EL FDA Aprueba VICTRELIS™ (boceprevir) de Merck, Inhibidor de la proteasa del...

EL FDA Aprueba VICTRELIS™ (boceprevir) de Merck, Inhibidor de la proteasa del virus de la Hepatitis C (VHC) primero en su clase por vía oral



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WHITEHOUSE STATION, Nueva Jersey, 16 de mayo de 2011 /PRNewswire-HISPANIC PR
WIRE/ — Merck (NYSE:MRK) (conocido como MSD fuera de Estados Unidos y Canadá)
anunció hoy que el Departamento de Control de Alimentos y Medicamentos de los
EE.UU. (FDA) aprobó VICTRELIS (boceprevir), el nuevo medicamento de la compañía
innovador en el tratamiento de la hepatitis C crónica (HCC). VICTRELIS se
aprueba para el tratamiento de HCC por genotipo 1, en combinación con
peginterferón alfa y ribavirina, en pacientes adultos (18 años de edad en
adelante) con enfermedad hepática compensada, incluyendo la cirrosis, sin
tratamiento previo o aquellos que previamente tuvieron terapia fallida de de
interferón y ribavirina.


Al iniciar VICTRELIS para el tratamiento de la infección de hepatitis C
crónica es necesario tener en cuenta los siguientes puntos:



  • VICTRELIS no puede ser utilizado como una monoterapia y solo debe ser
    utilizado en combinación con peginterferón alfa y ribavirina.
  • La eficacia de VICTRELIS no ha sido estudiada en pacientes que han tenido
    una terapia fallida previa con un régimen de tratamiento que incluya VICTRELIS
    u otra proteasa inhibidora de HCVNS3/4.
  • VICTRELIS en combinación con peginterferón alfa y ribavirina no ha sido
    estudiado en pacientes registrados como no respondedores en el histórico
    clínico (una reducción menor a 2 HCV-RNA en la semana 12 de tratamiento) en
    terapias previas de peginterferón alfa y ribavirina. Los estudios clínicos
    incluyeron pacientes con respuesta pobre al interferón. Se calcula que los
    pacientes con una reducción de menos de 0.5 HCV-RNA en la carga viral en la
    semana 4 de tratamiento con peginterferón alfa mas ribavirina solamente, no
    tendrán respuesta a la terapia (una reducción menor a 2 HCV-RNA en la semana
    12 de tratamiento) de peginterferón alfa y ribavirina.
  • Los pacientes con pobre respuesta al interferón que fueron tratados con
    VICTRELIS en combinación con peginterferón alfa y ribavirina tienen menor
    tendencia a lograr una respuesta virológica sostenida (RVS)(1) y una mayor
    tasa de detección de sustituciones asociadas a resistencia cuando el
    tratamiento falle en comparación con una mayor respuesta a peginterferón alfa
    y ribavirina.


VICTRELIS es el primero en nueva clase de medicamento aprobados para el
tratamiento de la hepatitis C crónica.


VICTRELIS es el primero en una nueva clase de medicinas conocidas como
inhibidores de la proteasa del virus de la hepatitis C (VCH) aprobado para ser
utilizado en combinación con peginterferón alfa y ribavirina, lo cual es la
terapia estándar actual para el tratamiento de la hepatitis C crónica.


“Este es un día muy emocionante para los médicos y los pacientes porque
VICTRELIS es el primer avance importante para el tratamiento de la hepatitis C
crónica en una década,” expresó Bruce Bacon, M.D. profesor de medicina interna,
Facultad de Medicina de la Universidad de Saint Louis e investigador clínico de
VICTRELIS. “En comparación a la terapia estándar, puede incrementar de manera
significativa la posibilidad de que los pacientes alcancen niveles no
detectables del virus, por ende obteniendo una RVS. En muchos pacientes,
VICTRELIS™ puede permitir un tratamiento más corto.”


“Merck está muy comprometido con la innovación con el fin de proporcionar
nuevos medicamentos que se enfoquen especialmente en necesidades medicas no
satisfechas, y VICTRELIS es un ejemplo destacado de cómo logramos nuestros
compromisos,” expresó Kenneth C. Frazier, presidente y director ejecutivo de
Merck. “Esperamos poder seguir construyendo sobre nuestro legado en la lucha
contra las enfermedades infecciosas y ser parte de esta emocionante nueva era en
el tratamiento de la hepatitis C crónica.”


