Revista Medicina y Salud Pública (MSP)

Prevalencia del dolor de cabeza en Puerto Rico Vigilancia terapéutica de drogas en Enfermedad Inflamatoria del Intestino: ajuste de terapia guiado y resultados clínicos en puertorriqueños con EII

TASA DE INCIDENCIA Y MORTALIDAD DE CĂ NCER EN PUERTO RICO

CĂ NCER DE PULMĂ“N Y BRONQUIOS

Mujeres: 315 Hombres: 477

NĂşmero de personas que viven en Puerto Rico y que actualmente o anteriormente han sufrido de cĂĄncer en el 2015:

CĂ NCER DE SENO

Mujeres: 2,188 Hombres: 17

LOS PRIMEROS 5 ASESINOS La tasa de muertes asociadas a 4 de los 5 cĂĄnceres con mayor mortalidad han caĂ­do ha medida que surgen nuevas proyecciones y tratamientos. El financiamiento federal total a travĂŠs del Instituto Nacional del CĂĄncer superĂł los $5 billones en el aĂąo fiscal 2015

LINFOMA DE HODGKIN

Mujeres: 44 Hombres: 59

Mujeres: 217 Hombres: 376

Mujeres: 432 Hombres: 12

LINFOMA NO HODGKIN

Mujeres: 10 Hombres: 16

Mujeres: 323 Mujeres: 59 Hombres: 330 Hombres: 91

Femenino (N= 11,727) Seno

CĂ NCER DE PĂ NCREAS

13.3%

Colon y recto

Mujeres: 189 Hombres: 179

9.7%

PulmĂłn y bronquios

18.5%

Mujeres: 155 Hombres: 168

CĂ NCER DE COLON 6.2%

PĂĄncreas

4.7%

HĂ­gado y conducto biliar intrahepĂĄtico

Masculino (N= 14,803)

16.6%

Mujeres: 896 Hombres: 1,020

Incidencia general de cĂĄncer en PR en el 2015:

16,372

Mortalidad general de cĂĄncer en PR en el 2015:

5,185

PrĂłstata

13.3%

PulmĂłn y bronquios

13.0%

Colon y recto

7.1%

HĂ­gado y conducto biliar intrahepĂĄtico

5.3%

PĂĄncreas

Mujeres: 298 Hombres: 364

CĂ NCER DE PRĂ“STATA

Hombres: 3,167

Hombres: 488

EPIDEMIOLOGÍA DE ENFERMEDADES DEL CORAZÓN EN PUERTO RICO

Diseño y fuente: Revista Medicina y Salud Pública (MSP)

Son la segunda causa de muerte en Puerto Rico y la primera en el resto del mundo, incluyendo los Estados Unidos.

MORTALIDAD POR ENFERMEDADES CARDIOVASCULARES

Las personas de 65 años o más reportaron la prevalencia más alta de ataques al miocardio (10.3 %), enfermedad coronaria (13.7 %), hipertensión (69.7 %) y apoplejías (3.8 %).

Las personas con un ingreso anual menor de $ 15,000 reportan la mayor prevalencia de ataques al miocardio (5.6 %), enfermedad coronaria (8.7 %), hipertensión (46.8 %) y apoplejías (stroke) (2.4 %).

324,255 personas utilizan servicios de salud para atender enfermedades cardiovasculares en Puerto Rico. 180,508 son mujeres (56 %) y 143,747 son hombres (44 %). El grupo de edad con mayor diagnóstico fue el de 65 a 69 años.

Las personas que no completaron la escuela superior reportan la prevalencia más alta de ataques al miocardio (7.3 %), enfermedad coronaria (11.1 %), hipertensión (56 %) y apoplejías (2.9 %).(10.3 %), enfermedad coronaria (13.7 %), hipertensión (69.7 %) y apoplejías (3.8 %).

MORTALIDAD POR ENFERMEDADES CARDIOVASCULARES

En los hombres la tasa de mortalidad es de 160.8, por cada 100,000 habitantes

En las mujeres la tasa de mortalidad es de 122.3, por cada 100,000 habitantes

2

da

35% fue pagado por los pacientes.

PREVALENCIA DE LAS CONDICIONES CARDIOVASCULARES EN PUERTO RICO

42,2%

de los puertorriqueños padecen hipertensión

La hipertensión es la más común en Puerto Rico y Estados Unidos.

Puerto Rico, tiene una mayor prevalencia de hipertensión y enfermedad coronaria que Estados Unidos.

Aguadilla, Fajardo y Arecibo son las regiones que presentan la mayor prevalencia para las condiciones cardiovasculares.

La región de Mayagüez tiene la menor prevalencia para todas las enfermedades.

Las mujeres tienen mayor prevalencia de hipertensión.

La tasa de mortalidad a causa de las enfermedades cardiovasculares es de 114.1, siendo la segunda causa de muerte.

65%

por las aseguradoras de salud.

Los hombres tienen una prevalencia más alta de infarto al miocardio.

Los retos más difíciles.

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Vigilancia terapéutica de drogas en Enfermedad Inflamatoria del Intestino: ajuste de terapia guiada y resultados clínicos en puertorriqueños con EII

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Infarto agudo al miocardio en paciente con linfoma de Hodgkin

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Tumores cardíacos

34

Manejo cardiovascular en paciente con cáncer: nuevas estrategias

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61

Enfrentando complejidades en el tratamiento de la piel del paciente diabético

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El cáncer gástrico: una perspectiva global

90

Malignidad en los pacientes trasplantados de corazón, un peligro subyacente

Radiografía del manejo y tratamiento de la dermatitis atópica

42

La quimioterapia y el corazón

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Prevalencia del dolor de cabeza en Puerto Rico

111 126 145

Trasplante de hígado: un gran avance en Puerto Rico

Agenda médica

Noticias de medicinaysaludpublica.com

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Trabajo en equipo clave para el manejo exitoso de infecciones de pie diabético

155

Convenciones

158 A ciencia cierta

Comité Editorial Científico

José Cordero, MD, MPH - Pasado Decano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis A. Rivera Pomales, MD, MBA, MPH (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España).

COMITÉ EDITORIAL

Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD Ileana Santiago Álvarez, MBA VICEPRESIDENTA EDITORIAL MUNDO Y FUNDADORA Laila Paloma Lorraine CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA PERIODISTAS Mayra Acevedo, Susana María Rico, Jean Vélez César Fuquen, Laura Mojica, Rosmery Cernadas REALIZADORA AUDIOVISUAL Alejandra Montenegro Arango PROGRAMADORES WEB Diego Esteban Gutiérrez, Frank Arley Carvajal Rincón ARTISTAS GRÁFICOS Pablo Bermúdez Robayo, Andrés Pinzón Segura, Lorena Castillo FOTOS : Revista Medicina y Salud Pública ASISTENTE DE PRODUCCIÓN Marta I. Vélez Ramos DIRECCIÓN GENERAL Y PRESIDENTE FUNDADOR Carlos Alexis Lugo Marrero JEFE DE OPERACIONES Y FUNDADOR Pedro Carlos Lugo Hernández III DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente EDITOR FUNDADOR

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LABORATORIO CLINICO Y SERVICIOS COMPLETOS DE PATOLOGÍA Se une a nuestra facultad médica el Dr. José de Jesús, FCAP tras culminar su Fellowship de Moffit Cancer Center en Breast Surgical Pathology

HRP Labs, provee el mejor servicio diagnóstico que incluye una interacción personal con nuestros patólogos “board certifed”, la más rápida entrega de resultados en el mercado, excelente servicio al cliente y una vasta experiencia.

