information

VICTRELIS was approved by the U.S. Food and Drug Administration on May
13 for the treatment of chronic hepatitis C genotype 1 infection, in
combination with peginterferon alfa and ribavirin, in adult patients (18
years of age and older) with compensated liver disease, including
cirrhosis, who are previously untreated or who have failed previous
interferon and ribavirin therapy.

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

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

All contraindications to peginterferon alfa and ribavirin also apply
since VICTRELIS must be administered with peginterferon alfa and
ribavirin. Because ribavirin may cause birth defects and fetal death,
VICTRELIS in combination with peginterferon alfa and ribavirin is
contraindicated in pregnant women and in men whose female partners are
pregnant. Avoid pregnancy in female patients and female partners of male
patients. Patients must have a negative pregnancy test prior to therapy;
have monthly pregnancy tests; and use two or more forms of effective
contraception, including intrauterine devices and barrier methods,
during treatment and for at least 6 months after treatment has
concluded. Systemic hormonal contraceptives may not be as effective in
women while taking VICTRELIS and concomitant ribavirin. VICTRELIS is
contraindicated in coadministration with drugs that are highly dependent
on CYP3A4/5 for clearance, and for which elevated plasma concentrations
are associated with serious and/or life-threatening events.

VICTRELIS also is contraindicated in coadministration with potent
CYP3A4/5 inducers where significantly reduced boceprevir plasma
concentrations may be associated with reduced efficacy. Drugs that are
contraindicated with VICTRELIS include: alfuzosin, carbamazepine,
phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine,
ergotamine, methylergonovine, cisapride, St. John’s Wort (hypericum
perforatum), lovastatin, simvastatin, drosperinone, Revatio^®
(sildenafil) or Adcirca^® (tadalafil) (when used for the
treatment of pulmonary arterial hypertension), pimozide, triazolam, and
midazolam (orally administered).

Anemia has been reported with peginterferon alfa and ribavirin therapy.
The addition of VICTRELIS to peginterferon alfa and ribavirin is
associated with an additional decrease in hemoglobin concentrations. The
addition of VICTRELIS may result in a worsening of neutropenia
associated with peginterferon alfa and ribavirin alone. Complete blood
counts should be obtained pretreatment, and at treatment weeks 4, 8 and
12, and should be monitored closely at other time points, as clinically
appropriate. If a patient has a serious adverse reaction potentially
related to peginterferon alfa and ribavirin therapy, the peginterferon
alfa and/or ribavirin dose should be reduced or discontinued. VICTRELIS
must not be administered in the absence of peginterferon alfa and
ribavirin.

The most commonly reported adverse reactions (greater than 35 percent)
in clinical trials in adult patients receiving the combination of
VICTRELIS with peginterferon alfa-2b and ribavirin were fatigue, anemia,
nausea, headache and dysgeusia. Of these commonly reported adverse
reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates
greater than or equal to 5 percent above the rates for peginterferon
alfa and ribavirin alone in either clinical study. The incidence of
these adverse reactions in previously untreated patients that were
treated with VICTRELIS combination therapy compared with peginterferon
and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30
percent), nausea (46 vs. 42 percent), dysgeusia (35 vs. 16 percent),
respectively. The incidence of these adverse reactions in previously
treated patients that were treated with VICTRELIS combination therapy
compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50
percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent),
dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by
CYP3A4/5. The potential for drug-drug interactions must be considered
prior to and during therapy.

Please see prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

Merck’s global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of
viral hepatitis by continuing to discover, develop and deliver vaccines
and medicines to help prevent and treat viral hepatitis. In hepatitis C,
company researchers developed the first approved therapy for chronic HCV
in 1991 and the first combination therapy in 1998. In addition to
ongoing studies with VICTRELIS, extensive research efforts are underway
to develop additional innovative oral therapies for viral hepatitis care.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in
research-focused healthcare with combined strengths in pharmaceuticals
and diagnostics. Roche is the world’s largest biotech company with truly
differentiated medicines in oncology, virology, inflammation, metabolism
and CNS. Roche is also the world leader in in-vitro diagnostics,
tissue-based cancer diagnostics and a pioneer in diabetes management.
Roche’s personalised healthcare strategy aims at providing medicines and
diagnostic tools that enable tangible improvements in the health,
quality of life and survival of patients. In 2010, Roche had over 80’000
employees worldwide and invested over 9 billion Swiss francs in R&D. The
Group posted sales of 47.5 billion Swiss francs. Genentech, United
States, is a wholly owned member of the Roche Group. Roche has a
majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.

About Merck

Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
Through our prescription medicines, vaccines, biologic therapies, and
consumer care and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
healthcare through far-reaching policies, programs and partnerships. For
more information, visit www.merck.com.

Merck forward-looking statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. Such statements may include,
but are not limited to, statements about the benefits of the merger
between Merck and Schering-Plough, including future financial and
operating results, the combined company’s plans, objectives,
expectations and intentions and other statements that are not historical
facts. Such statements are based upon the current beliefs and
expectations of Merck’s management and are subject to significant risks
and uncertainties. Actual results may differ from those set forth in the
forward-looking statements.

The following factors, among others, could cause actual results to
differ from those set forth in the forward-looking statements: the
possibility that the expected synergies from the merger of Merck and
Schering-Plough will not be realized, or will not be realized within the
expected time period; the impact of pharmaceutical industry regulation
and health care legislation; the risk that the businesses will not be
integrated successfully; disruption from the merger making it more
difficult to maintain business and operational relationships; Merck’s
ability to accurately predict future market conditions; dependence on
the effectiveness of Merck’s patents and other protections for
innovative products; the risk of new and changing regulation and health
policies in the United States and internationally and the exposure to
litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise. Additional factors that could cause results to differ
materially from those described in the forward-looking statements can be
found in Merck’s 2010 Annual Report on Form 10-K and the company’s other
filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (www.sec.gov).

VICTRELIS^™ is a trademark of Schering Corp.,
a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^®
are trademarks of their respective owners and are not trademarks of
Merck & Co., Inc., Whitehouse Station, N.J., USA.

# # #

Please see attached Prescribing Information and Medication Guide for
VICTRELIS. The Prescribing Information and Medication Guide for
VICTRELIS are also available at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf
and http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use
VICTRELIS safely and effectively. See full prescribing information for
VICTRELIS.

VICTRELIS™ (boceprevir) Capsules

Initial U.S. Approval: 2011

—————————INDICATIONS AND
USAGE—————————–

VICTRELIS is a hepatitis C virus (HCV) NS3/4A protease inhibitor
indicated for the treatment of chronic hepatitis C (CHC) genotype 1
infection, in combination with peginterferon alfa and ribavirin, in
adult patients (≥18 years of age) with compensated liver disease,
including cirrhosis, who are previously untreated or who have failed
previous interferon and ribavirin therapy. (1)

VICTRELIS must not be used as a monotherapy. (1)

—————————DOSAGE AND
ADMINISTRATION————————–

800 mg administered orally three times daily (every 7 – 9 hours) with
food (a meal or light snack). (2)
VICTRELIS must be administered in combination with peginterferon alfa
and ribavirin. (2)
Refer to peginterferon alfa and ribavirin Package Inserts for specific
dosing instructions. (2)

———————–DOSAGE FORMS AND STRENGTHS——————–

Capsules: 200 mg (3)

—————————–CONTRAINDICATIONS———————————

All contraindications to peginterferon alfa and ribavirin also
apply since VICTRELIS must be administered with peginterferon alfa and
ribavirin. (4)
Because ribavirin may cause birth defects and fetal death, boceprevir
in combination with peginterferon alfa and ribavirin is
contraindicated in pregnant women and in men whose female partners are
pregnant. (4)
Coadministration with drugs that are highly dependent on CYP3A4/5 for
clearance, and for which elevated plasma concentrations are associated
with serious and/or life-threatening events. (4)
Potent CYP3A4/5 inducers where significantly reduced boceprevir plasma
concentrations may be associated with reduced efficacy. (4)

———————–WARNINGS AND
PRECAUTIONS————————

Use of VICTRELIS with Ribavirin and
Peginterferon alfa:

Ribavirin may cause birth defects and fetal death; avoid pregnancy
in female patients and female partners of male patients. Patients
must have a negative pregnancy test prior to therapy; use two or more
forms of contraception, and have monthly pregnancy tests. (5.1)
Anemia – The addition of VICTRELIS to peginterferon alfa and ribavirin
is associated with an additional decrease in hemoglobin concentrations
compared with peginterferon alfa and ribavirin alone. (5.2)
Neutropenia – The addition of VICTRELIS to peginterferon alfa and
ribavirin may result in worsening of neutropenia associated with
peginterferon alfa and ribavirin therapy alone. (5.3)

——————————-ADVERSE
REACTIONS——————————

The most commonly reported adverse reactions (greater than 35% of
subjects) in clinical trials in adult subjects receiving the combination
of VICTRELIS with PegIntron and REBETOL were fatigue, anemia, nausea,
headache and dysgeusia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation,
a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.

