Una píldora, una vez al día para el mal de
Parkinson
Preguntas y respuestas sobre el mal de Parkinson— y cómo puede
ayudarle AZILECT® (rasagiline tablets) una vez al día
Después de recibir un diagnóstico
del mal de Parkinson (PD), usted
puede tener muchas preguntas. Este
folleto servirá para contestar algunas
de estas preguntas y guiarlo a usted
y a su familia hacia las fuentes de
mayor información. También sabrá
más detalles sobre el medicamento
que le recetó su médico, AZILECT®
(rasagiline tablets), un medicamento
para Parkinson que se toma una vez
al día y funciona solo o con otras
terapias para Parkinson dependiendo
de sus necesidades.
Vea la Información de seguridad
importante adicional en la página 12.
Consulte la Información de prescripción
completa en las páginas 14 a 21.
2
3
“¿Qué es el mal de Parkinson?”
El mal de Parkinson es un trastorno del sistema
nervioso central causado por una falta de dopamina,
un compuesto químico cerebral que se utiliza para
enviar mensajes a los músculos y hacer que se
muevan correctamente. Si tiene Parkinson, puede
que se le dificulten las cosas comunes y corrientes—
alcanzar un vaso o salir a hacer una caminata
pueden no resultarle tan fáciles como antes. A
algunos pacientes les puede temblar la mano o tener
temblores mientras descansan. Lo más probable es
que su médico busque ciertos síntomas comunes para
determinar si tiene Parkinson: temblor de una mano o
un brazo, rigidez, lentitud y pérdida del equilibrio.
Otros síntomas pueden incluir problemas para dormir,
dificultades para hablar o tragar, dificultades para
empezar a moverse y depresión.
Dado que el Parkinson es una enfermedad progresiva,
pueden empeorar los síntomas lentamente con el
paso del tiempo. Sin embargo, el cambio es diferente
en cada persona que tenga Parkinson. Lo que es más
importante recordar es que hay mucho que usted
puede hacer para ayudarse a sí mismo y mantenerse
activo en su vida diaria.
Un tratamiento efectivo, una vez al día,
para el mal de Parkinson
AZILECT es un medicamento que se toma una vez al día y
es indicado para tratar el mal de Parkinson. Se ha medido
la eficacia de AZILECT en varios estudios, y ha demostrado
mejoras en pacientes en todas las etapas del Parkinson—
en pacientes con enfermedad incipiente que estaban
tomando AZILECT solo, en pacientes con enfermedad
moderada además de un agonista de dopamina y en
pacientes con enfermedad moderada a avanzada además
de levodopa.
“¿Es tratable el Parkinson?”
Aunque no se ha encontrado aún una cura para
el Parkinson, hay varios tipos de medicamentos
diferentes disponibles para tratar los síntomas del mal
de Parkinson. La mayoría de los medicamentos para
el mal de Parkinson tratan la deficiencia de dopamina
al ayudar a reemplazarla, prevenir su degradación o
imitar sus efectos. Puede empezar con 1 medicamento,
pero con el tiempo lo más probable es que su médico
agregue o cambie medicamentos a medida que
cambien sus síntomas. Dado que estos medicamentos
funcionan de distintas maneras en el cerebro, puede
usarse más de 1 medicamento a la vez.
Con las observaciones que usted le indique, su
médico va a determinar cuáles medicamentos son los
correctos para usted.
No tome AZILECT si está tomando meperidina porque
podría causar una reacción grave como un coma o
la muerte. No tome tampoco AZILECT con tramadol,
metadona, propoxifeno, dextrometorfano, hierba de
San Juan o ciclobenzaprina. Asimismo, no debe tomar
AZILECT con otros inhibidores de monoaminaoxidasa
(MAOI), porque podría causar un aumento peligroso de la
presión sanguínea.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
3
“¿Cómo funciona AZILECT® (rasagiline
tablets), y cuáles son algunas de sus
ventajas?”
Con el paso del tiempo, el Parkinson le hará perder
cada vez más dopamina en el cerebro. La dopamina
es producida por las células cerebrales, o neuronas,
en un área particular del cerebro que se llama
sustancia negra.
Neurona sana
Neurona en el cerebro
Receptores de
Receptores
dopamina de
dopamina
Dopamina
Dopamina
Neurona con Parkinson
Liberación de
dopamina
Liberación de
dopamina
Liberación de
Liberación
dopamina de
dopamina
Dado que AZILECT es un medicamento que se toma
una vez al día para tratar el Parkinson, usted puede
apreciar que:
n Con una píldora de AZILECT al día, pueden mejorar los
Receptores de
dopamina
Receptores de
dopamina
síntomas y pueden facilitarse las actividades diarias
n AZILECT
puede tomarse solo o en combinación con
otros medicamentos para el Parkinson
Dopamina
Una enzima en el cerebro llamada MAO-B
(monoamina oxidasa tipo B) degrada la dopamina,
impidiendo su disponibilidad de manera que el
cerebro no puede utilizarla. Esto reduce los niveles
de dopamina incluso más en personas con el mal
de Parkinson. AZILECT es un inhibidor de MAO-B,
un medicamento que bloquea la MAO-B y permite
que haya más dopamina disponible para que la
utilice el cerebro. Puede usarse en toda etapa de
la enfermedad. AZILECT ayuda a preservar tanto la
dopamina propia del paciente como la dopamina
proveniente de levodopa (otro medicamento común
para el mal de Parkinson). Por eso, a medida que
mejoran los niveles de dopamina, pueden mejorar los
síntomas y pueden facilitarse las actividades diarias.
n AZILECT
ha demostrado tolerabilidad
Pueden ocurrir aumentos en la presión sanguínea durante
el tratamiento con AZILECT. Informe a su médico si
tiene un historial de alta presión sanguínea. Entre los
posibles síntomas de un aumento peligroso de la presión
sanguínea se incluyen dolores fuertes de cabeza, vista
nublada, dificultades para razonar, ataque convulsivo,
dolor en el pecho y náuseas/vómitos. Si sufre estos
síntomas, es importante que hable con su médico y
obtenga atención médica. Cuando se toma AZILECT
conforme a las dosis recomendadas, comúnmente no
se requiere restringir los alimentos y las bebidas que
contengan una sustancia llamada tiramina. Sin embargo,
se le aconseja evitar alimentos que contengan altas
cantidades de tiramina como los quesos maduros, ya que
algunos pacientes pueden tener una mayor sensibilidad
que pudiera provocar un aumento peligroso de la presión
sanguínea como se describe anteriormente.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
4
“¿Me conviene tomar AZILECT®
(rasagiline tablets)?”
Si siente los primeros síntomas del Parkinson,
podría convenirle tomar AZILECT solo.
El tratamiento de AZILECT por sí solo puede hacer
más fáciles las actividades diarias sencillas, como
disfrutar de una comida, hacer una caminata o
vestirse en la mañana. Su médico determinará si
usted necesita medicamentos adicionales y cuándo.
AZILECT puede ser la única terapia necesaria por
un tiempo. Hay varios motivos por los cuales puede
ser aconsejable que considere AZILECT como su
primer medicamento— es eficaz, ha demostrado tener
tolerabilidad y puede tomarse solo una vez al día.
¿Está tomando un agonista de dopamina? Si su
agonista de dopamina no funciona tan bien como
antes, agregar AZILECT puede darle mayor control de
los síntomas.
¿Está tomando levodopa? Casi todos los pacientes
de Parkinson usan carbidopa/levodopa en alguna
etapa. Si no funciona levodopa tan bien como
antes, AZILECT también puede serle útil. Dado que
el Parkinson es progresivo, un tratamiento que ha
sido eficaz durante meses o años puede tener que
cambiarse al pasar el tiempo.
Después de varios años de tomar carbidopa/levodopa,
puede encontrar que las ventajas de tomar el medicamento parecen estar disipándose más rápidamente,
produciendo lo que los médicos llaman fluctuación entre
ciclo “activo” a “inactivo”. Cuando esté “activo” puede
moverse bien, pero cuando esté “inactivo” puede tener
problemas de nuevo con temblores, movimiento más
lento, mayor rigidez, inmovilidad (la incapacidad de
moverse) o dificultades para caminar.
Si ya conoce estos problemas, su médico puede decidir
agregar AZILECT a su terapia de carbidopa/levodopa:
n A
ZILECT
puede ayudar a reducir el tiempo que usted
se sienta lento o rígido (“inactivo”) en unas 2 horas al
día
n A
ZILECT
puede servir para mejorar su capacidad para
moverse y hacer actividades cotidianas
En todo caso, su médico querrá verlo regularmente para
ver cómo le va con el tratamiento del Parkinson. Puede
cambiarle el medicamento si puede mejorar el control
de sus síntomas.
Informe a su médico si toma, o piensa tomar,
algún medicamento recetado o de venta libre,
especialmente antidepresivos y ciprofloxacina. La
combinación de inhibidores de monoaminaoxidasa
(MAO-B) como AZILECT y antidepresivos ha causado
una afección grave y a veces fatal llamada síndrome
de serotonina.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
5
“¿Cómo puede ayudar AZILECT®
(rasagiline tablets) a los pacientes
con Parkinson como yo?”
AZILECT puede ayudar a los pacientes como usted a lo
largo de la progresión del mal de Parkinson. Aunque
los perfiles siguientes no son de pacientes reales,
estos ejemplos pueden demostrarle cómo puede
ayudarle tomar AZILECT.
MARY: “Siento una lentitud
y se me nota... y no solo al
caminar o vestirme. Se me ve
también en la cara.”
GEORGE: “Como maestro,
tengo que estar listo para
trabajar en la mañana.”
n G
eorge,
quien sigue ya una terapia de levodopa,
tiene síntomas moderados de Parkinson pero está
empezando a sentir ciclos “inactivos” (momentos
durante el día en que su medicamento no funciona tan
bien)
n A
ZILECT
una vez al día, ofrece mayor control de los
síntomas y reduce el ciclo “inactivo” cuando se toma
con la terapia de levodopa
n M
ary,
recién diagnosticada, tiene 54 años y es activa,
pero siente una lentitud leve y temblor en su lado
derecho. Quiere continuar su estilo de vida activo
LILY: “Todo lo que quiero es
más tiempo en que no tenga
síntomas y menos tiempo en
que los tenga.”
n E
l
tratamiento de AZILECT una vez al día se puede
tomar solo para ayudar a mantener las funciones
antes de necesitar otras terapias
n L
ily,
JOE: “Tengo nietos pequeños
en casa; quisiera poder hacer
más cosas con ellos.”
n J oe,
a quien se le diagnosticó hace 4 años,
encuentra que su agonista de dopamina no funciona
tan bien como antes. Necesita una terapia que sirva
para mejorar sus síntomas y poder jugar con sus
nietos
n A
ZILECT,
una vez al día, cuando se toma con un
agonista de dopamina solo, ayuda a controlar mejor
los síntomas
a quien se diagnosticó hace 12 años, tiene más
problemas con el ciclo “inactivo” a medida que
avanzan los síntomas de Parkinson. Ya toma varios
medicamentos para el Parkinson
n A
ZILECT
una vez al día puede ayudar a mejorar los
síntomas cuando se suma a un agonista de dopamina y
reduce el ciclo “inactivo” cuando se agrega a levodopa
Las personas descritas no son pacientes reales que toman AZILECT.
Si usted sufre episodios de quedarse dormido o de
somnolencia durante actividades de la vida diaria,
no conduzca y sea precavido hasta ponerse en
contacto con su médico.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
6
“¿Cómo voy a saber si me hace efecto
AZILECT® (rasagiline tablets)?”
Al aliviar muchos de los síntomas del Parkinson,
AZILECT puede facilitarle muchas de las actividades
que realiza todos los días. Puede usar esta tabla para
seguir los cambios en sus síntomas y su capacidad
para realizar actividades diarias una vez que empiece
a tomar AZILECT. Simplemente traiga esta tabla a la
siguiente cita que tenga con su médico para poder ver
lo bien que le funciona el medicamento.
Síntomas
Iguales Mejores Peores
No
tiene
Lentitud de movimiento
(bradicinesia)
“¿Cómo tengo que tomar AZILECT”
Para sacar máximo provecho de la terapia de AZILECT
hay que seguirla correctamente. Aquí tiene cómo
tomar AZILECT:
n T
ome
una píldora solo una vez al día— ya sea la
primera vez que usted toma la terapia de Parkinson
o que haya estado tomando medicamentos de
Parkinson durante años
n S
e
puede tomar AZILECT con o sin alimentos; no hay
restricciones dietéticas requeridas al tomar AZILECT
en la dosis recomendada
n S
i
omite una dosis, no la duplique; simplemente
tome su siguiente dosis como de costumbre
“¿Quién no debe tomar AZILECT?”