+ Facultad de 16 patólogos + 7 subespecialistas + 5 laboratorios para procesamiento de muestras. + Laboratorios de inmunohistoquímica y molecular in-house + Laboratorio certificado por el CAP + Conectividad con Récord Médico Electrónico + Clínicas de Aspiración por Aguja Fina dirigidas por el Dr. Villarmarzo en 7 localidades

Además en Julio 2019 se une a nuestra práctica el Dr. José Rodríguez Medina, FCAP con fellowships en Hematopatología y en Oncología Molecular

Actualmente duplicando el espacio de nuestras facilidades en la Ave. Domenech #300

Laboratorio clínico para pacientes y pruebas de referencia

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GILBERTO RIVERA GAUTIER, MD, FACC, RPVI Board Certified por la American Board of Internal Medicine en Medicina Interna y Enfermedades Cardiovasculares Presidente de la Sociedad Puertorriqueña de Cardiología Director del Laboratorio Cardiovascular Invasivo y Laboratorio Cardiovascular No-Invasivo del Hospital Auxilio Mutuo

Enfermedad cardiovascular y cáncer: avances y estrategias del manejo Con los avances en el diagnóstico y tratamiento médico de numerosas condiciones, hemos observado un incremento en la detección más temprana del cáncer y mejores alternativas de tratamiento que han permitido una mayor sobrevida de estos pacientes.

Como resultado, observamos una mayor población de personas sobrevivientes de cáncer que se encuentran en igual o mayor riesgo de desarrollar enfermedad cardiovascular que la población general. No es un hecho novedoso que la enfermedad cardiovascular ha sido también identificada como una complicación del tratamiento de cáncer, incluyendo quimioterapias y radioterapias. Por otro lado, las modalidades de diagnóstico y tratamiento de enfermedad cardiovascular de la misma forma han permitido una mayor sobrevida de los pacientes con estas condiciones, lo que ha resultado en un incremento de pacientes con esta enfermedad que son identificados y requieren tratamiento para diferentes tipos de cáncer.

La detección, entrega de diagnóstico y manejo apropiado de las enfermedades cardiovasculares en los pacientes de cáncer y de igual manera en pacientes con enfermedad cardiovascular afectados con cáncer, nos permite lograr que estas poblaciones puedan mantener una mejor calidad de vida y sobrevida.

La presencia concurrente de estas condiciones ha promovido el desarrollo una modalidad integrativa

denominada cardio-oncología. Con el desarrollo de esta rama logramos aumentar el conocimiento y mayor implementación de estrategias de vigilancia y tratamiento para prevención del desarrollo de enfermedad cardiovascular en pacientes con cáncer.

De especial interés ha sido el grupo de pacientes expuestos a quimioterapias cardiotóxicas, con riesgo de desarrollo de cardiomiopatía así como pacientes expuestos a radioterapia, con riesgo de desarrollo de enfermedad del pericardio, miocardio y enfermedad vascular -incluyendo la coronaria-.

El tratamiento de otras comorbilidades es también de suma importancia en el manejo integral del paciente de cáncer y enfermedad cardiovascular.

El tratamiento de factores de riesgo, alternativas de manejo quirúrgico, rehabilitación y pruebas de cernimiento son áreas de gran interés que pueden ofrecer a nuestros pacientes cardio-oncológicos las mejores alternativas disponibles en la medicina moderna para el mantenimiento y mejoramiento de la salud.

La Sociedad Puertorriqueña de Cardiología junto con Revista Medicina y Salud Pública, Salud y Cardiología, ha liderado este esfuerzo dirigido a informar a nuestros médicos sobre estos temas de gran interés. Esperamos que estos artículos sean de ayuda en el mejoramiento del cuidado de nuestros pacientes.

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“El paso más importante como médico primario es el monitoreo apropiado para las complicaciones tardías en paciente en remisión de LH después de RT”

Infarto agudo al miocardio en paciente con linfoma de Hodgkin Autores: 1Kathy Caraballo Rivera, MD; 2Vielka Cintrón, MD; 3José Martínez Barroso, MD. Manatí Medical Center: 1Programa de Residencia de Medicina de Familia, PGY-1; 2

Departamento de Medicina de Familia; 3Departamento de Medicina Interna/Cardiología.

Manatí Medical Center, PO BOX 1142, Manatí, Puerto Rico, 00641

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Palabras Clave Linfoma de Hodgkin, infarto al miocardio, caso clínico, radioterapia supradiafragmática

Keywords Hodgkin's lymphoma, myocardial infarction, clinical case, supradiaphragmatic radiotherapy.

Resumen El tratamiento del linfoma de Hodgkin frecuentemente incluye la radioterapia supradiafragmática. Los sobrevivientes de linfoma de Hodgkin tienen una mayor incidencia de complicaciones cardiovasculares después de radioterapia. Este es el caso de un masculino de 30 años de edad que se presenta a nuestra sala de emergencia con náuseas, vómitos, malestar general y molestia en el pecho de tres días de evolución. El paciente afirmaba que su novia tenía los mismos síntomas para el mismo periodo de tiempo pero mejoró, por esto una infección bacteriana fue inicialmente sospechada. El paciente tiene un historial médico pasado de linfoma de Hodgkin a

los 22 años por lo cual había recibido radioterapia supradiafragmática. Considerando la poca respuesta del paciente al tratamiento inicial y el historial de linfoma de Hodgkin una evaluación cardiológica fue solicitada, la cual evidenció enzimas cardíacas elevadas y disquinesia en el ecocardiograma. La cateterización del lado izquierdo del corazón revelo una lesión de la arteria descendente anterior izquierda corregida con la implantación de un stent. El paciente fue posteriormente dado de alta para seguimiento externo con el médico primario y el cardiólogo.

Aunque la enfermedad coronaria aguda es una complicación conocida de la radioterapia, la

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MSP CASO CLÍNICO

Revista Puertorriqueña de Medicina y Salúd Pública

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presentación clínica de este caso fue inusual. Todos los pacientes con historial de radioterapia tienen que ser evaluados completamente para enfermedad coronaria comenzando a los 5-10 años después de terminado el tratamiento. El médico primario juega un papel fundamental en el monitoreo para complicaciones tardías en pacientes en remisión de linfoma de Hodgkin después de radioterapia.