——————————-DRUG
INTERACTIONS——————————

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized
by CYP3A4/5. The potential for drug-drug interactions must be
considered prior to and during therapy. (4, 7, 12.3)

————————–USE IN SPECIFIC
POPULATIONS———————

Cirrhosis: Safety and efficacy has not been studied in patients with
decompensated cirrhosis or in patients with an organ transplant. (8.7,
8.10)
Co-infection with Human Immunodeficiency Virus (HIV): Safety and
efficacy has not been established in patients co-infected with HCV and
HIV. (8.8)
Co-infection with Hepatitis B Virus (HBV): Safety and efficacy has not
been studied in patients co-infected with HCV and HBV. (8.9)
Pediatrics: Safety and efficacy has not been studied in pediatric
patients. (8.4)
Ribavirin Pregnancy Registry available. (8.1)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 05/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

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

2.2 VICTRELIS Combination Therapy: Patients with Cirrhosis

2.3 Dose Modification

2.4 Discontinuation of Dosing Based on Treatment Futility

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Pregnancy (Use with Ribavirin and Peginterferon Alfa)

5.2 Anemia (Use with Ribavirin and Peginterferon Alfa)

5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa)

5.4 Drug Interactions

5.5 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Potential for VICTRELIS to Affect Other Drugs

7.2 Potential for Other Drugs to Affect VICTRELIS

7.3 Established and Other Potential Significant Drug Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Human Immunodeficiency Virus (HIV) Co-Infection

8.9 Hepatitis B Virus (HBV) Co-Infection

8.10 Organ Transplantation

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy

17.2 Anemia

17.3 Neutropenia

17.4 Usage Safeguards

17.5 Missed VICTRELIS Doses

17.6 Hepatitis C Virus Transmission

*Sections or subsections omitted from the full prescribing information
are not listed.

– –

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

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

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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


Table 1 Duration of Therapy Using Response-Guided Therapy (RGT) Guidelines in Patients Without Cirrhosis Who Are Previously Untreated or Who Are Previous Partial Responders or Relapsers to Interferon and Ribavirin Therapy

	ASSESSMENT* (HCV-RNA Results^†)		RECOMMENDATION
	At Treatment Week 8	At Treatment Week 24	RECOMMENDATION
Previously Untreated Patients	Undetectable	Undetectable	Complete three-medicine regimen at TW28.
Previously Untreated Patients	Detectable	Undetectable	1. Continue all three medicines and finish through TW36; and then 2. Administer peginterferon alfa and ribavirin and finish through TW48.
Previous Partial Responders or Relapsers	Undetectable	Undetectable	Complete three-medicine regimen at TW36.
Previous Partial Responders or Relapsers	Detectable	Undetectable	1. Continue all three medicines and finish through TW36; and then 2. Administer peginterferon alfa and ribavirin and finish through TW48.
*TREATMENT FUTILITY If the patient has HCV-RNA results greater than or equal to 100 IU/mL at TW12, then discontinue three-medicine regimen. If the patient has confirmed, detectable HCV-RNA at TW24, then discontinue three-medicine regimen. ^†In clinical trials, HCV-RNA in plasma was measured using a Roche COBAS^® TaqMan^® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. See Warnings and Precautions (5.5) for a description of HCV-RNA assay recommendations.

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

2.2 VICTRELIS Combination Therapy: Patients with Cirrhosis

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

2.3 Dose Modification

Dose reduction of VICTRELIS is not recommended.

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

2.4 Discontinuation of Dosing Based on Treatment Futility

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

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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

VICTRELIS combination treatment is contraindicated in:

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


Table 2 Drugs that are contraindicated with VICTRELIS

Drug Class	Drugs Within Class that are Contraindicated With VICTRELIS	Clinical Comments
Alpha 1-Adrenoreceptor antagonist	Alfuzosin	Increased alfuzosin concentrations can result in hypotension.
Anticonvulsants	Carbamazepine, phenobarbital, phenytoin	May lead to loss of virologic response to VICTRELIS
Antimycobacterial	Rifampin	May lead to loss of virologic response to VICTRELIS.
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for cardiac arrhythmias.
Herbal Products	St. John’s Wort (hypericum perforatum)	May lead to loss of virologic response to VICTRELIS.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for myopathy, including rhabdomyolysis.
Oral Contraceptives	Drosperinone	Potential for hyperkalemia.
PDE5 enzyme Inhibitor	REVATIO^® (sildenafil) or ADCIRCA^® (tadalafil) when used for the treatment of pulmonary arterial hypertension*	Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
Neuroleptic	Pimozide	Potential for cardiac arrhythmias.
Sedative/Hypnotics	Triazolam; orally administered midazolam^†	Prolonged or increased sedation or respiratory depression.

* See Drug Interactions, Table 5 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction. ^† See Drug Interactions, Table 5 for parenterally administered midazolam.

5 WARNINGS AND PRECAUTIONS

5.1 Pregnancy (Use with Ribavirin and Peginterferon Alfa)

Ribavirin may cause birth defects and/or death of the exposed fetus.
Extreme care must be taken to avoid pregnancy in female patients and in
female partners of male patients. Ribavirin therapy should not be
started unless a report of a negative pregnancy test has been obtained
immediately prior to initiation of therapy. Women of childbearing
potential and men must use at least two forms of effective contraception
during treatment and for at least 6 months after treatment has
concluded. Routine monthly pregnancy tests must be performed during this
time. Systemic hormonal contraceptives may not be as effective in women
while taking VICTRELIS. Two alternative effective methods of
contraception, including intrauterine devices and barrier methods,
should be used in women during treatment with VICTRELIS and concomitant
ribavirin.

5.2 Anemia (Use with Ribavirin and Peginterferon Alfa)

Anemia has been reported with peginterferon alfa and ribavirin therapy.
The addition of VICTRELIS to peginterferon alfa and ribavirin is
associated with an additional decrease in hemoglobin concentrations.
Complete blood counts should be obtained pretreatment, and at Treatment
Weeks 4, 8, and 12, and should be monitored closely at other time
points, as clinically appropriate. If hemoglobin is less than 10 g/dL, a
decrease in dosage or interruption of ribavirin is recommended; and if
hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is
recommended [see Adverse Reactions (6.1) and Clinical Studies (14)].

Refer to the Package Insert for ribavirin for additional information
regarding dosage reduction and/or interruption.

In clinical trials with VICTRELIS, the proportion of subjects who
experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL
was higher in subjects treated with the combination of VICTRELIS with
PegIntron^®/REBETOL^® than in those treated with
PegIntron/REBETOL alone (see Table 4). With the interventions used for
anemia management in the clinical trials, the average additional
decrease of hemoglobin was approximately 1 g/dL. Certain adverse
reactions consistent with symptoms of anemia, such as dyspnea,
exertional dyspnea, dizziness and syncope were reported more frequently
in subjects who received the combination of VICTRELIS with
PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone [see
Adverse Reactions (6.1)].

In clinical trials with VICTRELIS, dose modifications (generally of
PegIntron/REBETOL) due to anemia occurred twice as often in subjects
treated with the combination of VICTRELIS with PegIntron/REBETOL (26%)
compared to PegIntron/REBETOL (13%). The proportion of subjects who
discontinued study drug due to anemia was 1% in subjects treated with
the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects
who received PegIntron/REBETOL. The use of erythropoiesis stimulating
agents was permitted for management of anemia, at the investigator’s
discretion, with or without ribavirin dose reduction in the Phase 2 and
3 clinical trials. The proportion of subjects who received an
erythropoiesis stimulating agent was 43% in the VICTRELIS-containing
arms compared to 24% in the PegIntron/REBETOL arms. The proportion of
subjects who received a transfusion for the management of anemia was 3%
of subjects in the VICTRELIS-containing arms compared to less than 1% in
subjects who received PegIntron/REBETOL alone.

Thromboembolic events have been associated with erythropoiesis
stimulating agent use in other disease states; and have also been
reported with peginterferon alfa use in hepatitis C patients.
Thromboembolic events were reported in clinical trials with VICTRELIS
among subjects receiving the combination of VICTRELIS with
PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone,
regardless of erythropoiesis stimulating agent use. No definite
causality assessment or benefit risk assessment can be made for these
events due to the presence of confounding factors and lack of
randomization of erythropoiesis stimulating agent use.

5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa)

In Phase 2 and 3 clinical trials, seven percent of subjects receiving
the combination of VICTRELIS with PegIntron/REBETOL had neutrophil
counts of less than 0.5 x 10⁹/L compared to 4% of subjects
receiving PegIntron/REBETOL alone (see Table 4). Three subjects
experienced severe or life-threatening infections associated with
neutropenia, and two subjects experienced life-threatening neutropenia
while receiving the combination of VICTRELIS with PegIntron/REBETOL.
Complete blood count (with white blood cell differential counts) must be
conducted in all patients prior to initiating VICTRELIS combination
therapy. Complete blood counts should be obtained at Treatment Weeks 4,
8, and 12, and should be monitored closely at other time points, as
clinically appropriate. Decreases in neutrophil counts may require dose
reduction or discontinuation of peginterferon alfa and ribavirin.

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

5.4 Drug Interactions

See Table 2 for a listing of drugs that are contraindicated for use with
VICTRELIS due to potentially life-threatening adverse events,
significant drug interactions or loss of virologic activity [see
Contraindications (4)]. Please refer to Table 5 for established and
other potentially significant drug interactions [see Drug
Interactions (7.3)].