Temblor/agitación
rítmica
Si tiene una enfermedad del hígado moderada a grave,
no debe tomar AZILECT.
Rigidez muscular
Dificultad con el
equilibrio, caminar
arrastrando los pies
Tiempo “inactivo”
(cuando su
medicamento no
funciona como debe)
Sensación de tener
las piernas “pegadas
al piso” (inmovilidad)
Caídas
Voz baja
Actividades
diarias
Iguales
Más
fácil
Más
difícil
Sin
dificultades
Vestirse
Conducir un vehículo
Sentarse a comer
Cocinar
Labores domésticas (doblar
ropa recién lavada)
Levantarse de la silla
Bañarse
Subir y bajar
escaleras
Caminar
No debe exceder una dosis de 0.5 mg por día de
AZILECT si tiene una enfermedad leve del hígado o
toma ciprofloxacina. Los pacientes no deben exceder
una dosis de 1 mg por día de AZILECT debido al
riesgo de que aumente la presión sanguínea.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
7
“¿Hay medicamentos que no debo
tomar con AZILECT® (rasagiline
tablets)?”
Siempre asegúrese de hablar con su médico o
farmacéutico antes de tomar cualquier medicamento
de venta libre o con receta si ya toma AZILECT.
Específicamente, no debe tomar AZILECT con los
siguientes, ya que tal vez pudiera causar una reacción
grave como un coma o la muerte.
Su médico puede decidir recetar Cipro y puede tener
que reducir su dosis de AZILECT. Alternativamente,
su médico puede considerar recetar un antibiótico
que no afecte la enzima CYP1A2. Los antibióticos
que han demostrado no interferir con CYP1A2
incluyen levofloxacina (Levaquin®), gatifloxacina
(Tequin®), moxifloxacina (Avelox®), gemifloxacina
(Factive®), azitromicina (Zithromax®) y
claritromicina (Biaxin®).*
n M
eperidine
(Demerol®), medicamento analgésico
de venta con receta
n T
ramadol
(Ultram®), metadona (Dolophine®),
propoxifeno (Darvon®) o ciclobenzaprina
(Flexeril®)*
n D
extrometorfano,
n Hierba
n Otros
supresor de la tos
de San Juan
inhibidores de monoamina oxidasa (MAOI)
“¿Qué pasa con AZILECT y otros
medicamentos?”
Informe a su médico si toma o si piensa tomar los
medicamentos siguientes porque va a tener que
ser precavido:
n A
ntidepresivos
n M
edicamentos
contra resfriados o alergias que
contengan descongestionantes
n P
reparados
reductores de peso que contengan
seudoefedrina
n T
odo
medicamento analgésico
Si su médico necesita recetar un antibiótico, confirme
que sepa que usted toma AZILECT. El antibiótico
ciprofloxacina (nombre de marca Cipro®) inhibe
la CYP1A2, una enzima en el cuerpo, y puede
causar niveles duplicados de AZILECT en la sangre,
aumentando así el riesgo de efectos secundarios.
*Consulte con su médico o farmacéutico para ver un listado
completo de nombres de marca.
“¿Hay efectos secundarios con el
tratamiento de AZILECT?”
Los efectos secundarios más comunes vistos con
AZILECT solo son el síndrome gripal, dolor en las
articulaciones, depresión e indigestión; al tomarlo
con un agonista de dopamina son hinchazón de
las piernas, caídas, dolor en las articulaciones,
tos e incapacidad de dormir; además al tomarlo
con levodopa, son movimientos descontrolados
(discinesia), lesiones accidentales, pérdida de peso,
baja presión sanguínea al estar parado, vómitos,
anorexia, dolor de las articulaciones, dolor abdominal,
náuseas, estreñimiento, boca seca, sarpullidos, sueños
anormales, caídas e hinchazón de los tendones. No
deje de decirle a su médico si siente alguno de estos u
otros efectos secundarios al tomar AZILECT.
Vea la Información de seguridad importante adicional
en la página 12. Consulte la Información de prescripción
completa en las páginas 14 a 21.
8
“¿Hay restricciones dietéticas con
AZILECT® (rasagiline tablets)?”
No hay restricciones dietéticas requeridas por lo común
al tomar AZILECT en la dosis recomendada.
Sin embargo, ciertos alimentos (como los quesos
maduros) contienen cantidades muy altas de una
sustancia llamada tiramina. Los inhibidores de MAO
pueden tal vez causar que se acumule tiramina en el
cuerpo y provocar un aumento drástico de la presión
sanguínea. Por este motivo, debe evitar alimentos
con muy alto contenido de tiramina, como los quesos
maduros, y siempre tomar AZILECT en la dosis
recomendada.
Si come alimentos ricos en tiramina y no se siente bien
poco después de comer, debe ponerse en contacto con
su médico lo más pronto posible.
“¿Hay algún examen de laboratorio
que necesite porque estoy tomando
AZILECT?”
No. No obstante, los estudios han demostrado que
las personas con Parkinson tienen mayor riesgo de
desarrollar melanoma (cáncer de la piel). Por este
motivo, se aconseja a todo paciente con Parkinson que
esté alerta al melanoma y se someta periódicamente
a exámenes de la piel realizados por un profesional de
salud calificado.
“¿Hay algo que deba saber antes de
comprar mi receta de AZILECT?”
Su médico eligió AZILECT para ayudarle a controlar sus
síntomas de Parkinson a fin de que pueda continuar
realizando las actividades que le gustan. Si tiene
preguntas antes de comprar su receta o cuando esté
en la farmacia, puede llamar a Parkinson’s Support
Solutions® (PSS), un programa de apoyo para personas
que toman AZILECT, y uno de sus representantes estará
complacido de ayudarle. Vea el reverso para saber más
detalles.
“¿Qué pasa si no puedo pagar mi receta
de AZILECT?”
Llame a Parkinson’s Support Solutions, y nuestros
representantes lo orientarán entre las opciones
financieras disponibles para ayudarle a hacer más
accesible AZILECT conforme a su presupuesto. PSS
ofrece opciones financieras para ayudarle ya sea que
tenga seguro comercial, Medicare, o esté sin seguro.
PSS puede ayudarle a:
n V
erificar
la cobertura de AZILECT que tiene su plan
actual
n A
yudarle
a evaluar su cobertura de Medicare, incluso
durante la inscripción abierta de Medicare
n O
frecer
asistencia con los copagos*
n O
frecer
orientación referente a programas de
asistencia
n B
uscar
soluciones para resolver problemas en la
farmacia
Vea la página 13 para saber más detalles sobre PSS.
*Dependiendo de la elegibilidad del paciente.
Debe vigilarse a todos los pacientes con enfermedad
de Parkinson en cuanto a cambios en la presión
sanguínea, movimientos descontrolados (discinesia),
alucinaciones, control de impulsos, confusión y
melanoma (cáncer de la piel). Puede ocurrir un posible
aumento de la temperatura corporal al dejar de tomar
AZILECT.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
9
“¿Cómo puedo aprovechar al máximo el
tiempo que tengo con mi médico?”
Aquí tiene algunas maneras de prepararse para su
visita al médico:
n T
raiga
consigo una lista de todos los medicamentos
(con receta y de venta libre) que esté tomando y
dígale a su médico si sigue el plan de medicación tal
como se le ha indicado
n D
ígale
a su médico cualquier problema o mejora
que tenga desde la última visita, incluso nuevos
síntomas o efectos secundarios, síntomas o efectos
secundarios disminuidos, empeoramiento o mejora
de síntomas o efectos secundarios y dificultades con
las actividades diarias
“¿Qué más puedo hacer para tomar el
control de mi salud y sentirme mejor?”
Adoptar un papel activo en su atención médica
y bienestar es algo que le hará sentir que tiene
el control. Aquí tiene algunas cosas que pueden
facilitarle la vida con Parkinson:
Empiece un programa de ejercicios terapéuticos.
Hable con su médico. Puede que le recomiende una
rutina que puede hacer por sí solo o que lo derive a un
fisioterapeuta. El ejercicio aporta los beneficios de:
n M
ayor
fuerza muscular
n M
ejor
movilidad y flexibilidad
n M
ejor
equilibrio
n Traiga
un bloc de notas con preguntas que tenga, y
anote las respuestas que reciba
Únase a un grupo de apoyo. Ya sea en Internet o en
persona, los grupos de apoyo le permiten compartir
experiencias y saber cómo enfrenta otra gente la vida
con Parkinson. También puede descubrir ideas que
pueden facilitarle las tareas cotidianas.
n Invite
a un familiar o a una persona clave que lo
apoye para acompañarlo a las citas:esa persona
puede aportar conocimiento de cambios en su
afección que usted puede no haber notado y hacer
preguntas que posiblemente no se le hayan ocurrido
a usted
n P
repárese
para expresar necesidades y, si tiene
muchas cosas de que hablar, pida una cita más larga
Aprenda sobre el Parkinson de tal modo que pueda
reconocer sus síntomas. A veces puede ser difícil
saber la diferencia entre los efectos secundarios
de ciertos medicamentos para el Parkinson y la
enfermedad misma. Entender los síntomas así como
los efectos secundarios le ayudará a usted y a su
médico a controlar su atención.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
10
“¿Dónde hay más información sobre
Parkinson para mí y mi familia?”
Hay muchos recursos a su disposición en toda la
red amplia y creciente de programas de apoyo y
comunitarios relacionados con el mal de Parkinson.
Para saber más detalles sobre Parkinson, noticias
de Parkinson, ensayos clínicos y cómo enfrentar
las dificultades que trae la enfermedad y recibir
información específicamente para la familia y los que
le prestan cuidado, aquí tiene algunos recursos:
American Parkinson Disease Association
www.apdaparkinson.org
800-223-2732
aregiver Action Network
C
www.caregiveraction.org
202-772-5050
Family Caregiver Alliance
www.caregiver.org
800-445-8106
Parkinson’s Action Network
www.parkinsonsaction.org
800-850-4726
The Parkinson Alliance
www.parkinsonalliance.org
800-579-8440
Parkinson’s Disease Foundation
www.pdf.org
800-457-6676
ParkinsonsHealth.com
www.parkinsonshealth.com
Parkinson’s Support Solutions
www.parkinsonssupportsolutions.com
866-880-8582
Visite www.azilect.com para obtener más
información sobre cómo trata AZILECT
eficazmente el mal de Parkinson.
The Michael J. Fox Foundation for
Parkinson’s Research
www.michaeljfox.org
800-708-7644
National Parkinson Foundation, Inc.
www.parkinson.org
800-473-4636
Informe a su médico si toma, o piensa
tomar, algún medicamento recetado o de
venta libre, especialmente antidepresivos y
ciprofloxacina. La combinación de inhibidores
de monoaminaoxidasa (MAO-B) como AZILECT y
antidepresivos ha causado una afección grave y a
veces fatal llamada síndrome de serotonina.
Vea la Información de seguridad importante
adicional en la página 12. Consulte la Información de
prescripción completa en las páginas 14 a 21.
11
Información de seguridad importante
n N
o
tome AZILECT® (rasagiline tablets) si está
tomando meperidina porque podría causar
una reacción grave como un coma o la muerte.