Merck empezará a enviar VICTRELIS a las farmacias en una semana para que los
pacientes empiecen a tener acceso a este nuevo medicamento lo más pronto
posible. Adicionalmente, la compañía está expandiendo su apoyo hacia programas
educativos y de toma de conciencia pública sobre la hepatitis C crónica. Los
recursos incluyen cupones para ayudar a los pacientes elegibles con los costos
de su medicamento, apoyo mediante reintegros para ayudar a que los pacientes
comprendan la cobertura del seguro de VICTRELIS, y apoyo telefónico de
enfermeras 24/7.


De manera independiente, Merck también incluirá a VICTRELIS dentro de su
programa de asistencia a pacientes, mediante el cual los pacientes elegibles
pueden recibir el producto sin costo alguno.


La terapia estándar actual para el VHC tiene como objetivo fortalecer la
respuesta natural inmune del cuerpo hacia el virus, pero solo el 40% de los
pacientes con infección de VHC crónica por genotipo 1 logran obtener una
respuesta virológica sostenida (RVS) lo que generalmente se considera una
curación virológica. VICTRELIS es un agente antiviral de acción directa (DAA)
que interfiere con la habilidad del virus de la hepatitis C para replicarse, ya
que inhibe una enzima viral esencial (serine proteasa NS3/4 A).


La aprobación de VICTRELIS por el FDA se debe a la eficacia y resultados
seguros de dos grandes ensayos clínicos Fase III que evaluaron aproximadamente
1.500 pacientes adultos con infección crónica de VCH por genotipo 1. Ambos
estudios incluían dos grupos de tratamiento con VICTRELIS: un grupo con terapia
guiada por respuesta (RGT por sus siglas en ingles) en la cual los pacientes con
presencia indetectable del virus (VCH-RNA) en la semana 8 de tratamiento eran
elegibles para una terapia de menor duración, así como un grupo de 48 semanas de
tratamiento. En estos estudios todos los pacientes, que recibieron VICTRELIS
fueron tratados primero con peginterferón alfa 2b y ribavirina P/R) durante una
fase previa de 4 semanas, seguida por la incorporación de VICTRELIS después de
la semana 4. Estos estudios también incluían un grupo control en el cual los
pacientes recibían 48 semanas de tratamiento solamente con P/R. Los pacientes no
respondedores dentro del histórico clínico no participaron en el estudio.


Añadir VICTRELIS a P/R logro un incremento significativo en las tasas de
curación virológica (RVS) en comparación a P/R solamente


Resultados primarios de dos estudios pivótales:



  • Pacientes con tratamiento fallido: La adición de VICTRELIS a P/R
    genero en un aumento de las tasas de RVS a 59% (96/162) para el grupo de RGT y
    66% (106/161) para el grupo de 48 semanas de tratamiento, comparado a 23%
    (18/80) para el grupo control. Las tasas de recaída fueron de 14% (16/111)
    para el grupo RGT y 12% (14/121) para el grupo de 48 semanas de tratamiento,
    comparado con el 28 % (7/25) para el control.
  • Pacientes sin tratamiento previo: La adición de VICTRELIS a P/R
    generó un incremento significativo (1.7 veces) a 63% (232/368) para el grupo
    de RGT y 66% (242/366) para el grupo de 48 semanas de tratamiento, comparado
    con un 38% (138/363) para el grupo control. Las tasas de recaída fueron de 9%
    (24/257) para el grupo de RGT y de 9% (24/265) para el grupo de 48 semanas de
    tratamiento comparado con el 22% (39/176) de control.


En una cohorte separada, pre especificada de 159 pacientes de raza negra sin
tratamiento previo, la adición de VICTRELIS al P/R, generó un incremento en RVS
del 42% (22/52) para el grupo de RGT y 53% (29/55) para el grupo de tratamiento
de 48 semanas, comparado con un 23% (12/52) para el grupo control. Las tasas de
recaída fueron del 12% (3/25) para el grupo RGT y 17% (6/35) para el grupo de
tratamiento de 48 semanas, comparado al 14% (2/14) del grupo control.