5.5 Laboratory Tests

HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24,
at the end of treatment, during treatment follow-up, and for other time
points as clinically indicated. Use of a sensitive real-time
reverse-transcription polymerase chain reaction (RT-PCR) assay for
monitoring HCV-RNA levels during treatment is recommended. The assay
should have a lower limit of HCV-RNA quantification of equal to or less
than 25 IU/mL, and a limit of HCV-RNA detection of approximately
10-15 IU/mL. For the purposes of assessing Response-Guided Therapy
milestones, a confirmed “detectable but below limit of quantification”
HCV-RNA result should not be considered equivalent to an “undetectable”
HCV-RNA result.

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

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

6 ADVERSE REACTIONS

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

6.1 Clinical Trials Experience

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

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

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

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

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

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

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

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


Table 3 Adverse Events Reported in ≥10% of Subjects Receiving the Combination of VICTRELIS with PegIntron/REBETOL and Reported at a Rate of ≥5% than PegIntron/REBETOL alone

Adverse Events	Previously Untreated (SPRINT-1 & SPRINT-2)		Previous Treatment Failures (RESPOND-2)
	Percentage of Subjects Reporting Adverse Events		Percentage of Subjects Reporting Adverse Events
Body System Organ Class	VICTRELIS + PegIntron + REBETOL (n=1225)	PegIntron + REBETOL (n=467)	VICTRELIS + PegIntron + REBETOL (n=323)	PegIntron + REBETOL (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	46	42	43	38
Dysgeusia	35	16	44	11
Diarrhea	25	22	24	16
Vomiting	20	13	15	8
Dry Mouth	11	10	15	9
General Disorders and Administration Site Conditions
Fatigue	58	59	55	50
Chills	34	29	33	30
Asthenia	15	18	21	16
Metabolism and Nutrition Disorders
Decreased Appetite	25	24	26	16
Musculoskeletal and Connective Tissue Disorders
Arthralgia	19	19	23	16
Nervous System Disorders
Dizziness	19	16	16	10
Psychiatric Disorders
Insomnia	34	34	30	24
Irritability	22	23	21	13
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea Exertional	8	8	11	5
Skin and Subcutaneous Tissue Disorders
Alopecia	27	27	22	16
Dry Skin	18	18	22	9
Rash	17	19	16	6

Other Important Adverse Reactions Reported in Clinical Trials

Among subjects (previously untreated subjects or those who failed
previous therapy) who received VICTRELIS in combination with
peginterferon alfa and ribavirin, the following adverse drug reactions
were reported. These events are notable because of their seriousness,
severity, or increased frequency in subjects who received VICTRELIS in
combination with peginterferon alfa and ribavirin compared with subjects
who received only peginterferon alfa and ribavirin.

Gastrointestinal Disorders

Dysgeusia (alteration of taste) was an adverse event reported at an
increased frequency in subjects receiving VICTRELIS in combination with
peginterferon alfa and ribavirin compared with subjects receiving
peginterferon alfa and ribavirin alone (Table 3). Adverse events such as
dry mouth, nausea, vomiting and diarrhea were also reported at an
increased frequency in subjects receiving VICTRELIS in combination with
peginterferon alfa and ribavirin.

Laboratory Values

Changes in selected hematological parameters during treatment of adult
subjects with the combination of VICTRELIS with PegIntron and REBETOL
are described in Table 4.

Hemoglobin

Decreases in hemoglobin may require a decrease in dosage/interruption or
discontinuation of ribavirin [see Warnings and Precautions (5.2) and
Clinical Studies (14); see Package Insert for ribavirin].

Neutrophils and Platelets

The proportion of subjects with decreased neutrophil and platelet counts
was higher in the VICTRELIS-containing arms compared to subjects
receiving PegIntron/REBETOL alone. Three percent of subjects receiving
the combination of VICTRELIS with PegIntron/REBETOL had platelet counts
of less than 50 x 10⁹/L compared to 1% of subjects receiving
PegIntron/REBETOL alone. Decreases in neutrophils or platelets may
require a decrease in dosage or interruption of peginterferon alfa, or
discontinuation of therapy [see Package Inserts for peginterferon
alfa and ribavirin].


Table 4 Selected Hematological Parameters

	Previously Untreated (SPRINT-1 & SPRINT-2)		Previous Treatment Failures (RESPOND-2)
	Percentage of Subjects Reporting Selected Hematological Parameters		Percentage of Subjects Reporting Selected Hematological Parameters
Hematological Parameters	VICTRELIS + PegIntron + REBETOL (n=1225)	PegIntron + REBETOL (n=467)	VICTRELIS + PegIntron + REBETOL (n=323)	PegIntron + REBETOL (n=80)
Hemoglobin (g/dL)
<10	49	29	49	25
<8.5	6	3	10	1
Neutrophils (x 10⁹/L)
<0.75	31	18	26	13
<0.5	8	4	7	4
Platelets (x 10⁹/L)
<50	3	1	4	0
<25	<1	0	0	0

7 DRUG INTERACTIONS

See also Contraindications (4), Warnings and Precautions (5.4), and
Clinical Pharmacology (12.3).

7.1 Potential for VICTRELIS to Affect Other Drugs

Boceprevir is a strong inhibitor of CYP3A4/5. Drugs metabolized
primarily by CYP3A4/5 may have increased exposure when administered with
VICTRELIS, which could increase or prolong their therapeutic and adverse
effects. Boceprevir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6 or CYP2E1 in vitro. In addition,
boceprevir 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.

7.2 Potential for Other Drugs to Affect VICTRELIS

Boceprevir is primarily metabolized by aldo-ketoreductase (AKR). In drug
interaction trials conducted with AKR inhibitors diflunisal and
ibuprofen, boceprevir exposure did not increase to a clinically
significant extent. VICTRELIS may be coadministered with AKR inhibitors.

Boceprevir is partly metabolized by CYP3A4/5. It is also a substrate for
p-glycoprotein. Coadministration of VICTRELIS with drugs that induce or
inhibit CYP3A4/5 could decrease or increase exposure to boceprevir.

7.3 Established and Other Potential Significant Drug
Interactions

Table 5 provides recommendations based on established or potentially
clinically significant drug interactions. VICTRELIS is contraindicated
with drugs that are potent inducers of CYP3A4/5 and drugs that are
highly dependent on CYP3A4/5 for clearance, and for which elevated
plasma concentrations are associated with serious and/or
life-threatening events [see Contraindications (4)].


Table 5 Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name	Effect on Concentration of Boceprevir or Concomitant Drug	Recommendations
Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine digoxin	↑ antiarrhythmics ↑ digoxin	Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS. Digoxin concentrations may be increased with VICTRELIS. Use the lowest dose initially with careful titration and monitoring of serum digoxin concentrations.
Anticoagulant: warfarin	↑ or ↓ warfarin	Concentrations of warfarin may be altered when co- administered with VICTRELIS. Monitor INR closely.
Antidepressants: trazadone, desipramine	↑ trazadone ↑ desipramine	Plasma concentrations of trazadone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazadone or desipramine.
Antifungals: ketoconazole, itraconazole, posaconazole, voriconazole	↑ boceprevir* ↑ itraconazole ↑ ketoconazole ↑ posaconazole ↑ voriconazole	Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day.
Anti-gout: colchicine	↑ colchicine	Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS. Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (maybe given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function.
Antimycobacterial: rifabutin	↓ boceprevir ↑ rifabutin	Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended.
Calcium Channel Blockers, dihydropyridine: felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Plasma concentrations of dihydropyridine calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended.
Corticosteroid, systemic: dexamethasone	↓ boceprevir	Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary.
Corticosteroid, inhaled: budesonide, fluticasone	↑ budesonide ↑ fluticasone	Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations.
Endothelin Receptor Antagonist: bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely.
HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz	↓ boceprevir*	Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination
HIV Protease Inhibitors: ritonavir	↓ boceprevir* ↑ or ↓ HIV protease inhibitors	Boceprevir concentrations decreased with ritonavir; the effect of ritonavir-boosted HIV protease inhibitors on boceprevir exposure is unknown. The effect of VICTRELIS on HIV protease inhibitor concentrations is unknown.
HMG-CoA Reductase Inhibitors: atorvastatin	↑ atorvastatin	Titrate atorvastatin dose carefully and do not exceed maximum daily dose of 20 mg during coadministration with VICTRELIS
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↑immunosuppressants	Plasma concentrations of cyclosporine, sirolimus and tacrolimus are expected to be increased significantly during coadministration with VICTRELIS. Close monitoring of immunosuppressant blood levels is recommended.
Inhaled beta-agonist: salmeterol	↑ salmeterol	Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol.
Narcotic Analgesic/Opioid Dependence: methadone, buprenorphine	↑ or ↓ methadone ↑ or ↓ buprenorphine	Plasma concentrations of methadone or buprenorphine may increase or decrease when coadministered with VICTRELIS. However, the combination has not been studied. Clinical monitoring is recommended as the dose of methadone or buprenorphine may need to be altered during concomitant treatment with VICTRELIS.
Oral hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone* ↓ ethinyl estradiol*	The effect of boceprevir on other progestins is unknown; however, increases in exposure are anticipated. Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Systemic hormonal contraceptives should not be relied upon as an effective method of contraception in women during treatment with VICTRELIS. Two alternative effective methods of contraception should be used during combination treatment with ribavirin, and may include intrauterine devices and barrier methods [see Use in Specific Populations (8.1)].
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO^® (sildenafil) or ADCIRCA^® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS [see Contraindications (4)]. Use of PDE5 inhibitors for erectile dysfunction: Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours
Sedative/hypnotics: alprazolam; IV midazolam	↑ midazolam ↑ alprazolam	Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered.
* These combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

VICTRELIS must be administered in combination with peginterferon alfa
and ribavirin [see Dosage and Administration (2)].