No tome tampoco AZILECT con tramadol,
metadona, propoxifeno, dextrometorfano, hierba
de San Juan o ciclobenzaprina. Asimismo, no
debe tomar AZILECT con otros inhibidores de
monoaminaoxidasa (MAOI), porque podría causar
un aumento peligroso de la presión sanguínea
n P
ueden
ocurrir aumentos en la presión sanguínea
durante el tratamiento con AZILECT. Informe a
su médico si tiene un historial de alta presión
sanguínea. Entre los posibles síntomas de un
aumento peligroso de la presión sanguínea se
incluyen dolores fuertes de cabeza, vista nublada,
dificultades para razonar, ataque convulsivo,
dolor en el pecho y náuseas/vómitos. Si sufre
estos síntomas, es importante que hable con su
médico y obtenga atención médica. Cuando se
toma AZILECT conforme a las dosis recomendadas,
comúnmente no se requiere restringir los
alimentos y las bebidas que contengan una
sustancia llamada tiramina. Sin embargo, se le
aconseja evitar alimentos que contengan altas
cantidades de tiramina como los quesos maduros,
ya que algunos pacientes pueden tener una mayor
sensibilidad que pudiera provocar un aumento
peligroso de la presión sanguínea como se
describe anteriormente
n I
nforme
a su médico si toma, o piensa tomar,
algún medicamento recetado o de venta libre,
especialmente antidepresivos y ciprofloxacina. La
combinación de inhibidores de monoaminaoxidasa
(MAO-B) como AZILECT y antidepresivos ha
causado una afección grave y a veces fatal llamada
síndrome de serotonina
n S
i
usted sufre episodios de quedarse dormido o de
somnolencia durante actividades de la vida diaria,
no conduzca y sea precavido hasta ponerse en
contacto con su médico
n S
i
tiene una enfermedad del hígado moderada a
grave, no debe tomar AZILECT. No debe exceder
una dosis de 0.5 mg por día de AZILECT si
tiene una enfermedad leve del hígado o toma
ciprofloxacina. Los pacientes no deben exceder
una dosis de 1 mg por día de AZILECT debido al
riesgo de que aumente la presión sanguínea
n D
ebe
vigilarse a todos los pacientes con
enfermedad de Parkinson en cuanto a cambios en
la presión sanguínea, movimientos descontrolados
(discinesia), alucinaciones, control de impulsos,
confusión y melanoma (cáncer de la piel). Puede
ocurrir un posible aumento de la temperatura
corporal al dejar de tomar AZILECT
n L
os
efectos secundarios más comunes vistos con
AZILECT solo son el síndrome gripal, dolor en las
articulaciones, depresión e indigestión; al tomarlo
con un agonista de dopamina son hinchazón de
las piernas, caídas, dolor en las articulaciones,
tos e incapacidad de dormir; además al tomarlo
con levodopa, son movimientos descontrolados
(discinesia), lesiones accidentales, pérdida de
peso, baja presión sanguínea al estar parado,
vómitos, anorexia, dolor de las articulaciones,
dolor abdominal, náuseas, estreñimiento, boca
seca, sarpullidos, sueños anormales, caídas e
hinchazón de los tendones
Lo alentamos a informar a la FDA sobre efectos
secundarios negativos de medicamentos recetados.
Visite www.fda.gov/medwatch o llame al
1-800-FDA-1088.
Consulte la Información de prescripción completa en
las páginas 14 a 21.
12
Entregado por
Parkinson’s Support Solutions® (PSS) es un programa de apoyo
integral diseñado para ofrecer recursos financieros que le sirvan para
empezar y mantenerse con la terapia de AZILECT® (rasagiline tablets).
PSS tiene una gama de opciones útiles, ya sea que usted tenga seguro
comercial, Medicare, o esté actualmente sin seguro.
PSS también ofrece materiales educativos para ayudarle a controlar
mejor su enfermedad.
¡Es fácil unirse!
Llame gratis al 1-866-880-8582
o bien
Visite www.parkinsonssupportsolutions.com
De lunes a viernes, desde las 9 a.m. hasta las 4 p.m.,
hora local del Centro
Vea la Información de seguridad importante en la página 12.
Consulte la Información de prescripción completa en las páginas 14 a 21.
©2015 Teva Neuroscience, Inc. AZI-41326
AZILECT es una marca comercial registrada de Teva Pharmaceutical Industries Ltd.
Parkinson’s Support Solutions es una marca de servicio registrada de
Teva Pharmaceutical Industries Ltd.
Los nombres de marcas indicados son marcas comerciales registradas de sus titulares respectivos.
13
HIGHLIGHTS OF PRESCRIBING INFORMATION
WARNINGS AND PRECAUTIONS
• May cause hypertension (including severe hypertensive syndromes) at recommendeddoses(5.1)
• Maycauseserotoninsyndromewhenusedwithantidepressants(5.2)
• Maycausefallingasleepduringactivitiesofdailyliving,daytimedrowsiness,and
somnolence(5.3)
• Maycausehypotension,especiallyorthostatic(5.6)
• Maycauseorexacerbatedyskinesia.Decreasingthelevodopadosemaylessenor
eliminatethissideeffect(5.7)
• Maycausehallucinationsandpsychotic-likebehavior(5.8)
• Maycauseimpulsecontrol/compulsivebehaviors(5.9)
• Maycausewithdrawal-emergenthyperpyrexiaandconfusion(5.10)
• Increasedriskofmelanoma:monitorpatientsformelanomaonaregularbasis(5.11)
These highlights do not include all the information needed to use AZILECT® safely
and effectively. See full prescribing information for AZILECT.
AZILECT (rasagiline mesylate) Tablets for Oral Use
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
• IndicationsandUsage(1)
• DosageandAdministration(2.1)
• WarningsandPrecautions(5.2,5.3,5.6,5.8,5.9)
05/2014
05/2014
05/2014
INDICATIONS AND USAGE
AZILECT,amonoamineoxidase(MAO)-Binhibitor(MAOI),isindicatedforthetreatmentofParkinson’sdisease(1)
•
•
•
•
•
ADVERSE REACTIONS
Mostcommonadversereactions(incidence3%orgreaterthanplacebo):
• AZILECTmonotherapy:flusyndrome,arthralgia,depression,dyspepsia(6.1)
• AZILECTusedasadjunctwithoutlevodopa:peripheraledema,fall,arthralgia,cough,
andinsomnia(6.1)
• AZILECTusedasadjuncttolevodopa:dyskinesia,accidentalinjury,weightloss,
posturalhypotension,vomiting,anorexia,arthralgia,abdominalpain,nausea,constipation,drymouth,rash,abnormaldreams,fall,andtenosynovitis(6.1)
DOSAGE AND ADMINISTRATION
Monotherapy:AZILECT1mgoncedaily(2.1)
Asadjunctwithoutlevodopa:AZILECT1mgoncedaily(2.1)
Asadjuncttolevodopa:AZILECT0.5mgoncedaily.Increasedoseto1mgdailyas
neededforsufficientclinicalresponse(2.1)
Patients taking ciprofloxacin or other CYP1A2 inhibitors: AZILECT 0.5 mg once
daily(2.2,5.4)
Patientswithmildhepaticimpairment:AZILECT0.5mgoncedaily.AZILECTshould
notbeusedinpatientswithmoderateorseverehepaticimpairment(2.3,5.5)
To report SUSPECTED ADVERSE REACTIONS, contact TEVA at 1-800-221-4026 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DOSAGE FORMS AND STRENGTHS
• AZILECT0.5mgtablets(containing,astheactiveingredient,rasagilinemesylate
equivalentto0.5mgofrasagilinebase)(3)
• AZILECT 1 mg tablets (containing, as the active ingredient, rasagiline mesylate
equivalentto1mgofrasagilinebase)(3)
DRUG INTERACTIONS
• Meperidine:Riskofserotoninsyndrome(4,7.1)
• Dextromethorphan:Riskofpsychosisorbizarrebehavior(4,7.2)
• MAOinhibitors:Riskofnon-selectiveMAOinhibitionandhypertensivecrisis(4,7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Based on animal data, may cause fetal harm. Do not use AZILECT
unlessthepotentialbenefitjustifiesthepotentialrisktothefetus(8.1)
CONTRAINDICATIONS
Concomitantuseofmeperidine,tramadol,methadone,propoxyphenedextromethorphan,St.John’swort,cyclobenzaprine,oranother(selectiveornon-selective)MAO
inhibitor(4)
See 17 for PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION: CONTENTS*
Revised: 05/2014
7.7 Tyramine/RasagilineInteraction
7.8 DopaminergicAntagonists
1. INDICATIONS AND USAGE
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 NursingMothers
8.4 PediatricUse
8.5 GeriatricUse
8.6 HepaticImpairment
8.7 RenalImpairment
2. DOSAGE AND ADMINISTRATION
2.1 GeneralDosingRecommendations
2.2 PatientsTakingCiprofloxacinorOtherCYP1A2Inhibitors
2.3 PatientswithHepaticImpairment
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
9. DRUG ABUSE AND DEPENDENCE
9.1 ControlledSubstance
9.2 Abuse
9.3 Dependence
5. WARNINGS AND PRECAUTIONS
5.1 Hypertension
5.2 SerotoninSyndrome
5.3 FallingAsleepDuringActivitiesofDailyLivingandSomnolence
5.4 CiprofloxacinorOtherCYP1A2Inhibitors
5.5 HepaticImpairment
5.6 Hypotension/OrthostaticHypotension
5.7 Dyskinesia
5.8 Hallucinations/Psychotic-LikeBehavior
5.9 ImpulseControl/CompulsiveBehaviors
5.10 Withdrawal-EmergentHyperpyrexiaandConfusion
5.11 Melanoma
10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY
12.1 MechanismofAction
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility
6. ADVERSE REACTIONS
6.1 ClinicalTrialsExperience
14. CLINICAL STUDIES
14.1 MonotherapyUseofAZILECT
14.2 AdjunctUseofAZILECT
7. DRUG INTERACTIONS
7.1 Meperidine
7.2 Dextromethorphan
7.3 MAOInhibitors
7.4 SympathomimeticMedications
7.5 Antidepressants
7.6 CiprofloxacinorOtherCYP1A2Inhibitors
16. HOW SUPPLIED/STORAGE AND HANDLING
17. PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
The recommended doses of AZILECT should not be exceeded because of risk of
hypertension[see Warnings and Precautions (5.1)].
2.2 Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors
Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not
exceedadoseofAZILECT0.5mgoncedaily[see Warnings and Precautions (5.4),
Drug Interactions (7.6), and Clinical Pharmacology (12.3)].
2.3 Patients with Hepatic Impairment
PatientswithmildhepaticimpairmentshouldnotexceedadoseofAZILECT0.5mg
oncedaily.AZILECTshouldnotbeusedinpatientswithmoderateorseverehepatic
impairment[see Warnings and Precautions (5.5), Use in Specific Populations (8.6),
and Clinical Pharmacology (12.3)].
AZILECT® (rasagiline tablets)
1. INDICATIONS AND USAGE
AZILECT(rasagilinetablets)isindicatedforthetreatmentofParkinson’sdisease(PD).
2. DOSAGE AND ADMINISTRATION
2.1 General Dosing Recommendations
WhenAZILECTisprescribedasmonotherapyorasadjuncttherapyinpatientsnottakinglevodopa,patientsmaystartAZILECTattherecommendeddoseof1mgadministeredorallyoncedaily.
Inpatientstakinglevodopa,withorwithoutotherPDdrugs(e.g.,dopamineagonist,
amantadine,anticholinergics),therecommendedinitialdoseofAZILECTis0.5mgonce
daily.Ifthepatienttoleratesthedaily0.5mgdose,butasufficientclinicalresponseis
notachieved,thedosemaybeincreasedto1mgoncedaily.WhenAZILECTisused
incombinationwithlevodopa,areductionofthelevodopadosemaybeconsidered,
baseduponindividualresponse.
3. DOSAGE FORMS AND STRENGTHS
AZILECT0.5mgTablets:Whitetooff-white,round,flat,beveledtablets,debossed
with“GIL0.5”ononesideandplainontheothersidecontaining,astheactiveingredient,rasagilinemesylateequivalentto0.5mgofrasagilinebase.
1
14
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT1mgTablets:Whitetooff-white,round,flat,beveledtablets,debossedwith
“GIL1”ononesideandplainontheothersidecontaining,astheactiveingredient,
rasagilinemesylateequivalentto1mgofrasagilinebase.
thesepatientsreportedsomnolencewhileonAZILECTwithotherdopaminergicmedications,someperceivedthattheyhadnowarningsigns,suchasexcessivedrowsiness,andbelievedthattheywerealertimmediatelypriortotheevent.Someofthese
eventshavebeenreportedmorethan1-yearafterinitiationoftreatment.
In Study 3, somnolence was a common occurrence in patients receiving AZILECT
andwasmorefrequentinpatientswithParkinson’sdiseasereceivingAZILECTthan
inrespectivepatientsreceivingplacebo(6%AZILECTcomparedto4%Placebo)[see
Adverse Reactions (6.1].
Before initiating treatment with AZILECT, patients should be advised of the potentialtodevelopdrowsinessandspecificallyaskedaboutfactorsthatmayincreasethe
riskwithAZILECTsuchasconcomitantsedatingmedications,thepresenceofsleep
disorders,andconcomitantmedicationsthatincreaserasagilineplasmalevels(e.g.,
ciprofloxacin)[see Drug Interactions (7.6)].Ifapatientdevelopssignificantdaytime
sleepinessorepisodesoffallingasleepduringactivitiesthatrequireactiveparticipation(e.g.,drivingamotorvehicle,conversations,eating),AZILECTshouldordinarily
bediscontinued.IfadecisionismadetocontinuethesepatientsonAZILECT,advise
themtoavoiddrivingandotherpotentiallydangerousactivities.Thereisinsufficient
informationtoestablishthatdosereductionwilleliminateepisodesoffallingasleep
whileengagedinactivitiesofdailyliving.