Abstract The treatment of Hodgkin's lymphoma frequently includes supradiaphragmatic radiotherapy. Survivors of Hodgkin lymphoma have a higher incidence of cardiovascular complications after radiotherapy. This is the case of a 30-year-old male who is presented to our emergency room with nausea, vomiting, general malaise and chest discomfort of three days of evolution. The patient claimed that his girlfriend had the same symptoms for the same period but improved, so a bacterial infection was initially suspected. The Introducción Los pacientes con linfoma de Hodgkin (LH) tienen una alta tasa de curación. El tratamiento de LH frecuentemente incluye radioterapia supradiafragmática ( RT ) en portales que incluyen parte del corazón. Numerosos estudios han demostrado que los sobrevivientes de LH tienen una alta incidencia de enfermedad cardiovascular, siendo la causa más común de muerte no-maligna1. Las complicaciones incluyen enfermedad del pericardio, isquemia al miocardio o infarto, cardiomiopatía, fallo cardíaco, anormalidad valvular o defectos de conducción. Estas complicaciones se piensan que son el producto de la radiación la cual induce inf lamación y f ibrosis en las estructuras cardiacas1.

Caso clínico Un masculino de 30 años de edad se presenta a nuestra sala de emergencia con síntomas gastrointestinales y malestar de pecho de tres días de evolución. Él indica que su novia tenía los 12

Revista Puertorriqueña de Medicina y Salúd Pública

patient has a medical history of Hodgkin lymphoma at age 22 and has received supradiaphragmatic radiotherapy. Considering the patient's little response to initial treatment and the history of Hodgkin's lymphoma, a cardiac evaluation was requested, which showed elevated and dyskinesia heart enzymes in the echocardiogram. Catheterization of the left side of the heart revealed a lesion of the left anterior descending artery corrected with implantation of a stent. The patient was subsequently discharged for external follow-up with the primary physician and cardiologist. Although acute coronary disease is a known complication of radiotherapy, the clinical presentation of this case was unusual. All patients with radiotherapy history must be fully evaluated for coronary artery disease starting at 5-10 years after the treatment is complete. The primary practitioner plays a key role in monitoring for late complications in patients in Hodgkin's lymphoma remission after radiotherapy.

mismos síntomas para el mismo periodo de tiempo aunque ella mejoró. El refiere náuseas, vómitos, malestar general, diarrea, fiebre, dolor abdominal y de espalda además del malestar del pecho. En el examen físico solamente un dolor abdominal difuso fue encontrado.

Los laboratorios realizados en la sala de emergencia se encontraban dentro de los límites normales.

Dado los síntomas y presentación del paciente fue sospechado primeramente una intoxicación alimentaria. El historial médico pasado del paciente incluye LH a los 22 años por el cual completó 20 ciclos de radioterapia, acompañado por su oncólogo quien le dio de alta de su servicio dos años después de finalizado el tratamiento.

Durante la admisión el paciente desarrolló falta de aire y dolor de pecho. Como parte de su evaluación fueron realizados gases arteriales los cuales mostraron hipoxemia y un electrocardiograma mostró cambios isquémicos no específicos. Dado el historial de LH una evaluación

cardiológica fue realizada para descartar cardiomiopatía. La ventriculografía nuclear mostró evidencia de hipocinesia focal apical del ventrículo izquierdo. Un set de enzimas cardíacas elevadas (troponin 13.84ng/mL) confirmó la sospecha de infarto al miocardio sin elevación de ST, síndrome agudo coronario (NSTEMI-ACS) (ICD10, I21.4). La cateterización del lado izquierdo del corazón reveló una lesión excéntrica severa de 95% de la arteria descendente izquierda. La intervención cardíaca percutánea de la arteria anterior descendente media con un ESTENT (3.5mm x 2.4 mm) fue realizada exitosamente dilatando la arteria a 4mm (Figura 1). Después de dos días el paciente fue dado de alta para continuar con el cuidado externo con su médico primario y cardiólogo.

Discusión Aunque la enfermedad coronaria aguda es una complicación de la radioterapia conocida, la presentación clínica de este caso fue

MSP CASO CLÍNICO

inusual. Según la población envejece y los tratamientos para el linfoma de Hodgkin mejoran, más pacientes son clasificados como sobreviviente de linfoma. Después del tratamiento de LH, y una vez alcanzada la remisión, los sobrevivientes de LH pasan al cuidado de su médico primario siendo la persona más indicada para atender todos los problemas después de la remisión. El paso más importante como médico primario es el monitoreo apropiado para las complicaciones tardías en paciente en remisión de LH después de RT. Los sobrevivientes están a mayor riesgo de recurrencia de cáncer, cáncer secundario, complicaciones cardiovasculares y problemas psicosociales entre otras complicaciones. Se ha encontrado que los sobrevivientes de LH tienen un mayor riesgo de infarto al miocardio y fallo cardíaco congestivo cuando se comparan a la población en general (proporción de incidencia estandarizada 3.6 y 4.9, respectivamente)2. La proporción de incidencia estandarizada para todas las enfermedades cardiovasculares combinadas se mantiene elevada al menos por veinticinco años2. Estudios recientes muestran una incidencia cumulativa de 40 años de 50% de riesgo de enfermedades cardiovasculares 3 .

Con estas estadísticas presentes es importante como médico primario estar consciente de las posibles complicaciones. Con una población de sobrevivientes de LH creciendo, todos los pacientes con malestar o dolor de pecho con historial médico de RT supradiafragmática debería tener una evaluación completa para enfermedad coronaria empezando 5-10 años después de completada la terapia. Como médico primario la primera evaluación de pacientes sobrevivientes de LH debería incluir un electrocardiograma y

Figura 1. El resultado del Angiograma coronario muestra la lesión excéntrica severa de 95% de la arteria anterior descendente: A. Lesión excéntrica de la arteria anterior descendente izquierda.

B. La arteria anterior descendente izquierda con la guía insertada.

C. La arteria anterior descendente izquierda con el ESTENT colocado.

D. ESTENT colocado exitosamente.

ecoc a rd iog r a ma ba se1. E l monitoreo de estos pacientes es desafiante porque no hay una guía completa aceptada para el manejo y cernimiento de las complicaciones4.

Después de la RT, el oncólogo usualmente sigue el paciente por 3-5 años y después es el médico primario el que asume su cuidado. Cada paciente debería ser individualizado al tratamiento previamente dado y a las comorbilidades presentes.

Conclusiones Como médico primario el paso más importante en cada cita de seguimiento en pacientes en remisión de LH después de RT es el monitoreo de las posibles complicaciones tardías y seguir las recomendaciones basadas en la edad y factores individualizados.

Este estudio fue aprobado por el IRB PHSU (protocolo número 170224-JM el 3/8/2017).

Bibliografía

1. Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma.

Br J Haematol 2011; 154:23.

2. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007; 109:1878.

3. Van Nimwegen, Schaapveld, Junus, et al. Cardiovascular disease after Hodgkin lymphoma treatment 40 year disease risk.

JAMA Internal Medicine 2015; 175:6.

4. Thompson, C. A., Mauck, K., Havyer, R., Bhagra, A., Kalsi, H., & Hayes, S. N. (2011).

Care of the Adult Hodgkin Lymphoma Survivor. The American Journal of Medicine, 124(12), 1106–1112.

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¿Qué se está desarrollando en Puerto Rico para contrarrestar los efectos del linfoma?