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 (4),
Warnings and Precautions (5.1) and ribavirin Package Inserts].
Interferons have abortifacient effects in animals and should be assumed
to have abortifacient potential in humans [see peginterferon alfa
Package Inserts].

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 [see Warnings and Precautions (5.1)].

In case of exposure during pregnancy, a Ribavirin Pregnancy Registry
has been established to monitor maternal-fetal outcomes of pregnancies
in female patients and female partners of male patients exposed to
ribavirin during treatment and for 6 months following cessation of
treatment. Physicians and patients are encouraged to report such cases
by calling 1-800-593-2214.

Pregnancy Category B: VICTRELIS

VICTRELIS must not be used as a monotherapy [see Indications and
Usage (1)]. There are no adequate and well-controlled studies with
VICTRELIS in pregnant women.

No effects on fetal development have been observed in rats and rabbits
at boceprevir AUC exposures approximately 11.8- and 2.0-fold higher,
respectively, than those in humans at the recommended dose of 800 mg
three times daily [see Nonclinical Toxicology (13.1)].

8.3 Nursing Mothers

It is not known whether VICTRELIS is excreted into human breast milk. Levels
of boceprevir and/or metabolites in the milk of lactating rats were
slightly higher than levels observed in maternal blood. Peak blood
concentrations of boceprevir and/or metabolites in nursing pups were
less than 1% of those of maternal blood concentrations. Because of the
potential for adverse reactions from the drug in nursing infants, a
decision must be made whether to discontinue nursing or discontinue
treatment with VICTRELIS, taking into account the importance of the
therapy to the mother.

8.4 Pediatric Use

The safety, efficacy, and pharmacokinetic profile of VICTRELIS in
pediatric patients have not been studied.

8.5 Geriatric Use

Clinical studies of VICTRELIS did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently
from younger subjects. In general, caution should be exercised in the
administration and monitoring of VICTRELIS in geriatric patients due to
the greater frequency of decreased hepatic function, concomitant
diseases and other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment of VICTRELIS is required for patients with any
degree of renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment of VICTRELIS is required for patients with mild,
moderate or severe hepatic impairment [see Clinical Pharmacology
(12.3)]. Safety and efficacy of VICTRELIS have not been studied in
patients with decompensated cirrhosis. See Package Inserts for
peginterferon alfa for contraindication in hepatic decompensation.

8.8 Human Immunodeficiency Virus (HIV) Co-Infection

The safety and efficacy of VICTRELIS alone or in combination with
peginterferon alfa and ribavirin for the treatment of chronic hepatitis
C genotype 1 infection have not been established in patients co-infected
with HIV and HCV.

8.9 Hepatitis B Virus (HBV) Co-Infection

The safety and efficacy of VICTRELIS alone or in combination with
peginterferon alfa and ribavirin for the treatment of chronic hepatitis
C genotype 1 infection in patients co-infected with HBV and HCV have not
been studied.

8.10 Organ Transplantation

The safety and efficacy of VICTRELIS alone or in combination with
peginterferon alfa and ribavirin for the treatment of chronic hepatitis
C genotype 1 infection in liver or other organ transplant recipients
have not been studied.

10 OVERDOSAGE

Daily doses of 3600 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
overdosage with VICTRELIS should consist of general supportive measures,
including monitoring of vital signs, and observation of the patient’s
clinical status.

11 DESCRIPTION

VICTRELIS (boceprevir) is an inhibitor of the hepatitis C virus (HCV)
non-structural protein 3 (NS3) serine protease.

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. Boceprevir has the following
structural formula:

(Graphic Omitted)

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.

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 red capsule cap consists of gelatin,
titanium dioxide, D&C Yellow #10, FD&C Blue #1, and FD&C Red #40. The
yellow capsule body contains gelatin, titanium dioxide, D&C Yellow #10,
FD&C Red #40, and FD&C Yellow #6. The capsule is printed with red and
yellow ink. The red ink contains shellac and red iron oxide, while the
yellow ink consists of shellac, titanium dioxide, povidone and D&C
Yellow #10 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

VICTRELIS is a direct acting antiviral drug against the hepatitis C
virus [see Microbiology (12.4)].

12.2 Pharmacodynamics

Evaluation of Effect of VICTRELIS on QTc Interval

The effect of boceprevir 800 mg and 1200 mg on QTc interval was
evaluated in a randomized, multiple-dose, placebo-, and
active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT
study in 36 healthy subjects. In the study with demonstrated ability to
detect small effects, the upper bound of the one-sided 95% confidence
interval for the largest placebo-adjusted, baseline-corrected QTc based
on individual correction method (QTcI) was below 10 ms, the threshold
for regulatory concern. The dose of 1200 mg yields a boceprevir maximum
exposure increase of approximately 15% which may not cover exposures due
to coadministration with strong CYP3A4 inhibitors or use in patients
with severe hepatic impairment. However, at the doses studied in the
thorough QT study, no apparent concentration-QT relationship was
identified. Thus, there is no expectation of a QTc effect under a higher
exposure scenario.

12.3 Pharmacokinetics

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

In healthy subjects who received 800 mg three times daily alone,
boceprevir drug exposure was characterized by AUC(т) of 5408 ng.hr/mL
(n=71), C_max of 1723 ng/mL (n=71), and C_min
of 88 ng/mL (n=71). Pharmacokinetic results were similar between healthy
subjects and HCV-infected subjects.

Absorption

Boceprevir was absorbed following oral administration with a median T_max
of 2 hours. Steady state AUC, C_max, and C_min
increased in a less-than-dose-proportional manner and individual
exposures overlapped substantially at 800 mg and 1200 mg, suggesting
diminished absorption at higher doses. Accumulation is minimal (0.8- to
1.5-fold) and pharmacokinetic steady state is achieved after
approximately 1 day of three times daily dosing.

The absolute bioavailability of boceprevir 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 65% at the 800 mg three times daily dose,
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.

Distribution

Boceprevir has a mean apparent volume of distribution (Vd/F) of
approximately 772 L at steady state in healthy subjects. Human plasma
protein binding is approximately 75% following a single dose of
boceprevir 800 mg. Boceprevir is administered as an approximately equal
mixture of two diastereomers, SCH534128 and SCH534129, which rapidly
interconvert in plasma. The predominant diastereomer, SCH534128, is
pharmacologically active and the other diastereomer is inactive.

Metabolism

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

Drug Interactions

Drug interaction studies were performed with boceprevir and drugs likely
to be coadministered or drugs commonly used as probes for
pharmacokinetic interactions. The effects of coadministration of
boceprevir on AUC, C_max and C_min are summarized in
Table 6 (effects of coadministered drugs on boceprevir) and Table 7
(effects of boceprevir on coadministered drugs).

Table 6

Summary of the Effect of Co-administered Drugs on Boceprevir in
Healthy Subjects or HCV Positive Genotype-1
Subjects

Co-
administered
Drug

Co-administered
Drug Dose/Schedule

Boceprevir
Dose/Schedule

Ratio Estimate of Boceprevir Pharmacokinetic Parameters (in
Combination
vs. Alone)

(90% CI of the Ratio Estimate)*

Change in mean
C_max

Change in mean
AUC

Change in mean
C_min

Ketoconazole

400 mg two times
daily x 6 days

400 mg single oral
dose

1.41
(1.00-1.97)

2.31
(2.00-2.67)

N/A

Ibuprofen

600 mg three times
daily x 6 days

400 mg single oral
dose

0.94
(0.67-1.32)

1.04
(0.90-1.20)

N/A

Diflunisal

250 mg two times
daily x 7 days

800 mg three times
daily x 12 days

0.86
(0.56-1.32)

0.96
(0.79-1.17)

1.31
(1.04-1.65)

Ritonavir

100 mg daily x 12
days

400 mg three times
daily x 15 days

0.73
(0.57-0.93)

0.81
(0.73-0.91)

1.04
(0.62-1.75)

Efavirenz

600 mg daily x 16
days

800 mg three times
daily x 6 days

0.92
(0.78-1.08)

0.81
(0.75-0.89)

0.56
(0.42-0.74)

Tenofovir

300 mg daily x 7
days

800 mg three times
daily x 7 days

1.05
(0.98-1.12)

1.08
(1.02-1.14)

1.08
(0.97-1.20)

Peginterferon
alfa-2b

1.5 mcg/kg
subcutaneous
weekly x 2 weeks

400 mg three times
daily x 1 week

0.88
(0.66-1.18)

1.00*
(0.89-1.13)

N/A

*No effect = 1.00

N/A = not available

Table 7

Summary of the Effect of Boceprevir on Co-administered Drugs in
Healthy Subjects or HCV Positive Genotype-1
Subjects

Co-
administered
Drug

Co-administered
Drug Dose/Schedule

Boceprevir
Dose/Schedule

Ratio Estimate of Co-administered Pharmacokinetic
Parameters
(in Combination vs. Alone)