Muchos de los pacientes que recibieron VICTRELIS en terapia combinada
respondieron de manera temprana en la semana 8 de tratamiento


Los análisis secundarios claves de los estudios pivótales fueron los
siguientes:



  • Pacientes con tratamiento fallido: 46% (74/162) de los pacientes en
    el grupo de RGT y 52% (84/161) de los pacientes que recibieron VICTRELIS no
    tenían presencia detectable del virus (HCV-RNA) en la semana 8 de tratamiento
    y se consideró que respondieron tempranamente, en comparación al 9% (7/80) en
    el grupo control P/R. La tasa de RSV para aquellos de respuesta temprana fue
    del 88% (65/74) en el grupo RGT y 88% (74/84) en el grupo de 48 semanas de
    tratamiento, comparado con el 100% (7/7) del grupo control. Los de respuesta
    temprana en el grupo de RGT fueron elegibles para suspender todo el
    tratamiento a la semana 36.
  • Pacientes sin tratamiento previo: El 57% (208/368) de los pacientes
    del grupo de RGT y el 56% (204/366) de los pacientes en el grupo de 48 semanas
    de tratamiento que recibieron VICTRELIS no tenían presencia detectable del
    virus (HCV-RNA) en la semana 8 de tratamiento y se considero que habían
    respondido de manera temprana comparado con el 17% (60/363) en el grupo
    control la tasa de RSV para estos pacientes que respondieron de manera
    temprana fue del 88% (184/208) en el grupo RGT y 90% (184/204) en el grupo de
    48 semanas de tratamiento, comparado con el 85% del grupo control. Los
    pacientes que respondieron de manera temprana en el grupo RGT fueron elegibles
    para suspender el tratamiento en la semana 28.


Tasas de RVS con VICTRELIS en terapia combinada en pacientes de respuesta
tardía



  • Pacientes con tratamiento fallido: Los pacientes que tenían
    presencia detectable de (HCV-RNA) en la semana 8 de tratamiento, pero
    presencia indetectable del virus (HCV-RNA) en la semana 12 de tratamiento y
    que habían completado al menos 36 semanas de tratamiento se consideraron
    pacientes de respuesta tardía. La tasa de RVS de estos pacientes de respuesta
    tardía en el grupo de RGT fue del 79% (27/34) y 72 % (29/40) en el grupo de
    tratamiento de 48 semanas. Los que respondieron de manera tardía en el grupo
    de RGT suspendieron VICTRELIS en la semana 36 y continuaron solamente con P/R
    por 12 semanas más (48 semanas en total).


Pacientes sin tratamiento previo: Los pacientes que tenían presencia
detectable del virus (HCV-RNA) en la semana 8 de tratamiento, pero presencia no
detectable del virus (HCV-RNA) en la semana 24 de tratamiento y completaron al
menos 28 semanas de tratamiento, se consideraron pacientes de respuesta tardía
La tasa de RVS para estos pacientes de respuesta tardía en el grupo de RGT fue
del 66% (45/68) en el grupo de RGT y 75% (55/73) en el grupo de tratamiento de
48 semanas. Los pacientes de respuesta tardía en el grupo RGT
suspendieron VICTRELIS en la semana 28 y continuaron solamente con P/R durante
20 semanas más (48 semanas en total).


VICTRELIS en terapia combinada incrementó las tasas de RVS en poblaciones
de pacientes



  • La adición de VICTRELIS a P/R en pacientes con una reducción menor a 1 en
    el virus (HCV-RNA) durante las 4 semanas de fase previa generó un incremento
    en las tasas de RVS hasta el 33% (15/46) para el grupo RGT y 34% (15/44) para
    el grupo de 48 semanas de tratamiento, en comparación con el 0% (0/12) del
    grupo control.
  • En pacientes con terapia fallida, con cirrosis en la línea de base, el 77%
    (17/22) alcanzaron la RVS con la adición de 44 semanas de VICTRELIS al P/R,
    comparado con el 35% (6/17) para aquellos que recibieron RGT.
  • En pacientes sin tratamiento previo, con cirrosis en la línea de base, el
    42%(10/24) alcanzaron la RVS con la adición de 44 semanas de VICTRELIS a P/R
    comparado con el 31% (5/16) de aquellos que recibieron RGT.