Aprueban nuevo tratamiento para dos tipos raros de linfoma no Hodgkin » Estos son: micosis fungoide (MF) / síndrome de Sézary (SS). » Tratamiento intravenoso para adultos, Poteligeo (mogamulizumab-kpkc). » Son tipos de linfoma no Hodgkin en el cual los linfocitos se vuelven cancerosos y afectan la piel. » Supervivencia sin progresión bajo Poteligeo es de 7.6 meses. » Entre los efectos secundarios más comunes del tratamiento con Poteligeo incluyen erupción cutánea, reacciones relacionadas con la infusión, fatiga, diarrea, dolor musculoesquelético e infección del tracto respiratorio superior. » Monoterapias: Ibrutinib y Nivolumab

La investigación del linfoma no Hodgkin en Puerto Rico El Dr. Fernando Cabanillas es el médico boricua que más se ha destacado en la investigación del linfoma. Entre sus logros sobresalen: » Pionero en aplicar la técnica del “PCR”, que detecta los residuos de linfomas foliculares y analiza los resultados. » Creación del esquema FND: Fludarabina, Novantrone y Dexametasona como parte del tratamiento para el linfoma no Hodgkin. » Diseño de un sistema que predice los resultados de tratamientos contra linfomas.

Predice su efectividad en pacientes. » Nuevas terapias para tipos inusuales de linfoma no Hodgkin: Poteligeo en inyección. » Demostrar por primera vez que los cambios citogenéticos en el cromosoma 17 son clínicamente esenciales en el pronóstico de pacientes con linfoma de células grandes. » Fundador y director del Centro de Cáncer del Hospital Auxilio Mutuo.

Médicos puertorriqueños registraron extraña variante genética en linfoma de células de manto » Fue diagnosticado en Puerto Rico y es el segundo en el mundo, según la literatura científica. » Lo reportaron el doctor William Marrero, médico interno del Hospital Auxilio Mutuo, el doctor Fernando Cabanillas, investigador de cáncer tipo linfoma en Puerto Rico y Estados Unidos y el doctor Alexis Cruz Chacón, director del Centro de Trasplante de Médula Ósea. » El doctor Cabanillas ha sido precursor de los avances hacia la cura.

Linfoma no Hodgkin en PR / Cáncer folicular » » » »

Constituye alrededor del 30% de todos los Linfomas no Hodgkin.

Se caracteriza por su lento crecimiento.

Los linfomas se pueden desarrollar en personas con sistemas inmunitarios debilitados.

Esta patología tiene mayor prevalencia en hombres.

Prometedora la sobrevivencia » Los investigadores buscan una nueva alternativa más agresiva para que sobreviva el 85% de los enfermos, acompañado de un sistema que predice los resultados de un tratamiento contra los linfomas y la técnica "PCR".

1 2

30% confirma la existencia del tumor más agresivo catalogado como un “subtipo” del mismo tumor primario.

Físicamente este subtipo se ve igual, pero se comporta más agresivo, según investigaciones en un grupo de pacientes que tienen el mismo tumor con distintas características.

3

75% de los pacientes se han librado de la enfermedad.

4

Se reportan entre un 7 a un 10% de los casos como Linfoma No Hodgkin (LNH).

¿Crónica de una muerte anunciada?

1999:

Se le detecta cáncer linfático. Recibe quimioterapia y aparentemente se cura.

6 de marzo de 2014: Última aparición en pٗúblico durante su cumpleaños.

31 de marzo de 2014 Se interna en el Instituto Nacional de Ciencias Médicas Salvador Zubirán.

16 de abril Nueve días después de dejar el hospital donde fue tratado por una infección pulmonar y de las vías urinarias, fallece en su casa de Ciudad de México.

Gabriel García Márquez Diseño y fuente: Revista Medicina y Salud Pública (MSP)

Treatment with XARELTO® helps raise the standards of thrombotic care and safeguard more lives CHRONIC CAD/PAD Significantly reduced a composite of CV death, MI, and stroke in combination with aspirin1

+

NVAF Proven stroke risk reduction in high-risk patients and an evidence-based prespecified renal dose2

+

DVT/PE Demonstrated to be superior to aspirin in reduction in the risk of recurrence†3 After 6 months initial treatment.

†

*XARELTO® 2.5 mg twice daily with aspirin (75 mg to 100 mg) once daily.

INDICATIONS XARELTO® is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

XARELTO® is indicated for the treatment of deep vein thrombosis (DVT). XARELTO® is indicated for the treatment of pulmonary embolism (PE). XARELTO® is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

XARELTO® is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

XARELTO® is indicated, in combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular [CV] death, myocardial infarction [MI], and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

IMPORTANT SAFETY INFORMATION WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO® increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal

CONTRAINDICATIONS

Active pathological bleeding Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of XARELTO® and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage.

• An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Because of high plasma protein binding, rivaroxaban is not dialyzable.

• Concomitant use of other drugs that impair hemostasis increases risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

CAD = coronary artery disease; CV = cardiovascular; DVT = deep vein thrombosis; MI = myocardial infarction; NVAF = nonvalvular atrial fibrillation; PAD = peripheral artery disease; PE = pulmonary embolism.

Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS, or visit www.XareltoHCP.com/PI.

WARNINGS AND PRECAUTIONS (cont’d)

B:11.75”

T:11.5”

S:10.3667”

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with concurrent use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO®. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®.

The next dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction.

Instruct patients to immediately report any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use in Patients with Renal Impairment: • Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute renal failure while on XARELTO®.

Clinical efficacy and safety studies with XARELTO® did not enroll patients with CrCl ≤30 mL/min or end-stage renal disease (ESRD) on dialysis.

• Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamics effects in this patient population.

• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamics effects in this patient population. Observe closely and promptly evaluate signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue treatment.

• Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15-30 mL/ min. In patients with CrCl ≤30 mL/min, a dose of 2.5 mg XARELTO® twice daily is expected to give an exposure similar to that in patients with moderate renal impairment, whose efficacy and safety outcomes were similar to those with preserved renal function. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis.

Use in Patients with Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased.

Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers.

Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

®

XARELTO is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2018 October 2018 cp-66067v1

Janssen Pharmaceuticals, Inc.

Patients with Prosthetic Heart Valves: Safety and efficacy of XARELTO® have not been studied in patients with prosthetic heart valves. Use of XARELTO® is not recommended in these patients.

Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

DRUG INTERACTIONS

Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding.

Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events.

XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding.

Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

USE IN SPECIFIC POPULATIONS

Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing.

Consider the benefits and risks of XARELTO® for the mother and possible risks to the fetus when prescribing to a pregnant woman.

• Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

• Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting.

• There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Postmarketing experience is currently insufficient to determine a rivaroxabanassociated risk for major birth defects or miscarriage.

Lactation: Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for XARELTO® and any potential adverse effects on the breastfed infant from XARELTO® or from the underlying maternal condition.

Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

OVERDOSAGE

Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

ADVERSE REACTIONS IN CLINICAL STUDIES

Most common adverse reactions with XARELTO® were bleeding complications.

cp-62551v2

IMPORTANT SAFETY INFORMATION (cont’d)

Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS, or visit www.XareltoHCP.com/PI. References: 1. Eikelboom JW, Connolly SJ, Bosch J, et al; for the COMPASS Investigators.

Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. 2. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883891. 3. Weitz JI, Lensing AWA, Prins MH, et al; for the EINSTEIN CHOICE Investigators.

Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):1211-1222.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3) in Full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in Full Prescribing Information].

B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1) in Full Prescribing Information].

Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions] WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the

XARELTO® (rivaroxaban) tablets transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.2, 2.3) and Clinical Studies (14.1) in Full Prescribing Information].

Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal antiinflammatory drugs (NSAIDs) [see Drug Interactions], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) in Full Prescribing Information]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations].

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population [see Use in Specific Populations].

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment [see Use in Specific Populations].

Use in Patients with Hepatic Impairment No clinical data are available for patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations].

Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions].

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions].

Risk of Pregnancy-Related Hemorrhage In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions].

Patients with Prosthetic Heart Valves The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the labeling: • Increased risk of stroke after discontinuation in nonvalvular atrial fibrillation [see Boxed Warning and Warnings and Precautions] • Bleeding risk [see Warnings and Precautions] • Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions]

Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days

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

During clinical development for the approved indications, 27,694 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

Hemorrhage The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Parameter

XARELTO Warfarin N=7111 N=7125 n (%/year) n (%/year)

Major Bleeding†

XARELTO vs. Warfarin HR (95% CI)

395 (3.6)

386 (3.5)

1.04 (0.90, 1.20)

55 (0.5)

84 (0.7)

0.67 (0.47, 0.93)

Hemorrhagic Stroke§

36 (0.3)

58 (0.5)

0.63 (0.42, 0.96)

Other ICH

19 (0.2)

26 (0.2)

0.74 (0.41, 1.34)

221 (2.0)

140 (1.2)

1.61 (1.30, 1.99)

27 (0.2)

55 (0.5)

0.50 (0.31, 0.79)

ICH

24 (0.2)

42 (0.4)

0.58 (0.35, 0.96)

Non-intracranial

3 (0.0)

13 (0.1)

0.23 (0.07, 0.82)

Intracranial Hemorrhage (ICH)‡

Gastrointestinal

(GI)¶

Fatal Bleeding#

Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Enoxaparin/ VKA† XARELTO† N=4130 N=4116 Parameter n (%) n (%) Major bleeding event 40 (1.0) 72 (1.7) Fatal bleeding 3 (<0.1) 8 (0.2) Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 (0.2) 29 (0.7) Intracranial‡ 3 (<0.1) 10 (0.2) 1 (<0.1) 8 (0.2) Retroperitoneal‡ Intraocular‡ 3 (<0.1) 2 (<0.1) 0 4 (<0.1) Intra-articular‡ Non-fatal non-critical organ bleeding§ 27 (0.7) 37 (0.9) Decrease in Hb ≥ 2 g/dL 28 (0.7) 42 (1.0) Transfusion of ≥2 units of whole blood or 18 (0.4) 25 (0.6) packed red blood cells Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.0) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/ VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 3: Bleeding Events* in EINSTEIN CHOICE XARELTO† 10 mg N=1127 n (%) 5 (0.4) 0 2 (0.2) 3 (0.3) 22 (2.0)

Acetylsalicylic Acid (aspirin)† 100 mg N=1131 n (%) 3 (0.3) 1 (<0.1) 1 (<0.1) 1 (<0.1) 20 (1.8)

Parameter Major bleeding event Fatal bleeding Non-fatal critical organ bleeding Non-fatal non-critical organ bleeding§ Clinically relevant non-major (CRNM) bleeding¶ Any bleeding 151 (13.4) 138 (12.2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. ¶ Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

Total treated patients Major bleeding event

XARELTO 10 mg

Enoxaparin†

N=4487 n (%)

N=4524 n (%)

14 (0.3)

9 (0.2)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

2 (<0.1)

3 (0.1)

Bleeding that required re-operation

7 (0.2)

5 (0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

4 (0.1)

1 (<0.1)

261 (5.8)

251 (5.6)

N=3281 n (%)

N=3298 n (%)

Any bleeding event‡ Hip Surgery Studies Major bleeding event

7 (0.2)

3 (0.1)

Fatal bleeding

1 (<0.1)

0

Bleeding into a critical organ

1 (<0.1)

1 (<0.1)

Bleeding that required re-operation

2 (0.1)

1 (<0.1)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

3 (0.1)

1 (<0.1)

201 (6.1)

191 (5.8)

N=1206 n (%)

N=1226 n (%)

7 (0.6)

6 (0.5)

0

0

Bleeding into a critical organ

1 (0.1)

2 (0.2)

Bleeding that required re-operation

5 (0.4)

4 (0.3)

Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells

1 (0.1)

0

60 (5.0)

60 (4.9)

Any bleeding event‡ Knee Surgery Study Major bleeding event Fatal bleeding

Any bleeding event‡

* Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication.

Patients may have more than one event. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

Table 5 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Table 5: Major Bleeding Events* in COMPASS - On Treatment Plus 2 days

Table 6: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction XARELTO 20 mg Enoxaparin/VKA EINSTEIN DVT Study N=1718 N=1711 n (%) n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) General disorders and administration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) XARELTO 20 mg Enoxaparin/VKA EINSTEIN PE Study N=2412 N=2405 n (%) n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator

Parameter Modified ISTH Major Bleeding‡

XARELTO plus Aspirin alone† XARELTO plus aspirin† N=9107 aspirin vs.

N=9134 Aspirin alone n (%/year) n (%/year) HR (95 % CI) 263 (1.6)

144 (0.9)

1.84 (1.50, 2.26)

12 (<0.1)

8 (<0.1)

1.51 (0.62, 3.69)

6 (<0.1) 6 (<0.1)

3 (<0.1) 5 (<0.1)

2.01 (0.50, 8.03) 1.21 (0.37, 3.96)

58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1)

43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1)

1.36 (0.91, 2.01) 1.09 (0.61, 1.98) 1.38 (0.68, 2.82) 0.67 (0.24, 1.88)

- Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)

7 (<0.1)

6 (<0.1)

1.17 (0.39, 3.48)

- Bleeding leading to hospitalization (nonfatal, not in critical organ, not requiring reoperation)

188 (1.1)

91 (0.5)

2.08 (1.62, 2.67)

117 (0.7)

49 (0.3)

2.40 (1.72, 3.35)

- Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial - Symptomatic bleeding in critical organ (non-fatal) ICH Hemorrhagic Stroke Other ICH

Major GI bleeding

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily, or aspirin 100 mg once daily ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.

CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Figure 2 shows the risk of modified ISTH major bleeding events across major subgroups.

Figure 2: Risk of Modified ISTH Major Bleeding Events by Baseline Characteristics in COMPASS – On Treatment Plus 2 Days

Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 6.

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 7.

Table 7: Other Adverse Drug Reactions* Reported by ≥1% of XARELTOTreated Patients in RECORD 1-3 Studies XARELTO 10 mg N=4487 n (%)

Enoxaparin† Body System N=4524 Adverse Reaction n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of doubleblind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Other clinical trial experience: In an investigational study of acute medically ill patients being treated with XARELTO 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

DRUG INTERACTIONS General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATPbinding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see Warnings and Precautions].

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established.

Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Lactation Risk Summary Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).

Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Geriatric Use Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in Full Prescribing Information].