(90% CI of the Ratio Estimate)*

Change in mean C_max

Change in mean AUC(τ)

Midazolam

4 mg single oral
dose

800 mg three times
daily x 6 days

2.77
(2.36-3.25)

5.30
(4.66-6.03)

Efavirenz

600 mg daily x 16
days

800 mg three times
daily x 6 days

1.11
(1.02-1.20)

1.20
(1.15-1.26)

Drospirenone/
Ethinyl
estradiol

Drospirenone:
3 mg + Ethinyl
estradiol :
0.02 mg
daily x 14
days

800 mg three times
daily x 7 days

Drospirenone: 1.57
(1.46-1.70)

Ethinyl estradiol: 1.00
(0.91-1.10)

Drospirenone: 1.99
(1.87-2.11)

Ethinyl estradiol: 0.76
(0.73-0.79)

Tenofovir

300 mg daily x 7
days

800 mg three times
daily x 7 days

1.32
(1.19-1.45)

1.05
(1.01-1.09)

Peginterferon
alfa-2b

1.5 mcg/kg
subcutaneous
weekly x 2 weeks

200 mg or 400 mg
three times daily x 1
week

N/A

0.99^†,‡
(0.83-1.17)

*No effect = 1.00

^†0-168 hours

^‡Reported AUC is 200 mg and 400 mg cohorts
combined.

N/A = not available

Elimination

Boceprevir is eliminated with a mean plasma half-life (t½) 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 feces and urine,
respectively, with approximately 8% and 3% of the dosed radiocarbon
eliminated as boceprevir in feces and urine. The data indicate that
boceprevir is eliminated primarily by the liver.

Special Populations

Hepatic Impairment

The pharmacokinetics of boceprevir was studied in adult non-HCV infected
subjects with normal, mild (Child-Pugh score 5-6), moderate (Child-Pugh
score 7-9), and severe (Child-Pugh score 10-12) hepatic impairment
following a single 400 mg dose of VICTRELIS. The mean AUC of the active
diastereomer of boceprevir (SCH534128) was 32% and 45% higher in
subjects with moderate and severe hepatic impairment, respectively,
relative to subjects with normal hepatic function. Mean C_max
values for SCH534128 were 28% and 62% higher in moderate and severe
hepatic impairment, respectively. Subjects with mild hepatic impairment
had similar SCH534128 exposure as subjects with normal hepatic function.
A similar magnitude of effect is anticipated for boceprevir. No dosage
adjustment of VICTRELIS is recommended for patients with hepatic
impairment [see Use in Specific Populations (8.7)]. See
peginterferon alfa Package Insert for contraindication in patients with
hepatic decompensation.

Renal Impairment

The pharmacokinetics of boceprevir was studied in non-HCV-infected
subjects with end-stage renal disease (ESRD) requiring hemodialysis
following a single 800 mg dose of VICTRELIS. The mean AUC of boceprevir
was 10% lower in subjects with ESRD requiring hemodialysis relative to
subjects with normal renal function. Hemodialysis removed less than 1%
of the boceprevir dose. No dosage adjustment of VICTRELIS is required in
patients with any degree of renal impairment.

Gender

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

Race

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

Age

Population pharmacokinetic analysis of VICTRELIS showed that boceprevir
exposure was not different across subjects 19 to 65 years old.

12.4 Microbiology

Mechanism of Action

Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary
for the proteolytic cleavage of the HCV encoded polyprotein into mature
forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently,
yet reversibly, binds to the NS3 protease active site serine (S139)
through an (alpha)-ketoamide functional group to inhibit viral
replication in HCV-infected host cells. In a biochemical assay,
boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b
NS3/4A protease enzymes, with K_i values of 14 nM for each
subtype.

Activity in Cell Culture

The EC₅₀ and EC₉₀ values for boceprevir against an
HCV replicon constructed from a single genotype 1b isolate were
approximately 200 nM and 400 nM, respectively, in a 72-hour cell culture
assay. Boceprevir cell culture anti-HCV activity was approximately
2-fold lower for an HCV replicon derived from a single genotype 1a
isolate, relative to the 1b isolate-derived replicon. In replicon
assays, boceprevir had approximately 2-fold reduced activity against a
genotype 2a isolate relative to genotype 1a and 1b replicon isolates. In
a biochemical assay, boceprevir had approximately 3- and 2-fold reduced
activity against NS3/4A proteases derived from single isolates
representative of HCV genotypes 2 and 3a, respectively, relative to a
genotype 1b-derived NS3/4A protease. The presence of 50% human serum
reduced the cell culture anti-HCV activity of boceprevir by
approximately 3-fold.

Evaluation of varying combinations of boceprevir and interferon alfa-2b
that produced 90% suppression of replicon RNA in cell culture showed
additivity of effect without evidence of antagonism.

Resistance

In Cell Culture

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.

In Clinical Studies

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 8). 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 68% 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.


Table 8 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)

	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

Persistence of Resistance-Associated Substitutions

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.

Effect of Baseline HCV Polymorphisms on Treatment Response

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.

Cross-Resistance

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.

12.5 Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B
rs12979860, a C to T change) is a strong predictor of response to
PegIntron/REBETOL. IL28B rs12979860 was genotyped in 653
of 1048 (62%) subjects in SPRINT-2 (previously untreated) and 259 of 394
(66%) subjects in RESPOND-2 (previous treatment failure) [see
Clinical Studies (14) for trial descriptions]. Among subjects that
received at least one dose of placebo or VICTRELIS
(Modified-Intent-to-Treat population), SVR rates tended to be lower in
subjects with the C/T and T/T genotypes compared to those with the C/C
genotype, particularly among previously untreated subjects receiving 48
weeks of PegIntron and REBETOL (see Table 9). Among previous treatment
failures, subjects of all genotypes appeared to have higher SVR rates
with VICTRELIS-containing regimens. The results of this retrospective
subgroup analysis should be viewed with caution because of the small
sample size and potential differences in demographic or clinical
characteristics of the substudy population relative to the overall trial
population.

Table 9

Sustained Virologic Response (SVR) Rates by IL28B rs12979860
Genotype

SVR, % (n/N)

Clinical Study

IL28B rs12979860
Genotype

PR48*

VICTRELIS-RGT*

VICTRELIS-PR48*

SPRINT-2 (Previously Untreated Subjects)

C/C

78 (50/64)

82 (63/77)

80 (44/55)

C/T

28 (33/116)

65 (67/103)

71 (82/115)

T/T

27 (10/37)

55 (23/42)

59 (26/44)

RESPOND-2 (Subjects Who Have Failed Previous Therapy)

C/C

46 (6/13)

79 (22/28)

77 (17/22)

C/T

17 (5/29)

61 (38/62)

73 (48/66)

T/T

50 (5/10)

55 (6/11)

72 (13/18)

*For description of each treatment arm, see Clinical Studies (14).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic
in in vitro and in vivo assays. Ribavirin was not
oncogenic in mouse and rat carcinogenicity studies at doses less than
the maximum recommended daily human dose. Please refer to ribavirin
Package Inserts for additional information.

Two-year carcinogenicity studies in mice and rats were conducted with
boceprevir. Mice were administered doses of up to 500 mg/kg in males and
650 mg/kg in females, and rats were administered doses of up to
125 mg/kg in males and 100 mg/kg in females. In mice, no significant
increases in the incidence of drug-related neoplasms were observed at
the highest doses tested resulting in boceprevir AUC exposures
approximately 2.3- and 6.0-fold higher in males and females,
respectively, than those in humans at the recommended dose of 800 mg
three times daily. In rats, no increases in the incidence of
drug-related neoplasms were observed at the highest doses tested
resulting in boceprevir AUC exposures similar to those in humans at the
recommended dose of 800 mg three times daily.

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

Impairment of Fertility

Use with Ribavirin and Peginterferon alfa: In fertility studies
in male animals, ribavirin induced reversible testicular toxicity; while
peginterferon alfa may impair fertility in females. Please refer to
Package Inserts for ribavirin and peginterferon alfa for additional
information.

Boceprevir-induced reversible effects on fertility and early embryonic
development in female rats, with no effects observed at a 75 mg/kg dose
level. At this dose, boceprevir AUC exposures are approximately 1.3-fold
higher than those in humans at the recommended dose of 800 mg three
times daily. Decreased fertility was also observed in male rats, most
likely as a consequence of testicular degeneration. No testicular
degeneration was observed at a 15 mg/kg dose level resulting in
boceprevir AUC exposures of less than those in humans at the recommended
dose of 800 mg three times daily. Testicular degeneration was not
observed in mice or monkeys administered boceprevir for 3 months at
doses of up to 900 or 1000 mg/kg, respectively. At these doses,
boceprevir AUC exposures are approximately 6.8- and 4.4-fold higher in
mice and monkeys, respectively, than those in humans at the recommended
dose of 800 mg three times daily. Additionally, limited clinical
monitoring has revealed no evidence of testicular toxicity in human
subjects.

14 CLINICAL STUDIES

The efficacy of VICTRELIS as a treatment for chronic hepatitis C
(genotype 1) infection was assessed in approximately 1500 adult subjects
who were previously untreated (SPRINT-2) or who had failed previous
peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical
studies.