Perfil de seguridad y tolerabilidad de VICTRELIS en 2,095 pacientes en
estudios de Fase II y Fase III



  • Se reportaron serios eventos adversos en 11% de pacientes que recibieron
    VICTRELIS en combinación con P/R en comparación al 8% que solamente recibieron
    P/R.
  • Durante todo el curso de tratamiento, la proporción de pacientes que
    descontinuaron el tratamiento debido a las reacciones adversas fue del 13% en
    pacientes que recibieron VICTRELIS en combinación con P/R en comparación al
    12% en pacientes que solamente recibieron P/R. Los eventos que generaron la
    descontinuación fueron similares a aquellos vistos en estudios previos de
    solamente P/R.
  • Las reacciones adversas que llevaron a las modificaciones de la dosis de
    cualquier medicamento (esencialmente P/R) se presentaron en el 39% de los
    pacientes que recibieron la combinación de VICTRELIS con P/R, comparado con el
    24% de los pacientes que solamente recibieron P/R.
  • La razón más común para la reducción de la dosis fue la anemia, que se
    presentó con mayor frecuencia en pacientes que recibieron una combinación de
    VICTRELIS con P/R, que en aquellos que recibieron solamente P/R.
  • La proporción de pacientes que presentaron anemia fue mayor en pacientes
    que recibieron VICTRELIS en combinación con P/R, que en aquellos tratados con
    P/R solamente. En el tratamiento en pacientes con anemia, la reducción
    adicional de hemoglobina promedio fue de aproximadamente 1g/dl. Las
    modificaciones en la dosis (generalmente de P/R) por causa de la anemia se
    presentaron con mayor frecuencia en pacientes tratados con VICTRELIS en
    combinación con P/R (26%), comparado con aquellos tratados solamente con P/R
    (13%). La descontinuación del tratamiento por causa del la anemia fue similar
    a la de aquellos pacientes que recibieron VICTRELIS en combinación con P/R
    (1%) comparado a aquellos tratados solamente con P/R (1%). A discreción del
    investigador de cada protocolo de estudio, se permitió la Eritropoyetina (EPO)
    con o sin reducción de la dosis de ribavirina para el manejo de la anemia.


En estudios clínicos pivótales, las 4 semanas de fase previa,
proporcionaron importantes descubrimientos clínicos


La respuesta al interferón (igual o mayor a 1 reducción en el virus (HCV-RNA)
en la semana 4 de tratamiento) era predictiva del RVS. Los pacientes que
recibieron VICTRELIS que demostraron una respuesta al interferón en la semana 4
de tratamiento lograron tasas de RVS más altas que aquellos con una respuesta
pobre al interferón (una reducción menor a 1 en el virus (HCV-RNA) en la semana
4 de tratamiento. Durante el periodo de fase previa de 4 semanas con P/R en los
grupos de tratamiento que contenían VICTRELIS, el 2% (28/163) de los pacientes
experimentaron reacciones adversas que conllevaron a la descontinuación del
tratamiento.


Antecedentes de los estudios pivótales Fase III para VICTRELIS


En el estudio HCV RESPOND 2 (pacientes con tratamiento fallido) y el estudio
HCV SPRINT 2 (pacientes sin tratamiento previo), cada uno evaluó dos estrategias
de tiramiento en los cuales se adiciono VICTRELIS a P/R para evaluar la
capacidad de VICTRELIS de mejorar las tasas de RVS y de potencialmente acortar
la duración total del tratamiento, en comparación a la utilización de P/R
solamente durante 48 semanas, que es la duración estándar actual de la
terapia.


En ambos estudios, todos los pacientes que recibieron VICTRELIS fueron
tratados durante una fase previa de 4 semanas con peginterferón alfa-2b (1.5
mkg/kg/semana) y una dosis en investigación de ribavirina (600-1,400 mg/día),
seguidos por una adición de VICTRELIS (800 mg tres veces al día) después de la
semana 4.