5.4 Ciprofloxacin or Other CYP1A2 Inhibitors
Rasagilineplasmaconcentrationsmayincreaseupto2foldinpatientsusingconcomitantciprofloxacinandotherCYP1A2inhibitors.PatientstakingconcomitantciprofloxacinorotherCYP1A2inhibitorsshouldnotexceedadoseofAZILECT0.5mg
oncedaily[see Dosage and Administration (2.2), Drug Interactions (7.6), and Clinical
Pharmacology (12.3)].
5.5 Hepatic Impairment
Rasagilineplasmaconcentrationmayincreaseinpatientswithhepaticimpairment.
PatientswithmildhepaticimpairmentshouldbegiventhedoseofAZILECT0.5mg
oncedaily.AZILECTshouldnotbeusedinpatientswithmoderateorseverehepatic
impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
5.6 Hypotension/Orthostatic Hypotension
InStudy3,theincidenceoforthostatichypotensionconsistingofasystolicbloodpressuredecrease(≥30mmHg)oradiastolicbloodpressuredecrease(≥20mmHg)
afterstandingwas13%withAZILECT(1mg/day)comparedto9%withplacebo[see
Adverse Reactions (6.1)].
Atthe1mgdose,thefrequencyoforthostatichypotension(atanytimeduringthe
study)wasapproximately44%forAZILECTvs33%forplaceboformildtomoderate
systolic blood pressure decrements (≥ 20 mm Hg), 40% for AZILECT vs 33% for
placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg),
7%forAZILECTvs3%forplaceboforseveresystolicbloodpressuredecrements
(≥ 40 mm Hg), and 9% for AZILECT vs 6% for placebo for severe diastolic blood
pressuredecrements(≥20mmHg).Therewasalsoanincreasedriskforsomeof
theseabnormalitiesatthelower0.5mgdailydoseandforanindividualpatienthaving
mild to moderate or severe orthostatic hypotension for both systolic and diastolic
bloodpressure.
InStudy2whereAZILECTwasgivenasanadjuncttherapyinpatientsnottaking
concomitantlevodopa,therewere5reportsoforthostatichypotensioninpatients
taking AZILECT 1 mg (3.1%) and 1 report in patients taking placebo (0.6%) [see
Adverse Reactions (6.1].
Clinicaltrialdatafurthersuggestthatorthostatichypotensionoccursmostfrequently
inthefirsttwomonthsofAZILECTtreatmentandtendstodecreaseovertime.
SomepatientstreatedwithAZILECTexperiencedamildlyincreasedriskforsignificantdecreasesinbloodpressureunrelatedtostandingbutwhilesupine.
Theriskforpost-treatmenthypotension(e.g.,systolic<90ordiastolic<50mmHg)
combinedwithasignificantdecreasefrombaseline(e.g.,systolic>30ordiastolic
>20mmHg)washigherforAZILECT1mg(3.2%)comparedtoplacebo(1.3%).
TherewasnoclearincreasedriskforloweringofbloodpressureorposturalhypotensionassociatedwithAZILECT1mg/dayasmonotherapy.
Whenusedasanadjuncttolevodopa,posturalhypotensionwasalsoreportedasan
adversereactioninapproximately6%ofpatientstreatedwithAZILECT0.5mg,9%
ofpatientstreatedwithAZILECT1mgand3%ofpatientstreatedwithplacebo.Posturalhypotensionledtodrugdiscontinuationandprematurewithdrawalfromclinical
trialsinone(0.7%)patienttreatedwithAZILECT1mg/day,nopatientstreatedwith
AZILECT0.5mg/dayandnoplacebo-treatedpatients.
5.7 Dyskinesia
Whenusedasanadjuncttolevodopa,AZILECTmaycausedyskinesiaorpotentiate
dopaminergic side effects and exacerbate pre-existing dyskinesia. In Study 3, the
incidenceofdyskinesiawas18%forpatientstreatedwith0.5mgor1mgAZILECT
asanadjuncttolevodopaand10%forpatientstreatedwithplaceboasanadjunctto
levodopa.Decreasingthedoseoflevodopamaymitigatethissideeffect[see Adverse
Reactions (6.1].
5.8 Hallucinations/Psychotic-Like Behavior
Inthemonotherapystudy(Study1),theincidenceofhallucinationsreportedasan
adverseeventwas1.3%inpatientstreatedwithAZILECT1mgand0.7%inpatients
treatedwithplacebo.InStudy1,theincidenceofhallucinationsreportedasanadverse
reactionandleadingtodrugdiscontinuationandprematurewithdrawalwas1.3%in
patientstreatedwithAZILECT1mgand0%inplacebo-treatedpatients.
Whenstudiedasanadjuncttherapywithoutlevodopa(Study2),hallucinationswere
reportedasanadversereactionin1.2%ofpatientstreatedwith1mg/dayAZILECTand
1.8%ofpatientstreatedwithplacebo.Hallucinationsledtodrugdiscontinuationand
prematurewithdrawalfromtheclinicaltrialin0.6%ofpatientstreatedwithAZILECT
1mg/dayandinnoneoftheplacebo-treatedpatients.
4. CONTRAINDICATIONS
AZILECTiscontraindicatedforusewithmeperidine,tramadol,methadone,propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors,
because of risk of serotonin syndrome [See Warnings and Precautions (5.2)]. At
least 14 days should elapse between discontinuation of AZILECT and initiation of
treatmentwiththesemedications.
AZILECTiscontraindicatedforusewithSt.John’swortandwithcyclobenzaprine.
AZILECTiscontraindicatedforusewithdextromethorphanbecauseofriskofepisodeofpsychosisorbizarrebehavior.
5. WARNINGS AND PRECAUTIONS
5.1 Hypertension
ExacerbationofhypertensionmayoccurduringtreatmentwithAZILECT.Medication
adjustmentmaybenecessaryifelevationofbloodpressureissustained.Monitor
patientsfornewonsethypertensionorhypertensionthatisnotadequatelycontrolled
afterstartingAZILECT.
In Study 3, AZILECT (1 mg/day) given in conjunction with levodopa, produced an
increasedincidenceofsignificantbloodpressureelevation(systolic>180ordiastolic
>100mmHg)of4%comparedto3%forplacebo[see Adverse Reactions (6.1)].
When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing
post-treatmenthighbloodpressure(e.g.,systolic>180ordiastolic>100mmHg)
combinedwithasignificantincreasefrombaseline(e.g.,systolic>30ordiastolic
>20mmHg)washigherforAZILECT(2%)comparedtoplacebo(1%).
Dietary tyramine restriction is not required during treatment with recommended
dosesofAZILECT.However,certainfoodsthatmaycontainveryhighamounts(i.e.,
more than 150 mg) of tyramine that could potentially cause severe hypertension
because of tyramine interaction (including various clinical syndromes referred to
ashypertensiveurgency,crisis,oremergency)inpatientstakingAZILECT,evenat
therecommendeddoses,duetoincreasedsensitivitytotyramine.Patientsshould
beadvisedtoavoidfoodscontainingaverylargeamountoftyraminewhiletaking
recommendeddosesofAZILECTbecauseofthepotentialforlargeincreasesinblood
pressureincludingclinicalsyndromesreferredtoashypertensiveurgency,crisis,or
emergency.AZILECTisaselectiveinhibitorofMAO-Battherecommendeddoses
of0.5or1mgdaily.SelectivityforinhibitingMAO-Bdiminishesinadose-related
mannerasthedoseisprogressivelyincreasedabovetherecommendeddailydoses.
5.2 Serotonin Syndrome
Serotonin syndrome has been reported with concomitant use of an antidepressant(e.g.,selectiveserotoninreuptakeinhibitors-SSRIs,serotonin-norepinephrine
reuptakeinhibitors-SNRIs,tricyclicantidepressants,tetracyclicantidepressants,triazolopyridineantidepressants)andanonselectiveMAOI(e.g.,phenelzine,tranylcypromine)orselectiveMAO-Binhibitors,suchasselegiline(Eldepryl)andrasagiline
(AZILECT). Serotonin syndrome has also been reported with concomitant use of
AZILECTwithmeperidine,tramadol,methadone,orpropoxyphene.AZILECTiscontraindicatedforusewithmeperidine,tramadol,methadone,propoxypheneandMAO
inhibitors (MAOIs), including other selective MAO-B inhibitors [see Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].
In the postmarketing period, potentially life-threatening serotonin syndrome has
beenreportedinpatientstreatedwithantidepressantsconcomitantlywithAZILECT.
Concomitant use of AZILECT with one of many classes of antidepressants (e.g.,
SSRIs,SNRIs,triazolopyridine,tricyclicortetracyclicantidepressants)isnotrecommended [see Drug Interactions (7.5)].
The symptoms of serotonin syndrome have included behavioral and cognitive/
mentalstatuschanges(e.g.,confusion,hypomania,hallucinations,agitation,delirium,headache,andcoma),autonomic effects (e.g., syncope, shivering, sweating,
highfever/hyperthermia,hypertension,tachycardia,nausea,diarrhea),andsomatic
effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifestedbyclonus,andtremor).Serotoninsyndromecanresultindeath.
AZILECTclinicaltrialsdidnotallowconcomitantuseoffluoxetineorfluvoxaminewith
AZILECT,andthepotentialdruginteractionbetweenAZILECTandantidepressants
hasnotbeenstudiedsystematically.AlthoughasmallnumberofAZILECT-treated
patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs
n=141),theexposure,bothindoseandnumberofsubjects,wasnotadequatetorule
outthepossibilityofanuntoward reaction from combiningthese agents. At least
14daysshouldelapsebetweendiscontinuationofAZILECTandinitiationoftreatment
withaSSRI,SNRI,tricyclic,tetracyclic,ortriazolopyridineantidepressant.Because
ofthelonghalf-livesofcertainantidepressants(e.g.,fluoxetineanditsactivemetabolite),atleastfiveweeks(perhapslonger,especiallyiffluoxetinehasbeenprescribed
chronicallyand/orathigherdoses)shouldelapsebetweendiscontinuationoffluoxetineandinitiationofAZILECT[see Drug Interactions (7.5)].
5.3 Falling Asleep During Activities of Daily Living and Somnolence
Ithasbeenreportedthatfallingasleepwhileengagedinactivitiesofdailylivingalways
occursinasettingofpreexistingsomnolence,althoughpatientsmaynotgivesuch
a history. For this reason, prescribers should monitor patients for drowsiness or
sleepiness,becausesomeoftheeventsoccurwellafterinitiationoftreatmentwith
dopaminergic medication. Prescribers should also be aware that patients may not
acknowledgedrowsinessorsleepinessuntildirectlyquestionedaboutdrowsinessor
sleepinessduringspecificactivities.
Cases of patients treated with AZILECT and other dopaminergic medications have
reportedfallingasleepwhileengagedinactivitiesofdailylivingincludingtheoperationofmotorvehicles,whichsometimesresultedinaccidents.Althoughmanyof
2
15
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
Table 1: Adverse Reactions* in Study 1
Whenstudiedasanadjuncttolevodopa(Study3),theincidenceofhallucinations
wasapproximately5%inpatientstreatedwithAZILECT0.5mg/day,4%inpatients
treatedwithAZILECT1mg/day,and3%inpatientstreatedwithplacebo.Theincidence of hallucinations leading to drug discontinuation and premature withdrawal
wasabout1%inpatientstreatedwith0.5mgAZILECTand1mgAZILECT/day,and
0%inplacebo-treatedpatients[see Adverse Reactions (6.1)].
Postmarketingreportsindicatethatpatientsmayexperienceneworworseningmental status and behavioral changes, which may be severe, including psychotic-like
behaviorduringtreatmentwithAZILECTorafterstartingorincreasingthedoseof
AZILECT.OtherdrugsprescribedtoimprovethesymptomsofParkinson’sdisease
canhavesimilareffectsonthinkingandbehavior.Thisabnormalthinkingandbehaviorcanconsistofoneormoreofavarietyofmanifestationsincludingparanoidideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation,
aggressivebehavior,agitation,anddelirium.
Patients should be informed of the possibility of developing hallucinations and
instructedtoreportthemtotheirhealthcareproviderpromptlyshouldtheydevelop.
PatientswithamajorpsychoticdisordershouldordinarilynotbetreatedwithAZILECT
becauseoftheriskofexacerbatingthepsychosiswithanincreaseincentraldopaminergictone.Inaddition,manytreatmentsforpsychosisthatdecreasecentraldopaminergictonemaydecreasetheeffectivenessofAZILECT[see Drug Interactions (7.8)].