Previously Untreated Subjects

SPRINT-2 was a randomized, double-blind, placebo-controlled study
comparing two therapeutic regimens of VICTRELIS 800 mg orally three
times daily in combination with PR [PegIntron 1.5 µg/kg/week
subcutaneously and weight-based dosing with REBETOL (600-1400 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 within two separate cohorts
(Cohort 1/non-Black and Cohort 2/Black) and were 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:

PegIntron + REBETOL for 48 weeks (PR48).
PegIntron + REBETOL for four weeks followed by VICTRELIS 800 mg three
times daily + PegIntron + REBETOL for 24 weeks. The subjects were then
continued on different regimens based on Treatment Week (TW) 8 through
TW 24 response-guided therapy (VICTRELIS-RGT). All subjects in this
treatment arm were limited to 24 weeks of therapy with VICTRELIS.
- Subjects with undetectable HCV-RNA at TW 8 (early responders) and
  who were also negative through TW24 discontinued therapy and
  entered follow-up at the TW 28 visit.
- Subjects with detectable HCV-RNA at TW 8 or any subsequent
  treatment week but subsequently negative at TW 24 (late
  responders) were changed in a blinded fashion to placebo at the TW
  28 visit and continued therapy with PegIntron + REBETOL for an
  additional 20 weeks, for a total treatment duration of 48 weeks.
PegIntron + REBETOL for four weeks followed by VICTRELIS 800 mg three
times daily + PegIntron + REBETOL for 44 weeks (VICTRELIS-PR48).

All subjects with detectable HCV-RNA in plasma at TW24 were discontinued
from treatment. Sustained Virologic Response (SVR) was defined as plasma
HCV-RNA undetectable at Follow-up Week 24. Plasma HCV-RNA results at
Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week
24 were missing.

Mean age of subjects randomized 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.

The addition of VICTRELIS to PegIntron and REBETOL significantly
increased the SVR rates compared to PegIntron and REBETOL 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). SVR rates for Blacks in
a predefined analysis who received the combination of VICTRELIS with
PegIntron and REBETOL were 42% to 53% (see Table 10).


Table 10 Sustained Virologic Response (SVR)^{, †} and Relapse Rates*^‡ for Previously Untreated Subjects

Study Cohorts	VICTRELIS-RGT	VICTRELIS-PR48	PR48
Cohort 1 Plus Cohort 2 (all subjects)	n=368	n=366	n=363
SVR^†%	63	66	38
Relapse^‡ % (n/N)	9 (24/257)	9 (24/265)	22 (39/176)
Cohort 1 Plus Cohort 2 (subjects without cirrhosis)
SVR^†,§% (n/N)	65 (228/352)	68 (232/342)	38 (132/350)
Cohort 1 (non-Black)	n=316	n=311	n=311
SVR^†%	67	68	40
Relapse^‡ % (n/N)	9 (21/232)	8 (18/230)	23 (37/162)
Cohort 2 (Black)	n=52	n=55	n=52
SVR^†%	42	53	23
Relapse^‡ % (n/N)	12 (3/25)	17 (6/35)	14 (2/14)
*The Full Analysis Set (FAS) consisted of all randomized subjects (N=1097) who received at least one dose of any study medication (PegIntron, REBETOL, or VICTRELIS). ^†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCV- RNA value in the period at or after FW24 was used. If HCV-RNA value at FW24 was missing, the FW12 value was carried forward. ^‡Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA (≥ 25 IU/mL) at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data. ^§ Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy.

In subjects with cirrhosis at baseline, sustained virologic response was
higher in those who received treatment with the combination of VICTRELIS
with PegIntron and REBETOL for 44 weeks after lead-in therapy with
PegIntron and REBETOL (10/24, 42%) compared to those who received RGT
(5/16 , 31%).

Sustained Virologic Response (SVR) Based on TW
8 HCV-RNA Results

Table 11 presents sustained virologic response based on TW 8 HCV-RNA
results in previously untreated subjects. 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 TW8 (early
responders) compared with 17% (60/363) of subjects in the PR48 arm.


Table 11 Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Previously Untreated Subjects in the Combined Cohort

	VICTRELIS-RGT	VICTRELIS-PR48	PR48
SVR by TW8 Detectability, % (n/N)*	N=337	N=335	N=331
Undetectable	88 (184/208)	90 (184/204)	85 (51/60)
Detectable	36 (46/129)	40 (52/131)	30 (82/271)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW 8 who had attained
undetectable HCV-RNA at TW 24 and completed at least 28 weeks of
treatment, the SVR rates were 66% (45/68) in VICTRELIS-RGT arm (4 weeks
of PegIntron and REBETOL then 24 weeks of VICTRELIS with PegIntron and
REBETOL followed by 20 weeks of PegIntron and REBETOL alone) and 75%
(55/73) in VICTRELIS-PR48 arms (4 weeks of PegIntron and REBETOL then 44
weeks of VICTRELIS with PegIntron and REBETOL).

Subjects Who Failed Previous Therapy with Peginterferon Alfa and
Ribavirin

RESPOND-2 was a randomized, parallel-group, double-blind study comparing
two therapeutic regimens of VICTRELIS 800 mg orally three times daily in
combination with PR [PegIntron 1.5 µg/kg/week subcutaneously and
weight-based ribavirin (600-1400 mg/day 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 greater than or
equal to 2-log₁₀ by Week 12, but never achieved SVR [partial
responders] or undetectable HCV-RNA at end of prior treatment with a
subsequent detectable HCV-RNA in plasma [relapsers]). Subjects with less
than 2-log₁₀ decrease in HCV-RNA by week 12 of previous
treatment (prior null responders) were not eligible for enrollment in
this trial. 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:

PegIntron + REBETOL for 48 weeks (PR48)
PegIntron + REBETOL for 4 weeks followed by VICTRELIS 800 mg three
times daily + PegIntron + REBETOL for 32 weeks. The subjects were then
continued on different treatment regimens based on TW8 and TW12
response-guided therapy (VICTRELIS-RGT). All subjects in this
treatment arm were limited to 32 weeks of VICTRELIS.
- Subjects with undetectable HCV-RNA at TW 8 (early responders) and
  TW 12 completed therapy at TW36 visit.
- 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
  PegIntron + REBETOL for an additional 12 weeks, for a total
  treatment duration of 48 weeks.
PegIntron + REBETOL for 4 weeks followed by VICTRELIS 800 mg three
times daily + PegIntron + REBETOL for 44 weeks (VICTRELIS-PR48).

All subjects with detectable HCV-RNA in plasma at TW 12 were
discontinued from treatment. Sustained Virologic Response (SVR) was
defined as plasma HCV-RNA undetectable at Follow-up Week 24. Plasma
HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results
at Follow-up Week 24 were missing.

Mean age of subjects randomized 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.

The addition of VICTRELIS to the PegIntron and REBETOL therapy
significantly increased the SVR rates compared to PegIntron/REBETOL
alone (59% to 66% VICTRELIS-containing arms vs. 23% PR48 control) for
randomized subjects who received at least one dose of any study
medication (Full-Analysis-Set population) (see Table 12).


Table 12 Sustained Virologic Response (SVR)^{, †} and Relapse^‡ Rates for Subjects Who have Failed Previous Therapy with Peginterferon Alfa and Ribavirin*

		VICTRELIS-RGT	VICTRELIS-PR48	PR48
		N=162	N=161	N=80
SVR^†%		59	66	23
Relapse^‡ % (n/N)		14 (16/111)	12 (14/121)	28 (7/25)
SVR (subjects without cirrhosis) ^§ (n/N)		62 (90/145)	65 (90/139)	26 (18/70)
SVR by Response to Previous Peginterferon and Ribavirin Therapy
Previous Response	Relapser, % (n/N)	70 (73/105)	75 (77/103)	31 (16/51)
Previous Response	Partial responder, % (n/N)	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 (PegIntron, REBETOL, or VICTRELIS). ^†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCV RNA value in the period at or after FW24 was used. If HCV RNA value at FW24 was missing, the FW12 value was carried forward. ^‡Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA (≥ 25 IU/mL) at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data. ^§ Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy. Previous Partial Responder = subject who failed to achieve SVR after at least 12 weeks of previous treatment with PegIntron/REBETOL, but demonstrated a ≥2-log₁₀ reduction in HCV-RNA by Week 12. Previous Relapser = subject who failed to achieve SVR after at least 12 weeks of previous treatment with PegIntron/REBETOL, but had undetectable HCV-RNA at the end of treatment.

In subjects with cirrhosis at baseline, sustained virologic response was
higher in those who received treatment with the combination of VICTRELIS
with PegIntron and REBETOL for 44 weeks after 4 weeks of lead-in therapy
with PegIntron and REBETOL (17/22, 77%) compared to those who received
RGT (6/17, 35%).

Sustained Virologic Response (SVR) Based on TW8
HCV-RNA Results

Table 13 presents sustained virologic response based on TW 8 HCV-RNA
results in subjects who have failed previous therapy. Forty-six percent
(74/162) of subjects in the VICTRELIS-RGT arm and 52% (84/161) in the
VICTRELIS-PR48 had undetectable HCV-RNA at TW 8 (early responders)
compared with 9% (7/80) in the PR48 arm.