En cada uno de los estudios los pacientes fueron divididos aleatoriamente en
tres grupos:



  • Terapia guiada por respuesta (RGT), en la cual los pacientes con
    presencia no detectable del virus (HCV-RNA) en la semana 8 de tratamiento se
    consideraban pacientes de respuesta temprana y podían ser elegidos para una
    terapia de menor duración. Lo pacientes sin tratamiento previo sin presencia
    detectable de HCV-RNA durante las semanas 8 a 24 eran elegibles para suspender
    todo el tratamiento en la semana 28. Los pacientes en los cuales fracasó el
    tratamiento, con presencia no detectable de HCV-RNA durante las semanas 8 y 12
    de tratamiento eran elegibles para suspender todo el tratamiento en la semana
    36.
  • 48 semanas de tratamiento, en la cual los pacientes recibían un
    tratamiento de fase previa de 4 semanas con P/R seguido por 44 semanas de
    VICTRELIS combinado con P/R.
  • Control, en el cual los pacientes recibieron P/R durante 48
    semanas.


En el estudio HCV RESPOND-2 a todos los pacientes con presencia detectable
del virus (HCV-RNA) en la semana 12 de tratamiento se les descontinuó el
tratamiento. En el estudio HCV SPRINT-2 a todos los pacientes con presencia
detectable del virus (HCV-RNA) en la semana 24 de tratamiento se les descontinuó
el tratamiento.


El estudio HCV RESPOND -2 se implementó en los EE.UU y en sedes
internacionales e incluyo a 403 pacientes adultos con tratamiento fallido,
incluyendo pacientes que habían sufrido recaídas o habían respondido de manera
parcial al tratamiento previo con terapia estándar. Los pacientes históricamente
no respondedores no participaron en el estudio. Los pacientes se aleatorizaron
en una proporción de 1:2:2 y se estratificaron con base a su respuesta al
régimen de calificación previo (pacientes con recaídas vs. pacientes con
respuesta parcial) y por genotipo VHC. (1 a o 1b).


El estudio HCV SPRINT- 2 se implementó en los EE.UU y en sedes
internacionales, y se aplicó a 1,097 pacientes adultos sin tratamiento previos.
Los pacientes se aleatorizaron en una proporción de 1:1:1 dentro de dos cohortes
separadas (938 pacientes de raza no negra y 159 pacientes de raza negra) y se
estratificaron mediante genotipo HCV (1a o 1b) mediante carga viral de HCV-RNA
(menor o igual a 400,000 IU/ml vs. mayor a 400,000 IU/ml). Históricamente
los pacientes de raza negra con VHC crónico han demostrado presentar mayores
dificultades para lograr un tratamiento exitoso.


Los resultados finales del HCV RESPOND-2 y del HCV SPRINT-2 se publicaron en
el New England Journal of Medicine el 31 de marzo de 2011.


Importante información de seguridad acerca de VICTRELIS


Todas las contraindicaciones al peginterferón alfa y a la ribavirina también
aplican, dado que el VICTRELIS debe ser suministrado con peginterferón alfa y
ribavirina. Dado que la ribavirina puede causar defectos de nacimiento y muerte
fetal, VICTRELIS en combinación con peginterferón alfa y ribavirina está
contraindicada en mujeres embarazadas y en hombres cuyas parejas femeninas están
en estado de embarazo.


Es necesario, en pacientes femeninas, evitar el estado de embarazo así como
en las parejas femeninas de pacientes masculinos. Antes de iniciar la terapia
las pacientes deben reportar un resultado negativo a una prueba de embarazo,
utilizar dos o más métodos anticonceptivos incluyendo los dispositivos
intrauterinos y métodos de barrera, durante el tratamiento y por lo menos 6
meses después de haber concluido el tratamiento. Los anticonceptivos hormonales
sistémicos pueden no ser muy efectivos en las mujeres que estén tomando
VICTRELIS y la concomitante ribavirina. VICTRELIS está contraindicado para la
coadministración con medicamentos que presenten alta dependencia en CYP3A4/5 y
en los cuales las concentraciones de plasma estén asociadas con eventos serios
y/o que constituyan una amenaza para la vida.


VICTRELIS también está contraindicado en inductores poderosos del CYP3A4/5 en
donde las significativas reducciones en las concentraciones de plasma boceprevir
puedan estar asociadas a una eficacia reducida. Los medicamentos contraindicados
con el VICTRELIS incluyen; alfuzosina, carbomazepina, fenobarbital, fenitoina,
rifampina, dihidroergotamina, ergonovina, ergotamina, metilergonovina,
cisapirida, hierba de san juan ( hypericum perforatum), lovasitina,
simvastatina, drosperidona, Revatio® ( sildenafil) o Adcirca® (tadalafil) (
cuando se utiliza para el tratamiento de la hipertensión pulmonar arterial),
pimozide, triazolam, y midazonlam( administrado por vía oral).