ConsiderdosereductionorstoppingthemedicationifapatientdevelopshallucinationsorpsychoticlikebehaviorswhiletakingAZILECT.
5.9 Impulse Control/Compulsive Behaviors
Casereportssuggestthatpatientscanexperienceintenseurgestogamble,increased
sexualurges,intenseurgestospendmoney,bingeeating,and/orotherintenseurges,
andtheinabilitytocontroltheseurgeswhiletakingoneormoreofthemedications,
including AZILECT, that increase central dopaminergic tone and that are generally
usedforthetreatmentofParkinson’sdisease.Insomecases,althoughnotall,these
urgeswerereportedtohavestoppedwhenthedosewasreducedorthemedication
wasdiscontinued.Becausepatientsmaynotrecognizethesebehaviorsasabnormal,
itisimportantforprescriberstospecificallyaskpatientsortheircaregiversabout
the development of new or increased gambling urges, sexual urges, uncontrolled
spendingorotherurgeswhilebeingtreatedwithAZILECT.Considerdosereduction
orstoppingthemedicationifapatientdevelopssuchurgeswhiletakingAZILECT.
5.10 Withdrawal-Emergent Hyperpyrexia and Confusion
A symptom complex resembling neuroleptic malignant syndrome (characterized by
elevatedtemperature,muscularrigidity,alteredconsciousness,andautonomicinstability),withnootherobviousetiology,hasbeenreportedinassociationwithrapiddose
reduction,withdrawalof,orchangesindrugsthatincreasecentraldopaminergictone.
5.11 Melanoma
EpidemiologicalstudieshaveshownthatpatientswithParkinson’sdiseasehavea
higher risk (2- to approximately 6-fold higher) of developing melanoma than the
general population. Whether the increased risk observed was due to Parkinson’s
diseaseorotherfactors,suchasdrugsusedtotreatParkinson’sdisease,isunclear.
Forthereasonsstatedabove,patientsandprovidersareadvisedtomonitorformelanomasfrequentlyandonaregularbasis.Ideally,periodicskinexaminationsshould
beperformedbyappropriatelyqualifiedindividuals(e.g.,dermatologists).
AZILECT 1 mg
(N=149)
Placebo
(N=151)
% of Patients
% of Patients
Headache
14
12
Arthralgia
7
4
Dyspepsia
7
4
Depression
5
2
Fall
5
3
Flusyndrome
5
1
Conjunctivitis
3
1
Fever
3
1
Gastroenteritis
3
1
Rhinitis
3
1
Arthritis
2
1
Ecchymosis
2
0
Malaise
2
0
NeckPain
2
0
Paresthesia
2
1
Vertigo
2
1
*Incidence2%orgreaterinAZILECT1mggroupandnumericallymorefrequent
thaninplacebogroup
Therewerenosignificantdifferencesinthesafetyprofilebasedonageorgender.
AdjunctUseofAZILECT
AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an
adjunct therapy to levodopa, with some patients also taking dopamine agonists,
COMTinhibitors,anticholinergics,oramantadine(Study3andStudy4).
InStudy2,approximately8%ofthe162patientstreatedwithAZILECTdiscontinued
treatmentduetoadversereactionscomparedto4%ofthe164patientswhoreceived
placebo.
Adversereactionsthatledtothediscontinuationofmorethanonepatientwerenauseaanddizziness.
ThemostcommonlyobservedadversereactionsinStudy2(incidenceinAZILECTtreated patients 3% or greater than incidence in placebo-treated patients) included
peripheraledema,fall,arthralgia,cough,andinsomnia.Table2listsadversereactions
thatoccurredin2%orgreaterinpatientsreceivingAZILECTasadjuncttherapywithoutlevodopaandnumericallymorefrequentthanintheplacebogroupinStudy2.
6. ADVERSE REACTIONS
The followingadversereactionsare described in more detail inthe Warnings and
Precautionssectionofthelabel:
• Hypertension[see Warnings and Precautions (5.1)]
• SerotoninSyndrome[see Warnings and Precautions (5.2)]
• FallingAsleepDuringActivitiesofDailyLivingandSomnolence[see Warnings and
Precautions (5.3)]
• Hypotension/OrthostaticHypotension[see Warnings and Precautions (5.6)]
• Dyskinesia[see Warnings and Precautions (5.7)]
• Hallucinations/Psychotic-LikeBehavior[see Warnings and Precautions (5.8)]
• ImpulseControl/CompulsiveBehaviors [see Warnings and Precautions (5.9)]
• Withdrawal-EmergentHyperpyrexiaandConfusion[see Warnings and Precautions
(5.10)]
• Melanoma[see Warnings and Precautions (5.11)]
6.1 Clinical Studies Experience
Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereaction rates observed in the clinical trials of a drug cannot be directly compared to
theincidenceofadversereactionsintheclinicaltrialsofanotherdrugandmaynot
reflecttheratesofadversereactionsobservedinpractice.
During the clinical development of AZILECT, Parkinson’s disease patients received
AZILECTasinitialmonotherapy(Study1)andasadjuncttherapy(Study2,Study3,
Study 4). As the populations in these studies differ, not only in the adjunct use of
dopamineagonistsorlevodopaduringAZILECTtreatment,butalsointheseverityand
durationoftheirdisease,theadversereactionsarepresentedseparatelyforeachstudy.
MonotherapyUseofAZILECT
InStudy1,approximately5%ofthe149patientstreatedwithAZILECTdiscontinued
treatmentduetoadversereactionscomparedto2%ofthe151patientswhoreceived
placebo.
Theonlyadversereactionthatledtothediscontinuationofmorethanonepatient
washallucinations.
ThemostcommonlyobservedadversereactionsinStudy1(incidenceinAZILECTtreatedpatients3%orgreaterthantheincidenceinplacebo-treatedpatients)included
flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions
thatoccurredin2%orgreaterofpatientsreceivingAZILECTasmonotherapyandwere
numericallymorefrequentthanintheplacebogroupinStudy1.
Table 2: Adverse Reactions* in Study 2
AZILECT 1 mg
(N=162)
Placebo
(N=164)
% of Patients
% of Patients
Dizziness
7
6
Peripheraledema
7
4
Headache
6
4
Nausea
6
4
Fall
6
1
Arthralgia
5
2
Backpain
4
3
Cough
4
1
Insomnia
4
1
Upperrespiratorytractinfection
4
2
Orthostatichypotension
3
1
*Incidence2%orgreaterinAZILECT1mggroupandnumericallymorefrequent
thaninplacebogroup
Therewerenosignificantdifferencesinthesafetyprofilebasedonageorgender.
In Study 3, adverse event reporting was considered more reliable than Study 4;
therefore,onlytheadverseeventdatafromStudy3arepresentedbelow.
InStudy3,approximately9%ofthe164patientstreatedwithAZILECT0.5mg/day
and7%ofthe149patientstreatedwithAZILECT1mg/daydiscontinuedtreatment
duetoadversereactions,comparedto6%ofthe159patientswhoreceivedplacebo.
TheadversereactionsthatledtodiscontinuationofmorethanoneAZILECT-treated
patientwerediarrhea,weightloss,hallucination,andrash.
ThemostcommonlyobservedadversereactionsinStudy3(incidenceinAZILECTtreatedpatients3%orgreaterthantheincidenceinplacebo-treatedpatients)included
dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia,
3
16
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
arthralgia,abdominalpain,nausea,constipation,drymouth,rash,abnormaldreams,
fallandtenosynovitis.
Table3listsadversereactionsthatoccurredin2%orgreaterofpatientstreatedwith
AZILECT1mg/dayandthatwerenumericallymorefrequentthantheplacebogroup
inStudy3.
7.4 Sympathomimetic Medications
TheconcomitantuseofAZILECTandsympathomimeticmedicationswasnotallowedin
clinicalstudies.SeverehypertensivereactionshavefollowedtheadministrationofsympathomimeticsandnonselectiveMAOinhibitors.Hypertensivecrisishasbeenreported
inpatientstakingtherecommendeddoseofAZILECTandsympathomimeticmedications.Severehypertensionhasbeenreportedinpatientstakingtherecommendeddose
ofAZILECTandophthalmicdropscontainingsympathomimeticmedications.
BecauseAZILECTisaselectiveMAOI,hypertensivereactionsarenotordinarilyexpected
with the concomitant use of sympathomimetic medications. Nevertheless, caution
shouldbeexercisedwhenconcomitantlyusingrecommendeddosesofAZILECTwith
anysympathomimeticmedicationsincludingnasal,oral,andophthalmicdecongestants
andcoldremedies.
7.5 Antidepressants
Concomitant use of AZILECT with one of many classes of antidepressants (e.g.,
SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended[see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
ConcomitantuseofAZILECTandMAOinhibitorsiscontraindicated[see Contraindications (4)].
7.6 Ciprofloxacin or Other CYP1A2 Inhibitors
Rasagilineplasmaconcentrationsmayincreaseupto2foldinpatientsusingconcomitantciprofloxacinandotherCYP1A2inhibitors.Thiscouldresultinincreased
adverseevents.PatientstakingconcomitantciprofloxacinorotherCYP1A2inhibitors
shouldnotexceedadoseofAZILECT0.5mgoncedaily[see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
7.7 Tyramine/Rasagiline Interaction
MAO in the gastrointestinal tract and liver (primarily type A) provides protection
fromexogenousamines(e.g.,tyramine)thathavethecapacity,ifabsorbedintact,
tocauseatyraminereactionwithhypertensionincludingclinicalsyndromesreferred
toashypertensiveurgency,crisis,oremergency.Foodsandmedicationscontaining
largeamountsofexogenousamines(e.g.,fromfermentedcheese,herring,over-thecountercough/coldmedications)maycausereleaseofnorepinephrineresultingina
riseinsystemicbloodpressure.
Resultsofaspecialtyraminechallengestudyindicatethatrasagilineisselectivefor
MAO-Batrecommendeddosesandcanbeusedwithoutdietarytyraminerestriction.
However,certainfoodsmaycontainveryhighamounts(i.e.,150mgorgreater)of
tyramineandcouldpotentiallycauseahypertensivereactioninindividualpatients
taking AZILECT due to increased sensitivity to tyramine. Selectivity for inhibiting
MAO-Bdiminishesinadose-relatedmannerasthedoseisprogressivelyincreased
abovetherecommendeddailydoses.
Therewerenocasesofhypertensivecrisisintheclinicaldevelopmentprogramassociated with 1 mg daily AZILECT treatment, in which most patients did not follow
dietarytyraminerestriction.
There have been postmarketing reports of patients who experienced significantly
elevatedbloodpressure(includingrarecasesofhypertensivecrisis)afteringestion
of unknown amounts of tyramine-rich foods while taking recommended doses of
AZILECT.Patientsshouldbeadvisedtoavoidfoodscontainingaverylargeamount
oftyraminewhiletakingrecommendeddosesofAZILECT[see Warnings and Precautions (5.1)].
7.8 Dopaminergic Antagonists
Itispossiblethatdopamineantagonists,suchasantipsychoticsormetoclopramide,
coulddiminishtheeffectivenessofAZILECT.
Table 3: Adverse Reactions* in Study 3
AZILECT 1 mg
(N=149)
AZILECT 0.5 mg
(N=164)
Placebo
(N=159)
% of patients
% of patients
% of patients
Dyskinesia
18
18
10
Accidentalinjury
12
8
5
Nausea
12
10
8
Headache
11
8
10
Fall
11
12
8
Weightloss
9
2
3
Constipation
9
4
5
Posturalhypotension
9
6
3
Arthralgia
8
6
4
Vomiting
7
4
1
Drymouth
6
2
3
Rash
6
3
3
Somnolence
6
4
4
Abdominalpain
5
2
1
Anorexia
5
2
1
Diarrhea
5
7
4
Ecchymosis
5
2
3
Dyspepsia
5
4
4
Paresthesia
5
2
3
Abnormaldreams
4
1
1
Hallucinations
4
5
3
Ataxia
3
6
1
Dyspnea
3
5
2
Infection
3
2
2
Neckpain
3
1
1
Sweating
3
2
1
Tenosynovitis
3
1
0
Dystonia
3
2
1
Gingivitis
2
1
1
Hemorrhage
2
1
1
Hernia
2
1
1
Myasthenia
2
2
1
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
PregnancyCategoryC
Therearenoadequateandwell-controlledstudiesofrasagilineinpregnantwomen.
AZILECTshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthe
potentialrisktothefetus.