Table 13 Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Subjects Who Have Failed Previous Therapy

	VICTRELIS-RGT	VICTRELIS-PR48	PR48
SVR by TW8 Detectability, % (n/N)*	N=146	N=154	N=72
Undetectable	88 (65/74)	88 (74/84)	100 (7/7)
Detectable	40 (29/72)	43 (30/70)	14 (9/65)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW 8 who attained an
undetectable HCV-RNA at TW 12 and completed at least 36 weeks of
treatment, the SVR rates were 79% (27/34) in VICTRELIS-RGT arm (4 weeks
of PegIntron and REBETOL then 32 weeks of VICTRELIS with PegIntron and
REBETOL followed by 12 weeks of PegIntron and REBETOL alone) and 72%
(29/40) in VICTRELIS-PR48 arm (4 weeks of PegIntron and REBETOL then 44
weeks of VICTRELIS with PegIntron and REBETOL).

Interferon Responsiveness during Lead-In Therapy with
Peginterferon alfa and Ribavirin

Previously Untreated Subjects

In previously untreated subjects evaluated in SPRINT-2,
interferon-responsiveness (defined as greater than or equal to 1-log₁₀
decline in viral load at TW 4) was predictive of SVR. VICTRELIS-treated
subjects who demonstrated interferon responsiveness at TW 4 achieved SVR
rates of 81% (203/252) in VICTRELIS-RGT arm and 79% (200/254) in
VICTRELIS-PR48 arm, compared to 52% (134/260) in subjects treated with
PegIntron/REBETOL.

VICTRELIS-treated subjects who demonstrated poor interferon
responsiveness (defined as less than 1-log₁₀ decline in viral
load at TW 4), achieved SVR rates of 28% (27/97) in VICTRELIS-RGT arm
and 38% (36/95) in VICTRELIS-PR48 arm, compared to 4% (3/83) in subjects
treated with PegIntron/REBETOL. Subjects with less than a 0.5-log₁₀
decline in viral load at TW4 achieved SVR rates of 28% (13/47) in
VICTRELIS-RGT arm and 30% (11/37) in VICTRELIS-PR48 arm, compared to 0%
(0/25) in subjects treated with PegIntron/REBETOL. Subjects with less
than a 0.5-log₁₀ decline in viral load at TW4 with
peginterferon alfa plus ribavirin therapy alone are predicted to have a
null response (less than 2-log₁₀ viral load decline at TW12)
to peginterferon alfa and ribavirin.

Subjects Who Failed Previous Therapy with
Peginterferon Alfa and Ribavirin

In subjects who were previous relapsers and partial responders evaluated
in RESPOND-2, interferon-responsiveness (defined as greater than or
equal to 1-log₁₀ decline in viral load at TW4) was predictive
of SVR. VICTRELIS-treated subjects who demonstrated interferon
responsiveness at TW4 achieved SVR rates of 74% (81/110) in
VICTRELIS-RGT arm and 79% (90/114) in VICTRELIS-PR48 arm, compared to
27% (18/67) in subjects treated with PegIntron/REBETOL.
VICTRELIS-treated subjects who demonstrated poor interferon
responsiveness (defined as less than 1-log₁₀ decline in viral
load at TW4) achieved SVR rates of 33% (15/46) in VICTRELIS-RGT arm and
34% (15/44) in VICTRELIS-PR48 arm, compared to 0% (0/12) in subjects
treated with PegIntron/REBETOL.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

VICTRELIS 200 mg capsules are comprised of a red-colored cap with the
Merck logo printed in yellow ink, and a yellow-colored body with “314”
printed in red ink. The capsules are packaged into a carton with 28
bottles containing 12 capsules (NDC 0085-0314-02).

16.2 Storage and Handling

VICTRELIS Capsules should be refrigerated at 2-8°C (36-46°F) until
dispensed. Avoid exposure to excessive heat. For patient use,
refrigerated capsules of VICTRELIS can remain stable until the
expiration date printed on the label. VICTRELIS can also be stored at
room temperature up to 25°C (77°F) for 3 months. Keep container tightly
closed.

17 PATIENT COUNSELING INFORMATION

[See FDA-approved Medication Guide.]

VICTRELIS must be used in combination with peginterferon alfa and
ribavirin, and thus all contraindications and warnings for peginterferon
alfa and ribavirin also apply.

17.1 Pregnancy

Ribavirin must not be used by women who are pregnant or by men whose
female partners are pregnant. Ribavirin therapy should not be initiated
until a report of a negative pregnancy test has been obtained
immediately before starting therapy. Female patients of childbearing
potential and male patients with female partners of childbearing
potential must be advised of the teratogenic/embryocidal risks of
ribavirin and must be instructed to practice effective contraception
during therapy and for 6 months post-therapy. Patients should be advised
to notify the healthcare provider immediately in the event of a
pregnancy [see Contraindications (4) and Warnings and Precautions
(5.1)].

Women of childbearing potential and men must use at least two forms of
effective contraception during treatment and for at least 6 months after
treatment has been stopped; routine monthly pregnancy tests must be
performed during this time. Because systemic hormonal contraceptives may
not be as effective in women while taking VICTRELIS, two alternative
effective methods of contraception, such as intrauterine devices and
barrier methods, should be used in women during treatment with VICTRELIS
and concomitant ribavirin [see Warnings and Precautions (5.1)].

To monitor maternal and fetal outcomes of pregnant women exposed to
ribavirin, the Ribavirin Pregnancy Registry has been established.
Patients should be encouraged to register by calling 1-800-593-2214.

17.2 Anemia

Patients should be informed that anemia may be increased when VICTRELIS
is administered with peginterferon alfa and ribavirin [see Warnings
and Precautions (5.2) and Adverse Reactions (6.1)]. Patients should
be advised that laboratory evaluations are required prior to starting
therapy and periodically thereafter [see Warnings and Precautions
(5.5)].

17.3 Neutropenia

Patients should be informed that neutropenia may be increased when
VICTRELIS is administered with peginterferon alfa and ribavirin [see
Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. Patients
should be advised that laboratory evaluations are required prior to
starting therapy and periodically thereafter [see Warnings and
Precautions (5.5)].

17.4 Usage Safeguards

Patients should be advised that VICTRELIS must not be used alone due to
the high probability of resistance without combination anti-HCV
therapies [see Indications and Usage (1)]. See peginterferon alfa
and ribavirin Package Inserts for additional patient counseling
information on the use of these drugs in combination with VICTRELIS.

Patients should be informed of the potential for serious drug
interactions with VICTRELIS, and that some drugs should not be taken
with VICTRELIS [see Contraindications (4), Warnings and Precautions
(5.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Patients should be advised that the total daily dose of VICTRELIS is
packaged into a single bottle containing 12-capsules and the patient
should take four capsules three times daily with food.

17.5 Missed VICTRELIS 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 dose is due, the patient
should take the missed dose with food and resume the normal dosing
schedule.

17.6 Hepatitis C Virus Transmission

Patients should be informed that the effect of treatment of hepatitis C
infection on transmission is not known, and that appropriate precautions
to prevent transmission of the hepatitis C virus should be taken.

Schering Corporation, a subsidiary of MERCK & CO., INC.,
Whitehouse Station, NJ 08889, USA

U.S. Patent Nos. 7,012,066; 7,244,721

Trademarks depicted herein are the property of their respective owners.

Issued: 05/11

B-35071601

34965501T

503034-BCV-CP-MG-6

MEDICATION GUIDE

VICTRELIS^™(vĭc-TRÉL-ĭs)

(boceprevir)

Read this Medication Guide before you start taking VICTRELIS, and each
time you get a refill. There may be important new information. This
information does not take the place of talking with your doctor, nurse
or physician assistant (healthcare provider) about your medical
condition or your care.

VICTRELIS is taken along with peginterferon alfa and ribavirin. You
should also read those Medication Guides.

What is the most important information I should
know about VICTRELIS?

VICTRELIS, in combination with peginterferon alfa and ribavirin, may
cause birth defects or death of your unborn baby. If you are pregnant or
your sexual partner is pregnant or plans to become pregnant, do not take
these medicines. You or your sexual partner should not become pregnant
while taking VICTRELIS, peginterferon alfa, and ribavirin combination
therapy and for 6 months after treatment is over.

Females and males must use 2 forms of birth control during treatment
and for 6 months after treatment with VICTRELIS, peginterferon alfa,
and ribavirin. Hormonal forms of birth control, such as birth control
pills, vaginal rings, implants and injections, may not work as well
during treatment with VICTRELIS. You may get pregnant while using
these birth control methods while on VICTRELIS. Talk to your
healthcare provider about other forms of birth control that may be
used during this time.
Females must have a pregnancy test before starting treatment with
VICTRELIS combination therapy, every month while being treated, and
every month for 6 months after treatment with VICTRELIS, peginterferon
alfa, and ribavirin is over.
If you or your female sexual partner becomes pregnant while taking
VICTRELIS, peginterferon alfa, and ribavirin or within 6 months after
you stop taking these medicines, tell your healthcare provider right
away. You or your healthcare provider should contact the Ribavirin
Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy
Registry collects information about what happens to mothers and their
babies if the mother takes ribavirin while she is pregnant.
Do not take VICTRELIS alone to treat chronic hepatitis C infection.
VICTRELIS must be used with peginterferon alfa and ribavirin to treat
chronic hepatitis C infection.