Se han reportado casos de anemia con la terapia de peginterferón alfa y
ribavirina. La adición de VICTRELIS a peginterferón alfa y ribavirina está
asociada con una reducción adicional de las concentraciones de hemoglobina. La
adición de VICTRELIS puede ocasionar un empeoramiento de la neutropenia asociado
a peginterferón alfa y ribavirina solamente. Se deben efectuar conteos hematicos
durante el pre tratamiento, en las semanas 4,8 y 12 de tratamiento, y deben ser
monitoreados cuidadosamente en otros momentos, cuando se considere apropiado
clínicamente. Si un paciente tiene una reacción adversa seria relacionada
potencialmente con la terapia de peginterferón alfa y ribavirina, la dosis de
peginterferón alta y/o ribavirina debe ser reducida o descontinuada. VICTRELIS
no puede ser administrada en ausencia de peginterferón alfa y ribavirina.


Las reacciones adversas más comúnmente reportadas (más del 35% de los
pacientes) en los ensayos clínicos en pacientes adultos que recibieron una
combinación de VICTRELIS con peginterferón alfa-2b y ribavirina fueron fatiga,
anemia, nauseas, cefalea y disgusia. De estas reacciones adversas comúnmente
reportadas la fatiga, la anemia, las nauseas y la disgusia se presentaron a
tasas iguales o mayores al 5% por encima de las ratas de peginterferón alfa y
ribavirina solamente en cualquiera los estudios clínicos. La incidencia de estas
reacciones adversas en pacientes sin tratamiento previo que se trataron con
terapia combinada de VICTRELIS en comparación con peginterferón y ribavirina
solamente fueron: fatiga (58% vs. 59%), anemia (50% vs. 30%) nauseas (46% vs.
42%), disgusia (35% vs. 16%), respectivamente. La incidencia de estas reacciones
adversas en pacientes con tratamiento previo que se trataron con terapia
combinada de VICTRELIS en comparación con peginterferón y ribavirina solamente
fueron: fatiga (55% vs. 50%), anemia (45 % vs 20%), nauseas (43% vs. 38%),
disgusia (44% vs. 11%) respectivamente.


VICTRELIS es un fuerte inhibidor del CYP3A4/5 y se metaboliza parcialmente
mediante CYP3A 4/5.


Se debe considerar el potencial para interacciones medicamento-medicamento
antes y después de la terapia.


Por favor ver la información sobre la prescripción en: www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf


Dosis y administración


VICTRELIS debe ser administrado en combinación con peginterferón alfa y
ribavirina. La terapia se inicia con peginterferón alfa y ribavirina durante 4
semanas. Iniciado el tratamiento, en la semana 5, se adiciona el VICTRELIS en
una dosis de 800 mg (cuatro capsulas de 200 mg) por vía oral tres veces al día
(cada 7-9 horas) con un alimento (un comida o merienda ligera). Basado en los
niveles de virus del paciente (HCV-RNA) en las semanas 8, 12 y 24 de tratamiento
la dosis se ajusta siguiendo los parámetros de la terapia guiada por la
respuesta.



  • Pacientes sin tratamiento previo: Los pacientes que son
    indetectables en las semanas 8 y 24 del tratamiento completan la terapia en la
    semana 28 de tratamiento. Los pacientes que son detectables en la semana 8 de
    tratamiento, pero no detectables en la semana 24 completan el VICTRELIS en la
    semana 36 de tratamiento y continúan con peginterferón alfa y ribavirina
    solamente hasta la semana 48 de tratamiento
  • Pacientes con tratamiento fallido: Los pacientes (con respuesta
    parcial previa o recaídas) que no tienen una presencia detectable a las 8 y 24
    semanas de tratamiento completan todo el tratamiento en la semana 36. Los
    pacientes que tienen presencia detectable en la semana 8 de tratamiento pero
    no detectable en la semana 24 de tratamiento completan el tratamiento con
    VICTRELIS en la semana de tratamiento 36 y continúan solamente con
    peginterferón alfa y ribavirina hasta la semana 48 de tratamiento. La terapia
    guiada por respuesta no se evaluó en pacientes con tratamiento fallido que
    presentaron una reducción de menos de 2 en el virus (HCV-RNA) en la semana 12
    del tratamiento previo (no respondedores).Si estos pacientes se tratan,
    deberían recibir 4 semanas de peginterferón alfa y ribavirina seguidos por 44
    semanas de VICTRELIS en combinación con peginterferón alfa y ribavirina.