Inacombinedmating/fertilityandembryo-fetaldevelopmentstudyinpregnantrats,
noeffectonembryo-fetaldevelopmentwasobservedatoraldosesupto3mg/kg/day
(approximately 30 times the plasma exposure (AUC) in humans at the maximum
recommendedhumandose[MRHD,1mg/day]).
Inpregnantrabbitsadministeredrasagilinethroughouttheperiodoforganogenesis
atoraldosesofupto36mg/kg/day,nodevelopmentaltoxicitywasobserved.Atthe
highestdosetested,theplasmaAUCwasapproximately800timesthatinhumans
attheMRHD.
Inpregnantratsadministeredrasagiline(0.1,0.3,1mg/kg/day)orallyduringgestation
andlactation,offspringsurvivalwasdecreasedandoffspringbodyweightwasreduced
at0.3mg/kg/dayand1mg/kg/day(10and16timestheplasmaAUCinhumansatthe
MRHD).Noplasmadatawereavailableattheno-effectdose(0.1mg/kg);however,that
doseissimilartotheMRHDonamg/m2basis.Theeffectofrasagilineonphysicaland
behavioraldevelopmentwasnotadequatelyassessedinthisstudy.
Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In
pregnantratsadministeredrasagiline(0.1,0.3,1mg/kg/day)andlevodopa/carbidopa
(80/20mg/kg/day)(aloneandincombination)orallythroughouttheperiodoforganogenesis,therewasanincreasedincidenceofwavyribsinfetusesfromratstreated
withrasagilineincombinationwithlevodopa/carbidopaat1/80/20mg/kg/day(approximately8timestherasagilineplasmaAUCinhumansattheMRHDandsimilartothe
MRHDoflevodopa/carbidopa[800/200mg/day]onamg/m2basis).Inpregnantrabbits
dosedorallythroughouttheperiodoforganogenesiswithrasagilinealone(3mg/kg)or
incombinationwithlevodopa/carbidopa(rasagiline:0.1,0.6,1.2mg/kg,levodopa/carbidopa:80/20mg/kg/day),anincreaseinembryo-fetaldeathwasnotedatrasagiline
dosesof0.6and1.2mg/kg/daywhenadministeredincombinationwithlevodopa/
*Incidence2%orgreaterinAZILECT1mggroupandnumericallymorefrequent
thaninplacebogroup
Severalofthemorecommonadversereactionsseemeddose-related,includingweight
loss,posturalhypotension,anddrymouth.
Therewerenosignificantdifferencesinthesafetyprofilebasedonageorgender.
DuringallParkinson’sdiseasephase2/3clinicaltrials,thelong-termsafetyprofile
wassimilartothatobservedwithshorterdurationexposure.
7. DRUG INTERACTIONS
7.1 Meperidine
Serious, sometimes fatal reactions have been precipitated with concomitant use
ofmeperidine(e.g.,Demerolandothertradenames)andMAOinhibitorsincluding
selectiveMAO-Binhibitors[see Contraindications (4)].
7.2 Dextromethorphan
The concomitant use of AZILECT and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been
reportedtocausebriefepisodesofpsychosisorbizarrebehavior.Therefore,inview
ofAZILECT’sMAOinhibitoryactivity,dextromethorphaniscontraindicatedforuse
withAZILECT[see Contraindications (4)].
7.3 MAO Inhibitors
AZILECT is contraindicated for use with other MAO inhibitors because of the
increasedriskofnonselectiveMAOinhibitionthatmayleadtoahypertensivecrisis
[see Contraindications (4)].
4
17
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
carbidopa(approximately7and13times,respectively,therasagilineplasmaAUCin
humansattheMRHD).Therewasanincreaseincardiovascularabnormalitieswith
levodopa/carbidopaalone(similartotheMRHDonamg/m2basis)andtoagreater
extentwhenrasagiline(atalldoses;1-13timestherasagilineplasmaAUCinhumans
attheMRHD)wasadministeredincombinationwithlevodopa/carbidopa.
8.3 Nursing Mothers
In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk
secretioninhumans.
Itisnotknownwhetherthisdrugisexcretedinhumanmilk.Becausemanydrugsare
excretedinhumanmilk,cautionshouldbeexercisedwhenAZILECTisadministered
toanursingwoman.
8.4 Pediatric Use
Thesafetyandeffectivenessinpediatricpatientshavenotbeenestablished.
8.5 Geriatric Use
Approximatelyhalfofpatientsinclinicaltrialswere65yearsandover.Therewereno
significantdifferencesinthesafetyprofileofthegeriatricandnongeriatricpatients.
8.6 Hepatic Impairment
Rasagilineplasmaconcentrationmaybeincreasedinpatientswithmild(upto2fold,
Child-Pughscore5-6),moderate(upto7fold,Child-Pughscore7-9),andsevere
(Child-Pughscore10-15)hepaticimpairment.Patientswithmildhepaticimpairment
shouldnotexceedadoseof0.5mg/day.AZILECTshouldnotbeusedinpatients
withmoderateorseverehepaticimpairment[see Dosage and Administration (2.3),
Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
DoseadjustmentofAZILECTisnotrequiredforpatientswithmildormoderaterenal
impairmentbecauseAZILECTplasmaconcentrationsarenotincreasedinpatients
with moderate renal impairment. Rasagiline has not been studied in patients with
severerenalimpairment[see Clinical Pharmacology (12.3)].
11. DESCRIPTION
AZILECT®tabletscontainrasagiline(asthemesylate),apropargylamine-baseddrug
indicatedforthetreatmentofidiopathicParkinson’sdisease.Itisdesignatedchemicallyas:1H-Inden-1-amine,2,3-dihydro-N-2-propynyl-,(1R)-,methanesulfonate.
Theempiricalformulaofrasagilinemesylateis(C12H13N)CH4SO3anditsmolecular
weightis267.34.
Itsstructuralformulais:
Rasagilinemesylateisawhitetooff-whitepowder,freelysolubleinwaterorethanol
and sparingly soluble in isopropanol. Each AZILECT tablet for oral administration
containsrasagilinemesylateequivalentto0.5mgor1mgofrasagilinebase.
Each AZILECT tablet also contains the following inactive ingredients: mannitol,
starch,pregelatinizedstarch,colloidalsilicondioxide,stearicacidandtalc.
12. CLINICAL PHARMACOLOGY
12.1. Mechanism of Action
AZILECTisaselective,irreversibleMAO-Binhibitorindicatedforthetreatmentofidiopathic Parkinson’s disease. The results of a clinical trial designed to examine the
effectsofAZILECTonbloodpressurewhenitisadministeredwithincreasingdosesof
tyramineindicatesthefunctionalselectivitycanbeincompletewhenhealthysubjects
ingestlargeamountsoftyraminewhilereceivingrecommendeddosesofAZILECT.
TheselectivityforinhibitingMAO-Bdiminishesinadose-relatedmanner.
MAO,aflavin-containingenzyme,isclassifiedintotwomajormolecularspecies,A
and B, and is localized in mitochondrial membranes throughout the body in nerve
terminals,brain,liverandintestinalmucosa.MAOregulatesthemetabolicdegradationofcatecholaminesandserotoninintheCNSandperipheraltissues.MAO-Bisthe
majorforminthehumanbrain.Inex vivoanimalstudiesinbrain,liver,andintestinal
tissues,rasagilinewasshowntobeapotent,irreversiblemonoamineoxidasetype
B(MAO-B)selectiveinhibitor.Rasagilineattherecommendedtherapeuticdosewas
alsoshowntobeapotentandirreversibleinhibitorofMAO-Binplatelets.Theprecise
mechanismsofactionofrasagilineareunknown.Onemechanismisbelievedtobe
relatedtoitsMAO-Binhibitoryactivity,whichcausesanincreaseinextracellularlevels
ofdopamineinthestriatum.Theelevateddopaminelevelandsubsequentincreased
dopaminergicactivityarelikelytomediaterasagiline’sbeneficialeffectsseeninmodelsofdopaminergicmotordysfunction.
12.2. Pharmacodynamics
TyramineChallengeTest
Resultsofatyraminechallengestudyindicatethatrasagilineatrecommendeddoses
isrelativelyselectiveforinhibitingMAO-Bandcanbeusedwithoutdietarytyramine
restriction.However,certainfoods(e.g.,agedcheeses,suchasStiltoncheese)may
containveryhighamountsoftyramine(i.e.,150mgorgreater)andcouldpotentially
causeseverehypertensioncausedbytyramineinteractioninpatientstakingAZILECT
duetomildincreasedsensitivitytotyramineatrecommendeddoses.RelativeselectivityofAZILECTforinhibitingMAO-Bdiminishedinadose-relatedmannerasthe
dose progressively increased above the highest recommended daily dose (1 mg)
[see Warnings and Precautions (5.1) and Drug Interactions (7.7)].
PlateletMAOActivityinClinicalStudies
Studies in healthy subjects and in Parkinson’s disease patients have shown that
rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week
after last dose. Almost 25-35% MAO-B inhibition was achieved after a single
rasagilinedoseof1mg/dayandmorethan55%ofMAO-Binhibitionwasachieved
afterasinglerasagilinedoseof2mg/day.Over90%inhibitionwasachieved3days
after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained
3dayspostdose.Multipledosesofrasagilineof0.5,1and2mgperdayresultedin
completeMAO-Binhibition.
12.3. Pharmacokinetics
Rasagilineintherangeof1-6mgdemonstratedamorethanproportionalincrease
inAUC,whileCmaxwasdoseproportional.Rasagilinemeansteady-statehalflifeis
3hoursbutthereisnocorrelationofpharmacokineticswithitspharmacologicaleffect
becauseofitsirreversibleinhibitionofMAO-B.
Absorption
Rasagilineisrapidlyabsorbed,reachingpeakplasmaconcentration(Cmax)inapproximately1hour.Theabsolutebioavailabilityofrasagilineisabout36%.
FooddoesnotaffecttheTmaxofrasagiline,althoughCmaxandexposure(AUC)are
decreasedbyapproximately60%and20%,respectively,whenthedrugistakenwitha
highfatmeal.BecauseAUCisnotsignificantlyaffected,AZILECTcanbeadministered
withorwithoutfood.
Distribution
Themeanvolumeofdistributionatsteady-stateis87L,indicatingthatthetissue
bindingofrasagilineisinexcessofplasmaproteinbinding.Plasmaproteinbinding
rangesfrom88-94%withmeanextentofbindingof61-63%tohumanalbuminover
theconcentrationrangeof1-100ng/mL.
MetabolismandElimination
Rasagilineundergoesalmostcompletebiotransformationintheliverpriortoexcretion.Themetabolismofrasagilineproceedsthroughtwomainpathways:N-dealkylationand/orhydroxylationtoyield1-aminoindan(AI),3-hydroxy-N-propargyl-1aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments
9. DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
AZILECTisnotacontrolledsubstance.
9.2 Abuse
Studiesconductedinmiceandratsdidnotrevealanypotentialfordrugabuseand
dependence.Clinicaltrialshavenotrevealedanyevidenceofthepotentialforabuse,
toleranceorphysicaldependence;however,systematicstudiesinhumansdesigned
toevaluatetheseeffectshavenotbeenperformed.
9.3 Dependence
Studiesconductedinmiceandratsdidnotrevealanypotentialfordrugabuseand
dependence.Clinicaltrialshavenotrevealedanyevidenceofthepotentialforabuse,
toleranceorphysicaldependence;however,systematicstudiesinhumansdesigned
toevaluatetheseeffectshavenotbeenperformed.
10. OVERDOSAGE
Inadoseescalationstudyinpatientsonchroniclevodopatherapytreatedwith10mg
ofAZILECTtherewerethreereportsofcardiovascularsideeffects(includinghypertensionandposturalhypotension)whichresolvedfollowingtreatmentdiscontinuation.
AlthoughnocasesofoverdosehavebeenobservedwithAZILECTduringtheclinical
developmentprogram,thefollowingdescriptionofpresentingsymptomsandclinical
courseisbaseduponoverdosedescriptionsofnonselectiveMAOinhibitors.
ThesignsandsymptomsofnonselectiveMAOIoverdosemaynotappearimmediately.Delaysofupto12hoursafteringestionofdrugandtheappearanceofsignsmay
occur.Thepeakintensityofthesyndromemaynotbereacheduntilforadayfollowing
theoverdose.Deathhasbeenreportedfollowingoverdose;therefore,immediatehospitalization,withcontinuouspatientobservationandmonitoringforatleasttwodays
followingtheingestionofsuchdrugsinoverdose,isstronglyrecommended.
TheseverityoftheclinicalsignsandsymptomsofMAOIoverdosevariesandmay
berelatedtotheamountofdrugconsumed.Thecentralnervousandcardiovascular
systemsareprominentlyinvolved.