Renal Impairment In pharmacokinetic studies, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl ≤30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar

XARELTO® (rivaroxaban) tablets to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD Patients with Chronic Kidney Disease not on Dialysis Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15-30 mL/min. In patients with CrCl ≤30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information], whose efficacy and safety outcomes were similar to those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. Hepatic Impairment In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho LLC Gurabo, PR 00778 or Bayer AG 51368 Leverkusen, Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

© 2011 Janssen Pharmaceutical Companies cp-62544v2

MSP ARTÍCULO ORIGINAL

Tumores cardíacos Por: José Lozada Costa, MD, FACP Hematólogo – Oncólogo Pasado Gobernador de la American College of Physicians, Capítulo de Puerto Rico

Resumen Los tumores cardíacos se definen como crecimientos neoplásicos anormales dentro del corazón o en sus válvulas. Hay varios tipos de tumores cardíacos, pero en general son muy poco comunes. Hay dos clasificaciones básicas: benignos vs. malignos, y primarios (de origen de células del corazón) vs metastásicos.

Las metástasis al corazón son mucho más frecuentes, y en algunas series de autopsias se han reportado dichas lesiones en más del 8% de pacientes que han muerto de cáncer. Estos más comúnmente provienen de pulmones, seno, estómago, riñones, hígado, o colon, pero también se han descrito en linfoma, leucemia, y melanoma.

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Revista Puertorriqueña de Medicina y Salúd Pública

Abstract Cardiac tumors are defined as abnormal neoplastic growths within the heart or in their valves. There are several types of heart tumours, but in general they are very rare.

There are two basic classifications: benign vs. Malignant, and primary (source of heart cells) vs metastatic. Metastases to the heart are much more frequent, and in some series of autopsies, these lesions have been reported in more than 8% of patients who have died of cancer. These most commonly come from lungs, sinus, stomach, kidneys, liver, or colon, but have also been described in lymphoma, leukemia, and melanoma.

MSP ARTÍCULO ORIGINAL

Palabras claves Tumores cardíacos, clasificación, neoplasias, metástasis, Corazón Keywords Cardiac tumors, classification, neoplasms, metastases, heart.

Revista Puertorriqueña de Medicina y Salúd Pública

25

MSP ARTÍCULO ORIGINAL

Introducción Los tumores cardíacos se definen como crecimientos neoplásicos anormales dentro del corazón o en sus válvulas. Hay varios tipos de tumores cardíacos, pero en general son muy poco comunes.

Hay dos clasificaciones básicas: benignos vs. malignos, y primarios (de origen de células del corazón) vs. metastásicos.

Los tumores primarios son los menos frecuentes, su incidencia menos de 10 en 12,000 (menos de 0.1%).

Por lo general, el 75% de estos son benignos, siendo el mixoma el más común. Otros tumores benignos incluyen fibroelastomas papilares y lipomas. En niños, los más comunes son los rabdomiomas y fibromas.

Las metástasis al corazón son mucho más frecuentes.

De hecho, en algunas series de autopsias se han reportado dichas lesiones en más del 8% de pacientes que han muerto de cáncer. Éstas más comúnmente provienen de pulmones, seno, estómago, riñones, hígado, o colon, pero también se han descrito en linfoma, leucemia, y melanoma.

y causar arritmias, o intracavitarios y causar embolismo sistémico.

Evaluación Es claro entonces que, la mayoría de síntomas serán cardiorrespiratorios. Por lo tanto, la evaluación inicial de cualquier paciente con tales quejas debe incluir estudios para descartar la presencia de un tumor. Para confirmar este diagnóstico, los estudios de imagen son los más importantes para el cardiólogo.

La ecocardiografía es la principal Simple, no invasiva, y accesible. Nos da información valiosa sobre el miocardio así como de las válvulas y recámaras del corazón. En la mayoría de los casos, esta técnica detecta la presencia del tumor y describe su movilidad. Aunque mayormente se puede hacer transtorácica, la técnica transesofágica nos puede dar información adicional o aclarar cuadros clínicos dudosos.

Resonancia Magnética (MRI) Signos y síntomas Es la modalidad preferida para caracterizar los Sin embargo, las manifestaciones clínicas de estos tumores cardiacos de modo radiológico. Provee al tumores tienden a ser independientes del tipo de tumor. especialista imágenes anatómicas de alta calidad, y las Lo que determina los signos y síntomas del paciente secuencias T1 y T2 pueden dar información sobre el es la localización del tumor dentro del corazón. Los microambiente químico del tumor. mecanismos de tratamiento para estas anomalías son variadas: embolización, típicamente sistémica, Tomografía Computarizada (CT) obstrucción de la circulación, afectar la función Esta modalidad es útil si el MRI está contraindicado. valvular, invasión directa del miocardio o estructuras Las imágenes tienden a ser aún más claras, pero da cercanas, y síntomas constitucionales. menos información fisiológica sobre el tumor.

En términos de localización Angiografía Coronaria • Aurícula izquierda: obstrucción de la luz, Estudiar la vascularidad del tumor es esencial para regurgitación mitral, embolia de fragmentos planificar la escisión y determinar qué arterias hay que tumorales o trombos. alterar.

• Aurícula derecho: síntomas de estenosis tricuspídea y fallo cardíaco derecho.

• Ventrículo derecho: obstrucción del vaciamiento, dando síntomas típicos de fallo cardíaco derecho.

• Ventrículo izquierdo: pueden ser intramurales 26

Revista Puertorriqueña de Medicina y Salúd Pública

Biopsia En general se hace de modo transvenoso. Sin embargo, todavía no es claro cuán beneficioso resulta el procedimiento antes de una cirugía. Se considera útil solo si es necesario para tomar la decisión terapéutica y si los posibles beneficios son mayores que los riesgos.

MSP ARTÍCULO ORIGINAL

“RECIENTEMENTE SE HA ESTUDIADO EL TRASPLANTE DE CORAZÓN COMO OPCIÓN PARA PACIENTES QUE NO TENGAN ENFERMEDAD FUERA DEL CORAZÓN”

Tumores Benignos

al corazón por vía sanguínea, invasión directa, o crecimiento directo del tumor desde la vena cava hasta Mixomas la aurícula derecha (típico de cáncer de riñón). Debemos La gran mayoría de los tumores benignos del corazón. pensar en metástasis cardíacas o pericárdicas en El 80% de éstos ocurren en la aurícula izquierda y casi cualquier paciente con cáncer que desarrolle síntomas todos los demás en la aurícula derecha. Alto riesgo de cardiovasculares nuevos. Por lo general, los tumores complicaciones cardiovasculares y embolia. Dentro de secundarios surgen como consecuencia de los siguientes esta categoría se agrupan los siguientes tipos de tumores: tipos de cáncer: • • • • • • •

Fibroelastomas papilares Rabdomiomas Fibromas Teratomas Hamartomas Lipomas-fibrolipomas Hipertrofia lipomatosa del septo interauricular

Tumores que pueden ser benignos o malignos • Paragangliomas • Mesotelioma Tumores Malignos Cabe destacar que son extremadamente poco comunes.

Sarcomas El tipo más común de esta categoría. Usualmente crecen rápidamente y causan la muerte por su infiltración del miocardio, obstrucción circulatoria, o metástasis. De ellos, el 40% son angiosarcomas. Dentro de los menos comunes se clasifican los siguientes: rabdomiosarcoma, fibrosarcoma, leiomiosarcoma, liposarcoma, y sarcoma sinovial.