Los pacientes con cirrosis compensada deben recibir 4 semanas de
peginterferón alfa y ribavirina seguidos por 44 semanas de VICTRELIS en
combinación con peginterferón alfa y ribavirina.


Los pacientes que tienen resultados de HCV-RNA mayores o iguales a 100IU7mL
en la semana 12 de tratamiento, descontinúan el régimen de tres medicinas.
Pacientes que tienen una presencia detectable de HCV-RNA en la semana 24 de
tratamiento, descontinúan el régimen de tres medicinas.


El costo de adquisición de VICTRELIS para el mayorista es de US$ 1,100 por
semana.


Acerca de Merck


Hoy en día, Merck es un líder global en atención al saludo que trabaja para
ayudar a que el mundo esté bien. Merck se conoce como MSD por fuera de los
Estados Unidos y Canadá. A través de nuestros medicamentos de prescripción,
vacunas, terapias biológicas y productos para el cuidado del consumidor y la
salud animal, trabajamos con clientes y operamos en más de 140 países para
suministrar soluciones innovadoras para la salud. También demostramos nuestro
compromiso hacia incrementar el acceso a la atención en salud a través de
políticas de largo alcance, programas y sociedades. Para mayor información,
viste www.merck.com


Declaración de carácter predictivo


Este comunicado de prensa contienen “declaraciones de carácter predictivo”
dentro del contexto de los amparos de protección (safe harbor) bajo la Ley de
Reforma de Litigios sobre Valores Privados de 1995. Tales declaraciones pueden
incluir, pero no están limitadas a; declaraciones sobre los beneficios de la
fusión entre Merck y Schering-Plough, incluyendo resultados financieros y de
operaciones futuros, los planes combinados de las compañías, objetivos,
expectativas e intenciones y otras declaraciones que no son hechos históricos.
Tales declaraciones están basadas en creencias actuales y expectativas de la
administración de Merck y están sujetas a riesgos e incertidumbres
significativos. Los resultados reales pueden diferir de aquellos planteados en
las declaraciones de carácter predictivo.


Los siguientes factores entre otros, pueden generar que los resultados reales
difieran de aquellos expuestos en las declaraciones de carácter predictivo: la
posibilidad de que las sinergias esperadas a partir de la fusión de Merck y
Schering-Plough no se cristalicen, o no se lleven a cabo durante el periodo de
tiempo esperado; el impacto de las regulaciones de la industria farmacéutica y
de la legislación del cuidado de la salud; el riesgo de que el negocio no se
integre de manera exitosa, alteraciones producto de la fusión que dificulten el
mantener las relaciones comerciales y operacionales. La habilidad de Merck para
predecir de manera precisa las condiciones futuras de los mercados, dependencia
en la efectividad de las patentes de Merck y otras protecciones para productos
innovadores; el riesgo de nuevas y cambiantes regulaciones y políticas de salud
en los EEUU y a nivel internacional y la exposición a litigios y/ o acciones
regulatorias.


Merck no asume ninguna obligación de actualizar públicamente cualquier
declaración de carácter predictivo, como resultado de nueva información, eventos
futuros o de cualquier otro tipo. Factores adicionales que pueden generar que
los resultados difieran materialmente de aquellas descritas en los carácter de
índole predictivo se pueden encontrar en el Reporte Anual de Merck de 2010 en el
Formato 10-K y los otros archivos en el Securities and Exchange
Commission
(SEC) disponibles en la página web de SEC. (www.sec.gov).


Por favor ver la información de prescripción y guía de
Medicamento de VICTRELIS adjunta. La información sobre la prescripción y guia de
Medicamento también está disponible: en www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

and www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf. 



(1) RVS, punto de eficacia primario especificado en el
protocolo de los estudios pivótales, se define como el logro de HCV-RNA no
detectable 24 semanas después de finalizado el tratamiento de en todos los
pacientes aleatorizados tratados con cualquier medicamento bajo estudio. En cada
protocolo, si un paciente no se le hacia una evaluación en las 24 semanas
posteriores al tratamiento, se utilizaba el evaluación post tratamiento 12
semanas.