SignsandsymptomsofMAOIoverdosemayinclude:drowsiness,dizziness,faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus,
opisthotonos,convulsions,andcoma;rapidandirregularpulse,hypertension,hypotension and vascular collapse; precordial pain, respiratory depression and failure,
hyperpyrexia,diaphoresis,andcool,clammyskin.
ThereisnospecificantidoteforAZILECToverdose.Thefollowingsuggestionsare
offeredbasedupontheassumptionthatAZILECToverdosemaybemodeledafter
nonselectiveMAOinhibitorpoisoning.TreatmentofoverdosewithnonselectiveMAO
inhibitorsissymptomaticandsupportive.Respirationshouldbesupportedbyappropriatemeasures,includingmanagementoftheairway,useofsupplementaloxygen,
and mechanical ventilatory assistance, as required. Body temperature should be
monitoredclosely.Intensivemanagementofhyperpyrexiamayberequired.Maintenanceoffluidandelectrolytebalanceisessential.Forthisreason,incasesofoverdosewithAZILECT,dietarytyraminerestrictionshouldbeobservedforseveralweeks
toreducetheriskofhypertensivetyraminereaction.
Apoisoncontrolcentershouldbecalledforthemostcurrenttreatmentguidelines.
Apostmarketingreportdescribedasinglepatientwhodevelopedanonfatalserotonin
syndromeafteringesting100mgofAZILECTinasuicideattempt.Anotherpatient
whowastreatedinerrorwith4mgAZILECTdailyandtramadolalsodevelopeda
serotoninsyndrome.Onepatientwhowastreatedinerrorwith3mgAZILECTdaily
experiencedalternatingepisodesofvascularfluctuationsconsistingofhypertension
andorthostatichypotension.
5
18
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
indicatethatbothroutesofrasagilinemetabolismaredependentonthecytochrome
P450(CYP)system,withCYP1A2beingthemajorisoenzymeinvolvedinrasagiline
metabolism.Glucuronideconjugationofrasagilineanditsmetabolites,withsubsequenturinaryexcretion,isthemajoreliminationpathway.
Afteroraladministrationof14C-labeledrasagiline,eliminationoccurredprimarilyvia
urineandsecondarilyviafeces(62%oftotaldoseinurineand7%oftotaldosein
fecesover7days),withatotalcalculatedrecoveryof84%ofthedoseoveraperiod
of38days.Lessthan1%ofrasagilinewasexcretedasunchangeddruginurine.
SpecialPopulations
Hepatic Impairment
Followingrepeatdoseadministration(7days)ofrasagiline(1mg/day)insubjects
withmildhepaticimpairment(Child-Pughscore5-6),AUCandCmaxwereincreased
by2foldand1.4fold,respectively,comparedtohealthysubjects.Insubjectswith
moderatehepaticimpairment(Child-Pughscore7-9),AUCandCmaxwereincreased
by 7 fold and 2 fold, respectively, compared to healthy subjects [see Dosage and
Administration (2.3) and Warnings and Precautions (5.5)].
Renal Impairment
Followingrepeatdoseadministration(8days)ofrasagiline(1mg/day)insubjects
withmoderaterenalimpairment,rasagilineexposure(AUC)wassimilartorasagiline
exposureinhealthysubjects,whilethemajormetabolite1-AIexposure(AUC)was
increased1.5-foldinsubjectswithmoderaterenalimpairment,comparedtohealthy
subjects.Because1-AIisnotanMAOinhibitor,nodoseadjustmentisneededfor
patientswithmildandmoderaterenalimpairment.Dataarenotavailableforpatients
withsevererenalimpairment.
Elderly
Sinceagehaslittleinfluenceonrasagilinepharmacokinetics,itcanbeadministered
attherecommendeddoseintheelderly(≥65years).
Pediatric
AZILECThasnotbeeninvestigatedinpatientsbelow18yearsofage.
Gender
Thepharmacokineticprofileofrasagilineissimilarinmenandwomen.
Drug-DrugInteractions
Levodopa
AstudyinParkinson’sdiseasepatients,inwhichtheeffectoflevodopa/carbidopa
(LD/CD) on rasagiline pharmacokinetics at steady state was investigated, showed
thatthepharmacokineticsofrasagilinewerenotaffectedbyconcomitantadministrationofLD/CD.
Effect of Other Drugs on the Metabolism of AZILECT
In vitrometabolismstudiesshowedthatCYP1A2wasthemajorenzymeresponsible
forthemetabolismofrasagiline.Thereisthepotentialforinhibitorsofthisenzymeto
alterAZILECTclearancewhencoadministered[see Dosage and Administration (2.2)
and Warnings and Precautions (5.4)].
Ciprofloxacin: When ciprofloxacin, an inhibitor of CYP1A2, was administered to
healthyvolunteers(n=12)at500mg(BID)withrasagilineat2mg/day,theAUCof
rasagilineincreasedby83%andtherewasnochangeintheeliminationhalflife [see
Dosage and Administration (2.2) and Warnings and Precautions (5.4)].
Theophylline:Coadministrationofrasagiline1mg/dayandtheophylline,asubstrate
ofCYP1A2,upto500mgtwicedailytohealthysubjects(n=24)didnotaffectthe
pharmacokineticsofeitherdrug.
Antidepressants:SevereCNStoxicity(occasionallyfatal)associatedwithhyperpyrexiaaspartofaserotoninsyndrome,hasbeenreportedwithcombinedtreatment
ofanantidepressant(e.g.,fromoneofmanyclassesincludingtricyclicortetracyclic
antidepressants, SSRIs, SNRIs, triazolopyridine antidepressants) and nonselective
MAOIoraselectiveMAO-Binhibitor[see Warnings and Precautions (5.2)].
Effect of AZILECT on Other Drugs
Noadditionalin vivotrialshaveinvestigatedtheeffectofAZILECTonotherdrugs
metabolizedbythecytochromeP450enzymesystem.In vitrostudiesshowedthat
rasagilineataconcentrationof1mcg/ml(equivalenttoalevelthatis160timesthe
averageCmax~5.9-8.5ng/mLinParkinson’sdiseasepatientsafter1mgrasagiline
multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6,
CYP2C9,CYP2C19,CYP2D6,CYP2E1,CYP3A4andCYP4A.Theseresultsindicate
that rasagiline is unlikely to cause any clinically significant interference with substratesoftheseenzymes.
(Ames) assay and in the in vivo micronucleus assay in mice. Rasagiline was also
negativeinthe in vivomicronucleusassayinmicewhenadministeredincombination
withlevodopa/carbidopa.
ImpairmentofFertility
Rasagilinehadnoeffectonmatingperformanceorfertilityinratstreatedpriortoand
throughoutthematingperiodandcontinuinginfemalesthroughgestationday17at
oraldosesofupto3mg/kg/day(approximately30timestheplasmaAUCinhumans
attheMRHD).Theeffectofrasagilineadministeredincombinationwithlevodopa/
carbidopaonmatingandfertilityhasnotbeenexamined.
14. CLINICAL STUDIES
TheeffectivenessofAZILECTforthetreatmentofParkinson’sdiseasewasestablished
infour18-to26-week,randomized,placebo-controlledtrials,asinitialmonotherapy
oradjuncttherapy.
14.1 Monotherapy Use of AZILECT
Study1wasadouble-blind,randomized,fixed-doseparallelgroup,26-weekstudy
in early Parkinson’s disease patients not receiving any concomitant dopaminergic
therapyatthestartofthestudy.Themajorityofthepatientswerenottreatedwith
medicationsforParkinson’sdiseasebeforereceivingAZILECT.
InStudy1,404patientswererandomlyassignedtoreceiveplacebo(138patients),
AZILECT1mg/day(134patients)orAZILECT2mg/day(132patients).Patientswere
notallowedtotakelevodopa,dopamineagonists,selegilineoramantadine,butcould
take stable doses of anticholinergic medication, if necessary. The average Parkinson’sdiseasedurationwasapproximately1year(range0to11years).
The primary measure of effectiveness was the change from baseline in the total
scoreoftheUnifiedParkinson’sDiseaseRatingScale(UPDRS),[mentation(PartI)
+activitiesofdailyliving(ADL)(PartII)+motorfunction(PartIII)].TheUPDRSis
amulti-itemratingscalethatmeasurestheabilityofapatienttoperformmentaland
motortasksaswellasactivitiesofdailyliving.Areductioninthescorerepresents
improvementandabeneficialchangefrombaselineappearsasanegativenumber.
AZILECT(1or2mgoncedaily)wassuperiortoplaceboontheprimarymeasureof
effectivenessinpatientsreceivingsixmonthsoftreatmentandnotondopaminergic
therapy. The effectiveness of AZILECT 1 mg and 2 mg was comparable. Table 4
showstheresultsofStudy1.Therewerenodifferencesineffectivenessbasedon
ageorgenderbetweenAZILECT1mg/dayandplacebo.
Table 4: Change in Total UPDRS Score in Study 1
Baseline score
Change from baseline to
termination score
p-value vs.
placebo
Placebo
24.5
3.9
---
AZILECT1mg
24.7
0.1
0.0001
AZILECT2mg
25.9
0.7
0.0001
14.2 Adjunct Use of AZILECT
Study2wasadouble-blind,randomized,placebo-controlled,parallelgroup,18-week
study,investigatingAZILECT1mgasadjuncttherapytodopamineagonistswithout
levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean
8mg/dayorpramipexole,mean1.5mg/day)therapyfor≥30days,butatdosesnot
sufficienttocontrolParkinson’sdiseasesymptoms.
In Study 2, 321 patients randomly received placebo (162 patients) or AZILECT
1mg/day(159patients)andhadapost-baselineassessment.TheaverageParkinson’sdiseasedurationwasapproximately2years(range0.1to14.5years).
Theprimarymeasureofeffectivenesswasthechangefrombaselineinthetotalscore
oftheUnifiedParkinson’sDiseaseRatingScale(UPDRS)[mentation(PartI)+activitiesofdailyliving(ADL)(PartII)+motorfunction(PartIII)].
InStudy2,AZILECT1mgwassuperiortoplaceboontheprimarymeasureofeffectiveness(seeTable5).
Table 5: Change in Total UPDRS Score in Study 2
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Two-yearcarcinogenicitystudieswereconductedinmiceatoraldosesof1,15,and
45mg/kg/dayandinratsatoraldosesof0.3,1,and3mg/kg/day(males)or0.5,2,
5,and17mg/kg/day(females).Inrats,therewasnoincreaseintumorsatanydose
tested.Plasmaexposures(AUC)atthehighestdosetestedwereapproximately33
and260times,inmaleandfemalerats,respectively,thatinhumansatthemaximum
recommendedhumandose(MRHD)of1mg/day.
Inmice,therewasanincreaseinlungtumors(combinedadenomas/carcinomas)at
15and45mg/kginmalesandfemales.Atthelowestdosetested,plasmaAUCswere
approximately5timesthoseexpectedinhumansattheMRHD.
Thecarcinogenicpotentialofrasagilineadministeredincombinationwithlevodopa/
carbidopahasnotbeenexamined.
Mutagenesis
Rasagilinewasreproduciblyclastogenicin in vitrochromosomalaberrationassaysin
humanlymphocytesinthepresenceofmetabolicactivationandwasmutagenicand
clastogenicinthein vitromouselymphomatkassayintheabsenceandpresenceof
metabolicactivation.Rasagilinewasnegativeinthein vitrobacterialreversemutation
Baselinescore
Changefrombaselineto
terminationscore*
p-valuevs.
placebo
Placebo
29.8
–1.2
---
AZILECT1mg
32.1
–3.6
0.012
*AnegativechangefrombaselineindicatesimprovementintheUPDRS
SecondaryoutcomeassessmentoftheindividualsubscalesoftheUPDRSindicates
that the UPDRS Part III motor subscale was primarily responsible for the overall
AZILECTeffectontheUPDRSscore(seeTable6).
Table 6: Secondary Measures of Effectiveness in Study 2
Baseline
(score)
Change from baseline to termination score
UPDRS ADL Part II (Activities of Daily Living) subscale score
Placebo
7.9
0.4
AZILECT1mg
8.6
-0.3
UPDRS Part III Motor subscale score
6
Placebo
20.4
-1.2
AZILECT1mg
22.2
-3.7
19
AZILECT® (rasagiline mesylate) Tablets for Oral Use
AZILECT® (rasagiline mesylate) Tablets for Oral Use
Table 9: Secondary Measures of Effectiveness in Study 3
Study 3 and Study 4 were randomized, multinational trials conducted in more
advancedParkinson’sdiseasepatientstreatedchronicallywithlevodopaandexperiencingmotorfluctuations(includingbutnotlimitedto,endofdose“wearingoff,”
suddenorrandom“off,”etc.).Study3wasconductedinNorthAmerica(U.S.and
Canada) and compared AZILECT 0.5 mg and 1 mg daily to placebo. Study 4 was
conductedoutsideofNorthAmericainEurope,ArgentinaandIsrael,andcompared
AZILECT1mgdailytoplacebo.