• Linfomas • Plasmacitomas extramedulares Tumores Secundarios Anomalía relativamente común. Pueden llegar

• • • • • • • • • •

Melanomas Pulmón Seno Sarcomas Riñón Esófago Hepatocelular Tiroides Leucemia Linfoma

Tratamiento El tratamiento principal de estos tumores es la cirugía.

En el caso de los tumores benignos, esta es curativa en la mayor parte de los casos. En los mixomas, en particular, la tasa de recaídas luego de resección es menos del 5%.

En los demás tumores benignos hay muy pocos casos registrados en estadísticas confiables, pero en general el pronóstico es muy bueno si se hace una resección completa.

Los sarcomas son muy agresivos y tienden a invadir temprano en su curso. Aunque el paciente esté tratado con terapia curativa requiere cirugía. Estudios recientes demuestran que con quimioterapia preoperatoria hay mejores posibilidades de llegar a resección. Sin embargo, el pronóstico sigue siendo problemático: La tasa de sobrevida a uno, tres, y cinco años es aproximadamente 47, 16, y 11%, respectivamente.

Recientemente se ha estudiado el trasplante de corazón como opción para pacientes que no tengan enfermedad fuera del corazón. La gran mayoría reciben Revista Puertorriqueña de Medicina y Salúd Pública

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quimioterapia y radioterapia previo al trasplante. En los pacientes que son candidatos, esto parece mejorar el pronóstico.

Los linfomas y leucemias se tratan con quimioterapia e inmunoterapia. La efectividad en esos casos depende más que nada en el subtipo de linfoma-leucemia. A pesar de ello, muchos son curables.

Las metástasis al corazón son parte de una enfermedad incurable. Pero a menudo responden a la quimioterapia que se usa para el tumor primario. En general no se operan, pero en pacientes cuidadosamente selectos, se pueden operar para

mejorar el control de síntomas y sobrevida.

En resumen, los tumores cardíacos no son muy comunes, en particular los primarios del corazón. La gran mayoría son benignos y se curan con cirugía. Los tumores malignos y las metástasis son más retantes, y su tratamiento depende del tumor primario y del cuadro clínico del paciente. Lo más importante es tener un alto nivel de sospecha, y descartarlos en cualquier paciente que desarrolle síntomas cardiovasculares de súbito, particularmente arritmias, embolias sistémicas, y fallo cardíaco derecho.

Referencias:

Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (Eds), IARC Press, Lyon 2004. p.287.

14. Cooley DA. Surgical treatment of cardiac neoplasms: 32-year experience. Thorac Cardiovasc Surg 1990; 38 Suppl 2:176.

15. Vander Salm, TJ. Mediastinal pheochromocytoma. Worcester, University of Massachusetts Medical Center. Society of Thoracic Surgeons, Surgical Motion Pictures 1994.

16. Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart.

Cancer 1992; 69:387.

17. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. World Health Organization Classification of tumours of soft tissue and bone, 4th ed, IARC Press, Lyon 2013.

18. Uberfuhr P, Meiser B, Fuchs A, et al. Heart transplantation: an approach to treating primary cardiac sarcoma? J Heart Lung Transplant 2002; 21:1135.

19. Talbot SM, Taub RN, Keohan ML, et al. Combined heart and lung transplantation for unresectable primary cardiac sarcoma. J Thorac Cardiovasc Surg 2002; 124:1145.

20. Blackmon SH, Reardon MJ. Surgical treatment of primary cardiac sarcomas. Tex Heart Inst J 2009; 36:451.

21. Ikeda H, Nakamura S, Nishimaki H, et al. Primary lymphoma of the heart: case report and literature review. Pathol Int 2004; 54:187.

22. Nakagawa Y, Ikeda U, Hirose M, et al. Successful treatment of primary cardiac lymphoma with monoclonal CD20 antibody (rituximab). Circ J 2004; 68:172.

23. Khankirawatana B, Ginete WL. Primary extramedullary plasmacytoma of the heart. Clin Cardiol 2004; 27:368.

24. Reynen K, Köckeritz U, Strasser RH. Metastases to the heart.

Ann Oncol 2004; 15:375.

25. Messner G, Harting MT, Russo P, et al. Surgical management of metastatic melanoma to the ventricle. Tex Heart Inst J 2003; 30:218.

1. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol 1996; 77:107.

2. Salcedo EE, Cohen GI, White RD, Davison MB. Cardiac tumors: diagnosis and management. CurrProblCardiol 1992; 17:73.

3. Silvestri F, Bussani R, Pavletic N, Mannone T. Metastases of the heart and pericardium. G Ital Cardiol 1997; 27:1252.

4. Lee VH, Connolly HM, Brown RD Jr. Central nervous system manifestations of cardiac myxoma. Arch Neurol 2007; 64:1115.

5. Engberding R, Daniel WG, Erbel R, et al. Diagnosis of heart tumours by transoesophageal echocardiography: a multicentre study in 154 patients. European Cooperative Study Group. Eur Heart J 1993; 14:1223.

6. Constantine G, Shan K, Flamm SD, Sivananthan MU. Role of MRI in clinical cardiology. Lancet 2004; 363:2162.

7. Gulati G, Sharma S, Kothari SS, et al. Comparison of echo and MRI in the imaging evaluation of intracardiac masses. Cardiovasc InterventRadiol 2004; 27:459.

8. Hoey ET, Mankad K, Puppala S, et al. MRI and CT appearances of cardiac tumours in adults. Clin Radiol 2009; 64:1214.

9. Molina JE, Edwards JE, Ward HB. Primary cardiac tumors: experience at the University of Minnesota. Thorac Cardiovasc Surg 1990; 38 Suppl 2:183.

10. Tazelaar HD, Locke TJ, McGregor CG. Pathology of surgically excised primary cardiac tumors. Mayo Clin Proc 1992; 67:957.

11. Centofanti P, Di Rosa E, Deorsola L, et al. Primary cardiac tumors: early and late results of surgical treatment in 91 patients. Ann Thorac Surg 1999; 68:1236.

12. Bakaeen FG, Reardon MJ, Coselli JS, et al. Surgical outcome in 85 patients with primary cardiac tumors. Am J Surg 2003; 186:641.

13. Pathology and genetics of tumours of the lung, pleura, thymus, and heart. In: World Health Organization classification of tumours,

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Manejo cardiovascular en el paciente con cáncer: nuevas estrategias Por: Gilberto Rivera Gautier, MD, FACC, RPVI

Board Certified por la American Board of Internal Medicine en Medicina Interna y Enfermedades Cardiovasculares Presidente de la Sociedad Puertorriqueña de Cardiología Director del Laboratorio Cardiovascular Invasivo y Laboratorio Cardiovascular No-Invasivo del Hospital Auxilio Mutuo

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Resumen: Los daños cardiovasculares en pacientes con cáncer deben ser analizados exhaustivamente con base en la malignidad que se trata el individuo, la primera opción del tratamiento definida por el oncólogo y el historial clínico. De estos y otros factores dependerá el riesgo que presente el paciente con cáncer de desarrollar enfermedad cardiovascular y de la cardiotoxicidad inducida por los fármacos y agentes químicos a los que los pacientes deben ser sometidos. Por ende, en este artículo se exponen nuevos métodos que minimizan los riesgos y destacan la importancia del trabajo multidisciplinar.