What is VICTRELIS?

VICTRELIS is a prescription medicine used with the medicines
peginterferon alfa and ribavirin to treat chronic (long-lasting)
hepatitis C infection in adults who have not been treated before
or who have failed previous treatment.

It is not known if VICTRELIS is safe and effective in children under 18
years of age.

Who should not take VICTRELIS?

See “What is the most important information I should know about
VICTRELIS?”

Do not take VICTRELIS if you:

take certain medicines. VICTRELIS may cause serious side effects
when taken with certain medicines. Read the section “What should I
tell my healthcare provider before taking VICTRELIS?”

Talk to your healthcare provider before taking VICTRELIS if you have any
of the conditions listed below.

What should I tell my healthcare provider
before taking VICTRELIS?

Before you take VICTRELIS, tell your healthcare provider if you:

have certain blood disorders such as anemia (low red blood cell count).
have liver problems other than hepatitis C infection.
have human immunodeficiency virus (HIV) or any other immunity problems.
have had an organ transplant.
plan to have surgery.
have any other medical condition.
are breastfeeding. It is not known if VICTRELIS passes into breast
milk. You and your healthcare provider should decide if you will take
VICTRELIS or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take,
including prescription and non-prescription medicines, vitamins, and
herbal supplements.

VICTRELIS and other medicines may affect each other, causing side
effects or affecting the way VICTRELIS and your other medicines work. Do
not start taking a new medicine without telling your healthcare provider
or pharmacist.

Do not take VICTRELIS if you take:

alfuzosin hydrochloride (UROXATRAL^®)
anti-seizure medicines:
- carbamazepine (CARBATROL^®, EPITOL^®, EQUETRO^®,
  TEGRETOL^®, TEGRETOL XR^®, TERIL^®)
- phenobarbital
- phenytoin (DILANTIN^®)
cisapride (PROPULSID^®)
drosperinone-containing medicines, including:
- YAZ^®, YASMIN^®, ZARAH^®, OCELLA^®,
  GIANVI^®, BEYAZ^®, SAFYRAL^®
ergot-containing medicines, including:
- dihydroergotamine mesylate (D.H.E. 45^®, MIGRANAL^®)
- ergonovine and methylergonovine (ERGOTRATE^®, METHERGINE^®),
  ergotamine
- ergotamine tartrate (CAFERGOT^®, MIGERGOT^®,
  ERGOMAR^®, ERGOSTAT^®, MEDIHALER ERGOTAMINE^®,
  WIGRAINE^®, WIGRETTES^®)
lovastatin (ADVICOR^®, ALTOPREV^®, MEVACOR^®)
midazolam (VERSED^®), when taken by mouth
pimozide (ORAP^®)
rifampin (RIFADIN^®, RIFAMATE^®, RIFATER^®,
RIMACTANE^®)
sildenafil (REVATIO^®), when used for treating lung problems
simvastatin (SIMCOR^®, VYTORIN^®, ZOCOR^®)
St. John’s Wort (Hypericum perforatum) or products containing St.
John’s Wort
tadalafil (ADCIRCA^®), when used for treating lung problems
triazolam (HALCION^®)

Tell your healthcare provider if you are taking or starting to take
any of these medicines:

clarithromycin (BIAXIN^®, BIAXIN XL^®, PREVPAC^®)
dexamethasone
efavirenz (SUSTIVA^®, ATRIPLA^®)
itraconazole (SPORANOX^®)
ketoconazole (NIZORAL^®)
posaconazole (NOXAFIL^®)
rifabutin (MYCOBUTIN^®)
ritonavir (NORVIR^®, KALETRA^®)
voriconazole (VFEND^®)

Your healthcare provider may need to monitor your therapy more
closely if you take VICTRELIS with the following medicines. Talk to your
doctor if you are taking or starting to take these medicines:

alprazolam (XANAX^®)
amiodarone (CORDARONE^®, EXTERONE^®, PACERONE^®)
atorvastatin (LIPITOR^®)
bepridil (VASCOR^®)
bosentan (TRACLEER^®)
budesonide (PULMICORT^®, PULMICORT FLEXIHALER^®,
RHINOCORT^®, PULMICORT RESPULES^®, SYMBICORT^®)
buprenorphine (BUTRANS^®, BUPRENEX^®, SUBOXONE^®,
SUBUTEX^®)
cyclosporine (GENGRAF^®, NEORAL^®, SANDIMMUNE^®)
desipramine (NORPRAMIN^®)
digoxin (LANOXIN^®)
felodipine (PLENDIL^®)
flecainide (TAMBOCOR^®)
fluticasone (VERAMYST^®, FLOVENT HFA^®, FLOVENT
DISKUS^®, ADVAIR HFA^®, ADVAIR DISKUS^®)
hormonal forms of birth control, including birth control pills,
vaginal rings, implants and injections
methadone (DOLOPHINE^®)
nifedipine (PROCARDIA^®, ADALAT CC^®, PROCARDIA XL^®,
AFEDITAB CR^®)
nicardipine (CARDENE SR^®, CARDENE^®)
propafenone (RHYTHMOL^®, RHYTHMOL SR^®)
quinidine
salmeterol (ADVAIR HFA^®, ADVAIR DISKUS^®, SEREVENT^®)
sirolimus (RAPAMUNE^®)
tacrolimus (PROGRAF^®)
voriconazole (VFEND^®)
colchicine (COLCRYS^®, Probenecid and Colchicine,
COL-Probenecid)
trazadone (DESYREL^®)
vardenafil (STAXYN^®, LEVITRA^®)
warfarin (COUMARIN^®)

How should I take VICTRELIS?

Take VICTRELIS exactly as your healthcare provider tells you. Your
healthcare provider will tell you how much to take and when to take it.
Take VICTRELIS with food (a meal or light snack).
VICTRELIS is packaged into single daily-use bottles. Each bottle has
your entire day’s worth of medicine. Make sure you are taking the
correct amount of medicine each time.
If you miss a dose of VICTRELIS and it is less than 2 hours before the
next dose, the missed dose should be skipped.
If you miss a dose of VICTRELIS and it is more than 2 hours before the
next dose, take the missed dose with food. Take your next dose at your
normal time and continue the normal dosing schedule. Do not double the
next dose. If you have questions about what to do, call your
healthcare provider.
Your healthcare provider should do blood tests before you start
treatment, at weeks 4, 8, 12, and 24, and at other times as needed
during treatment, to see how well the medicines are working and to
check for side effects.
If you take too much VICTRELIS, call your healthcare provider or go to
the nearest hospital emergency room right away.

What are the possible side effects of VICTRELIS?

VICTRELIS may cause serious side effects, including:

See “What is the most important information I should know about
VICTRELIS?”

Blood problems. VICTRELIS can affect your bone marrow and cause low red
blood cell, and low white blood cell, counts. In some people, these
blood counts may fall to dangerously low levels. If your blood cell
counts become very low, you can get anemia or infections.

The most common side effects of VICTRELIS in combination with
peginterferon alfa and ribavirin include:

tiredness
nausea
headache
change in taste

Tell your healthcare provider about any side effect that bothers you or
that does not go away.

These are not all the possible side effects of VICTRELIS. For more
information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.

How should I store VICTRELIS?

Store VICTRELIS capsules in a refrigerator at 36°-46°F (2-8°C). Safely
throw away refrigerated VICTRELIS after the expiration date.
VICTRELIS capsules may also be stored at room temperature up to 77°F
(25°C) for 3 months.
Keep VICTRELIS in a tightly closed container and away from heat.

Keep VICTRELIS and all medicines out of the reach of children.

GENERAL INFORMATION ABOUT THE SAFE AND
EFFECTIVE USE OF VICTRELIS.

Medicines are sometimes prescribed for purposes other than those listed
in a Medication Guide.

Do not use VICTRELIS for a condition for which it was not prescribed. Do
not give VICTRELIS to other people, even if they have the same symptoms
that you have. It may harm them.

This Medication Guide summarizes the most important information about
VICTRELIS. If you would like more information, talk with your healthcare
provider. You can ask your pharmacist or healthcare provider for
information about VICTRELIS that is written for health professionals.

For more information, go to www.victrelis.com
or call 1-877-888-4231.

What are the ingredients in VICTRELIS?

Active ingredients: boceprevir

Inactive ingredients: sodium lauryl sulfate, microcrystalline
cellulose, lactose monohydrate, croscarmellose sodium, pre-gelatinized
starch, and magnesium stearate.

Red capsule shell: gelatin, titanium dioxide, D&C Yellow #10,
FD&C Blue #1, FD&C Red #40.

Yellow capsule shell: gelatin, titanium dioxide, D&C Yellow #10,
FD&C Red #40, FD&C Yellow #6.

Red printing ink: shellac, red iron oxide. Yellow printing ink:
shellac, povidone, titanium dioxide, D&C Yellow #10 Aluminum Lake.

This Medication Guide has been approved by the U.S. Food and Drug
Administration.

Schering Corporation, a subsidiary of MERCK & CO., INC.,
Whitehouse Station, NJ 08889, USA

Issued: May 2011

B-35071601

34966400T

Trademarks depicted herein are the property of their respective owners.

Merck
Media:
Ian McConnell, 908-423-3046
or
Investors:
Carol Ferguson, 908-423-4465

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