PatientshadParkinson’sdiseaseforanaverageof9years(range5monthsto33years),
hadtakenlevodopaforanaverageof8years(range5monthsto32years),andhad
motorfluctuationsforapproximately3to4years(range1monthto23years).Patients
kepthomeParkinson’sdiseasediariesjustpriortobaselineandatspecifiedintervals
duringthetrial.Diariesrecordedoneofthefollowingfourconditionsforeachhalf-hour
interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON”
withtroublesomedyskinesia,“OFF”(periodofrelativelypoorfunctionandmobility)
orasleep.“Troublesome”dyskinesiaisdefinedasdyskinesiathatinterfereswiththe
patient’sdailyactivity.Allpatientshadinadequatecontroloftheirmotorsymptomswith
motorfluctuationstypicalofadvancedstagediseasedespitereceivinglevodopa/decarboxylaseinhibitor.Theaveragedoseoflevodopatakenwithadecarboxylaseinhibitor
wasapproximately700to800mg(range150to3000mg/day).Patientscontinued
theirstabledosesofadditionalanti-PDmedicationsatentryintothetrials.Approximately65%ofpatientsinbothstudieswerealsotakingadopamineagonist.Inthe
NorthAmericanstudy(Study3),approximately35%ofpatientstookentacaponewith
levodopa/decarboxylaseinhibitor.Themajorityofpatientstakingentacaponewerealso
takingadopamineagonist.
InStudy3andStudy4,theprimarymeasureofeffectivenesswasthechangeinthe
meannumberofhoursspentinthe“OFF”stateatbaselinecomparedtothemean
numberofhoursspentinthe“OFF”stateduringthetreatmentperiod.
In Study 3, patients were randomly assigned to receive placebo (159 patients),
AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients) for 26
weeks.Patientsaveraged6hoursdailyinthe“OFF”stateatbaselineasconfirmed
byhomediaries.
In Study 4, patients were randomly assigned to receive placebo (229 patients),
AZILECT 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken
alongwithscheduleddosesoflevodopa/decarboxylaseinhibitor(227patients)for
18weeks.Patientsaveraged5.6hoursdailyinthe“OFF”stateatbaselineasconfirmedbyhomediaries.
InStudy3andStudy4,AZILECT1mgoncedailyreduced“OFF”timecomparedto
placebowhenaddedtolevodopainpatientsexperiencingmotorfluctuations(Tables
7and8).Thelowerdose(0.5mg)ofAZILECTalsosignificantlyreduced“OFF”time
(Table7),buthadanumericallysmallereffectthanthe1mgdoseofAZILECT.In
Study4,theactivecomparatoralsoreduced“OFF”timewhencomparedtoplacebo.
Baseline (score)
UPDRS ADL (Activities of Daily Living) subscale score while “OFF”
Change from baseline to
treatment period (hours)
p-value vs. placebo
Placebo
6.0
-0.9
---
AZILECT0.5mg
6.0
-1.4
0.0199
AZILECT1.0mg
6.3
-1.9
<0.0001
Change from baseline to
treatment period (hours)
Placebo
5.5
-0.40
---
AZILECT1.0mg
5.6
-1.2
0.0001
15.5
0.68
AZILECT0.5mg
15.8
-0.60
AZILECT1mg
15.5
-0.68
Placebo
20.8
1.21
AZILECT0.5mg
21.5
-1.43
AZILECT1mg
20.9
-1.30
Table 10: Secondary Measures of Effectiveness in Study 4
Baseline (score)
Change from baseline to last value
UPDRS ADL (Activities of Daily Living) subscale score while “OFF”
Placebo
AZILECT1mg
18.7
-0.89
19.0
-2.61
UPDRS Motor subscale score while “ON”
Placebo
23.5
-0.82
AZILECT1mg
23.8
-3.87
16. HOW SUPPLIED/STORAGE AND HANDLING
AZILECT0.5mgTablets:
Whitetooff-white,round,flat,beveledtablets,debossedwith“GIL0.5”ononeside
andplainontheotherside.Suppliedasbottlesof30tablets(NDC68546-142-56).
AZILECT1mgTablets:
Whitetooff-white,round,flat,beveledtablets,debossedwith“GIL1”ononeside
andplainontheotherside.Suppliedasbottlesof30tablets(NDC68546-229-56).
Storage:
Storeat25°C(77°F)withexcursionspermittedto15°-30°C(59°-86°F).
17. PATIENT COUNSELING INFORMATION
Hypertension
AdvisepatientsthattreatmentwithrecommendeddosesofAZILECTmaybeassociatedwithelevationsofbloodpressure.Tellpatientswhoexperienceelevationof
bloodpressurewhiletakingAZILECTtocontacttheirhealthcareprovider.
The risk of using higher than recommended daily doses of AZILECT should be
explained,andabriefdescriptionofthetyramineassociatedhypertensivereaction
provided.
Advise patients to avoid certain foods (e.g., aged cheese) containing a very large
amount of tyramine while taking recommended doses of AZILECT because of the
potentialforlargeincreasesinbloodpressure.Ifpatientseatfoodsveryrichintyramine and do not feel well soon after eating, they should contact their healthcare
provider[see Warnings and Precautions (5.1)].
Serotonin Syndrome
Tellpatientstoinformtheirphysicianiftheyaretaking,orplanningtotake,anyprescriptionorover-the-counterdrugs,especiallyantidepressantsandover-the-counter
cold medications, since there is a potential for interaction with AZILECT. Because
patientsshouldnotusemeperidineorcertainotheranalgesicswithAZILECT,they
shouldcontacttheirhealthcareproviderbeforetakinganalgesics[see Contraindications (4) and Warnings and Precautions (5.2)].
Falling Asleep During Activities of Daily Living and Somnolence
Advise and alert patients about the potential for sedating effects associated with
AZILECT and other dopaminergic medications, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living.
Becausesomnolencecanbeafrequentadversereactionwithpotentiallyseriousconsequences,patientsshouldneitherdriveacarnorengageinotherpotentiallydangerousactivitiesuntiltheyhavegainedsufficientexperiencewithAZILECTandother
dopaminergic medications to gauge whether or not it affects their mental and/or
motorperformanceadversely.Advisepatientsthatifincreasedsomnolenceornew
episodesoffallingasleepduringactivitiesofdailyliving(e.g.,watchingtelevision,
passengerinacar,etc.)areexperiencedatanytimeduringtreatment,theyshould
notdriveorparticipateinpotentiallydangerousactivitiesuntiltheyhavecontacted
their physician. Patients should not drive, operate machinery, or work at heights
duringtreatmentiftheyhavepreviouslyexperiencedsomnolenceand/orhavefallen
asleepwithoutwarningpriortouseofAZILECT.
Because of possible additive effects, advise patients to exercise caution when
patientsaretakingothersedatingmedications,alcohol,orothercentralnervoussystemdepressants(e.g.,benzodiazepines,antipsychotics,antidepressants)incombinationwithAZILECTorwhentakingconcomitantmedicationsthatincreaseplasma
levelsofrasagiline(e.g.,ciprofloxacin)[see Warnings and Precautions (5.3)].
Ciprofloxacin or Other CYP1A2 Inhibitors
InformpatientsthattheyshouldcontacttheirhealthcareproviderofAZILECTifthey
take ciprofloxacin or a similar drug that could increase blood levels of rasagiline
becauseoftheneedtoadjustthedoseofAZILECT[see Dosage and Administration
(2.2) and Warnings and Precautions (5.4)].
Table 8: Change in mean total daily “OFF” time in Study 4
Baseline
(hours)
Placebo
UPDRS Motor subscale score while “ON”
Table 7: Change in mean total daily “OFF” time in Study 3
Baseline
(hours)
Change from baseline to last value
p-value vs. placebo
In Study 3 and Study 4, dose reduction of levodopa was allowed within the first
6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations.InStudy3,thelevodopadosewasreducedin8%ofpatientsintheplacebo
group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day AZILECT
groups,respectively.Whenlevodopawasreduced,thedosewasreducedby7%,9%,
and13%intheplacebo,0.5mg/day,and1mg/daygroups,respectively.InStudy4,
levodopadosereductionoccurredin6%ofpatientsintheplacebogroupandin9%
intheAZILECT1mg/daygroups,respectively.Whenlevodopawasreduced,itwas
reducedby13%and11%intheplaceboandtheAZILECTgroups,respectively.
TherewerenodifferencesineffectivenessbasedonageorgenderbetweenAZILECT
1mg/dayandplacebo.
Several secondary outcome assessments in the two studies showed statistically
significantimprovementswithrasagiline.Theseincludedeffectsontheactivitiesof
dailyliving(ADL)subscaleoftheUPDRSperformedduringan“OFF”periodandthe
motorsubscaleoftheUPDRSperformedduringan“ON”period.Inbothscales,a
negativeresponserepresentsimprovement.Tables9and10showtheseresultsfor
Studies3and4.
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20
AZILECT® (rasagiline mesylate) Tablets for Oral Use
Hepatic Impairment
TellpatientswhohavehepaticproblemstocontacttheirhealthcareproviderregardingpossiblechangesinAZILECTdosing[see Warnings and Precautions (5.5)].
Hypotension/Orthostatic Hypotension
Patientsshouldbeadvisedthattheymaydeveloporthostatichypotensionwithorwithoutsymptomssuchasdizziness,nausea,syncope,andsometimessweating.Hypotensionand/ororthostaticsymptomsmayoccurmorefrequentlyduringinitialtherapyor
withanincreaseindoseatanytime(caseshavebeenseenafterweeksoftreatment).
Accordingly,patientsshouldbecautionedagainststandinguprapidlyaftersittingor
lyingdown,especiallyiftheyhavebeendoingsoforprolongedperiods,andespecially,
attheinitiationoftreatmentwithAZILECT[see Warnings and Precautions (5.6)].
Dyskinesia
AdvisepatientstakingAZILECTasadjuncttolevodopathatthereisapossibilityof
dyskinesiaorincreaseddyskinesia[see Warnings and Precautions (5.7)].
Hallucinations/Psychotic-Like Behavior
Informpatientsthathallucinationsorothermanifestationsofpsychotic-likebehavior
canoccurwhentakingAZILECT.Advisepatientsthat,iftheyhaveamajorpsychotic
disorder,thatAZILECTshouldnotordinarilybeusedbecauseoftheriskofexacerbatingthepsychosis.Patientswithamajorpsychoticdisordershouldalsobeaware
thatmanytreatmentsforpsychosismaydecreasetheeffectivenessofAZILECT[see
Warnings and Precautions (5.8)].
Impulse Control/Compulsive Behaviors
Advisepatientsthattheymayexperienceintenseurgestogamble,increasedsexual
urges,otherintenseurges,andtheinabilitytocontroltheseurgeswhiletakingone
ormoreofthemedicationsthatincreasecentraldopaminergictoneandthataregenerallyusedforthetreatmentofParkinson’sdisease(includingAZILECT).Althoughit
isnotproventhatthemedicationscausedtheseevents,theseurgeswerereported
tohavestoppedinsomecaseswhenthedosewasreducedorthemedicationwas
stopped.Prescribersshouldaskpatientsaboutthedevelopmentofneworincreased
gambling urges, sexual urges, or other urges while being treated with AZILECT.
Patientsshouldinformtheirphysicianiftheyexperienceneworincreasedgambling
urges,increasedsexualurges,orotherintenseurgeswhiletakingAZILECT.PhysiciansshouldconsiderdosereductionorstoppingthemedicationifapatientdevelopssuchurgeswhiletakingAZILECT[see Warnings and Precautions 5.9].
Withdrawal-Emergent Hyperpyrexia and Confusion
TellpatientstocontacttheirhealthcareprovideriftheywishtodiscontinueAZILECT
[see Warnings and Precautions (5.10)].
Missing Dose
Instruct patients to take AZILECT as prescribed. If a dose is missed, the patient
should not double-up the dose of AZILECT. The next dose should be taken at the
usualtimeonthefollowingday.
Marketedby:TEVANeuroscience,Inc.,OverlandPark,KS66211
Distributedby:TEVAPharmaceuticalsUSA,Inc.,NorthWales,PA19454
AZI-40850
8
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