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







Previously


Untreated


Patients


Undetectable


Undetectable


Complete three-medicine regimen at TW28.





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.





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 > 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-log(10) 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 10(9)/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 > 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 10(9)/L)






<0.75


31


18


26


13


<0.5


8


4


7


4


Platelets (x 10(9)/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


^ antiarrhythmics


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


^ digoxin


Digoxin concentrations may be increased with VICTRELIS.
Use the lowest dose initially with careful titration and monitoring of
serum digoxin concentrations.





Anticoagulant: warfarin


^ or v 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.






^ boceprevir*






Antifungals: ketoconazole, itraconazole, posaconazole,
voriconazole


^ 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.







Significant increases in colchicine levels are expected;
fatal colchicine toxicity has been reported with other strong CYP3A4
inhibitors.





Anti-gout: colchicine


^ colchicine


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


v 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


v 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


v 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


v boceprevir*


^ or v 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 v methadone


^ or v 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*


v 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)].







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)].





PDE5 inhibitors: sildenafil, tadalafil, vardenafil


^ sildenafil


^ tadalafil


^ vardenafil


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 C(27)H(45)N(5)O(5) 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(T) 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 (14)C-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






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


Co-


administered


Drug


Co-


administered


Drug Dose/


Schedule


Boceprevir


Dose/Schedule


(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






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


Co-
administered
Drug


Co-administered
Drug
Dose/Schedule


Boceprevir
Dose/Schedule


(90% CI of the Ratio Estimate)
*





Change in mean C(max)


Change in mean AUC(T)


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 (14)C-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 EC(50) and EC(90) 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-log(10) 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-log(10) 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


Subjects Infected with



HCV Genotype 1a


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++ %


9


9


22






(n/N)


(24/257)


(24/265)


(39/176)






Cohort 1 Plus Cohort 2 (subjects without
cirrhosis)





SVR+,+++ %


65


68


38






(n/N)


(228/352)


(232/342)


(132/350)






Cohort 1 (non-Black)


n=316


n=311


n=311


SVR+ %


67


68


40


Relapse++ %


9


8


23






(n/N)


(21/232)


(18/230)


(37/162)






Cohort 2 (Black)


n=52


n=55


n=52


SVR+ %


42


53


23


Relapse++ %


12


17


14






(n/N)


(3/25)


(6/35)


(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
r
esults 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-log(10) 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-log(10) 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


12


28




(16/111)


(14/121)


(7/25)







SVR (subjects without cirrhosis)
+++



62


65


26







(n/N)



(90/145)


(90/139)


(18/70)







SVR by Response to Previous Peginterferon and Ribavirin
Therapy


Previous
Response


Relapser, % (n/N)



Partial responder, % (n/N)


70 (73/105)



40 (23/57)


75 (77/103)



52 (30/58)


31 (16/51)



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-log(10)
reduction in HCV-RNA by Week 12. Previous Relapser = subject who failed to
achieve SVR after at least 12 weeks of previous treatment with
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-log(10) 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-log(10) 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-log(10) 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-log(10) decline in viral load at TW4 with peginterferon alfa plus ribavirin
therapy alone are predicted to have a null response (less than 2-log(10) 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-log(10) 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-log(10) 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 degrees C (36-46 degrees 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 degrees C (77
degrees 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.


Copyright © 2011 Schering Corporation, a subsidiary of Merck &
Co.,
Inc. All rights reserved.


Issued: 05/11


B-35071601


34965501T


MEDICATION GUIDE
VICTRELIS™ (vic-TREL-is)
(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 degrees – 46 degress F
    (2-8 degrees C). Safely throw away refrigerated VICTRELIS after the expiration
    date.
  • VICTRELIS capsules may also be stored at room temperature up to 77°F (25
    degrees 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


Trademarks depicted herein are the property of their respective owners.

Copyright © 2011 Schering Corporation, a subsidiary of Merck &
Co.,
Inc. All rights reserved.



Issued: May 2011
B-35071601
34966400T




FUENTE  Merck



EL FDA Aprueba VICTRELIS™ (boceprevir) de Merck, Inhibidor de la proteasa del virus de la Hepatitis C (VHC) primero en su clase por vía oral