Abstract: Card iovascular damage in cancer patients should be analyzed exhaustively based on the malignancy presented by the individual, the first choice of treatment defined by the oncologist and the clinical record. Of these and other factors will depend the risk that the cancer patient develops cardiovascular disease and of the cardio-toxicity induced by the drugs and chemical agents to which the patients should be subjected. This article sets out new methods that minimize risks and emphasize the importance of multidisciplinary work.

Palabras clave: Enfermedad cardiovascular, cáncer, cardiotoxicidad, tratamiento

Key Words: Cardiovascular disease, cancer, cardiac toxicity, treatment

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“El manejo cardiovascular del paciente con cáncer debe comenzar con un análisis de riesgo del paciente, combinando los factores de riesgo cardiovascular preexistentes con el riesgo de cardiotoxicidad del medicamento a utilizarse”

L

a evaluación y manejo de pacientes con cáncer y enfermedad cardiovascular debe tomar en consideración la etiología de la enfermedad cardiovascular y el tipo de terapia recibida. Podemos encontrarnos con pacientes con cáncer y enfermedad cardiovascular primaria concurrente, así como pacientes con cáncer que desarrollan enfermedad cardiovascular como complicación del tratamiento para el propio cáncer.

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“LOS PACIENTES DE CÁNCER SE ENCUENTRAN EN RIESGO DE DESARROLLAR PROBLEMAS CARDIOVASCULARES SIGNIFICATIVOS ASOCIADO AL TRATAMIENTO RECIBIDO” Hemos definido la presencia de cardiotoxicidad inducida por quimioterapia como una disminución en la fracción de expulsión del ventrículo izquierdo igual o mayor del 5 % a una función menor de 55% en un paciente con una presentación clínica de fallo cardíaco, o, una disminución igual o mayor a un 10% a una función menor de 55% en un paciente asintomático.

Tomando en consideración los posibles efectos cardiovasculares de agentes farmacológicos, considerados cardiotóxicos, podemos dividirlos en diferentes grupos: los que afectan primordialmente la función cardíaca (ej. antraciclinas y trastuzumab), los que afectan la función vascular (ej. 5-fluorouracil y capecitabine) y los que afectan ambos (ej. bevacizumab y sunitinib). La terapia de radiación puede ser causante de daño cardiovascular en diferentes niveles, incluyendo daño al miocardio, pericardio, aparatos valvulares y vasos sanguíneos (ej. arterias coronarias).

La cardiotoxicidad inducida por quimioterapia ha sido clasificada en 2 grupos: la tipo 1, caracterizada por daño estructural irreversible al músculo cardíaco -típicamente encontrada con el tratamiento con antraciclinas- y la tipo 2, caracterizada por ausencia de anormalidades estructurales y reversibilidad posible -típicamente encontrada con el tratamiento con trastuzumab-. Se ha observado el desarrollo de enfermedad cardiovascular más agresiva en pacientes que reciben la combinación de farmacoterapia con potencial cardiotóxico y radioterapia.

El manejo cardiovascular del paciente con cáncer debe comenzar con un análisis de riesgo del paciente, combinando los factores de riesgo cardiovascular preexistentes con el riesgo de cardiotoxicidad del medicamento a utilizarse. La combinación de estos factores nos permiten establecer una puntuación de riesgo para cardiotoxicidad, utilizado para dictar las recomendaciones de monitoreo y manejo previo, durante y después del tratamiento. El electrocardiograma y ecocardiograma son frecuentemente utilizados como 36

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herramienta para la estratificación de los pacientes.

Una vez iniciado el tratamiento del paciente, se debe decidir si se requiere un seguimiento cardiovascular tomando en cuenta el perfil de riesgo cardiovascular de base, el régimen de tratamiento para cáncer utilizado y el desarrollo de síntomas cardiovasculares o eventos cardiovasculares mayores.

Los primeros protocolos validados para monitoreo cardiovascular de lo pacientes con cáncer tratados con antraciclinas fueron desarrollados para las décadas de los 70’s-80’s. Éstos se sustentaron con estudios de ventriculografía por radionucleótidos (MUGA) que permitían identificar cambios en la función ventricular previo el desarrollo de fallo cardíaco clínico. Estas pruebas nucleares han sido paulatinamente sustituidas por la ecocardiografía bidimensional. Recientemente, la ecocardiografía bidimensional con contraste y la ecocardiografía tridimensional han sido considerados como herramientas comparables al MUGA (Multigated Analysis) en su capacidad de evaluación de función ventricular, añadiendo también la posibilidad de evaluación de otra área del corazón como el pericardio, válvulas y otros datos hemodinámicos. La modalidad en ecocardiograma del “strain rate imaging” ha sido más introducida en la evaluación cardíaca y permite identificar ciertas deformidades en el músculo del corazón, que tienden a preceder el proceso de disminución en contracción cardíaca. Esta modalidad permite una identificación aún más temprana del paciente a riesgo de desarrollo de cambios en función cardíaca por toxicidad. El biomarcador que mejor ha demostrado capacidad de predicción de cardiotoxicidad ha sido la cTn, aunque su utilidad no ha superado la evaluación con ecocardiografía.

El tratamiento de pacientes con cardiomiopatía por cardiotoxicidad asociada a terapia de cáncer debe realizarse con base en las recomendaciones establecidas por la Asociación Americana del Corazón/Colegio Americano de Cardiología (AHA/ACC). El uso de los agentes inhibidores de la enzima convertidora de angiotensina (ECA) son considerados como primera línea de tratamiento en pacientes con reducción de contracción cardíaca. El uso de los bloqueadores de receptores de angiotensina (ARB) pueden ser utilizados en pacientes con intolerancia a los inhibidores de ECA. El uso de inhibidores de aldosterona puede ser considerado en pacientes con síntomas de fallo cardíaco y una función menor o igual al 35%. Los bloqueadores beta -particularmente carvedilol- son considerados el segundo grupo mayor de medicamentos a ser

utilizados en el tratamiento de cardiomiopatía y, en combinación con los inhibidores de ECA, han demostrado un efecto significativo en mejoría de función cardíaca. El uso de sacubitril (un inhibidor de neprilisin) con valsartan (un bloqueador de receptor de angiotensina) ha demostrado una reducción significativa en mortalidad y hospitalización de pacientes con fallo cardíaco y reducción de la fracción de expulsión. Esta terapia, sin embargo, no ha sido validada en pacientes de cardiomiopatía por tratamiento de cáncer; pero si eventualmente pudiera demostrarse su beneficio, se convertiría en una valiosa herramienta.

Los pacientes que fallan a la terapia médica podrían beneficiarse de dispositivos para apoyo hemodinámico como terapia aguda temporera o como puente para trasplante cardíaco. El uso de desfibrilador automático implantable puede también considerarse en pacientes con cardiomiopatía severa y/o arritmias malignas cuya sobrevida esperada es mayor a un año y tomando en consideración otros aspectos clínicos asociados al pronóstico general.

El pobre pronóstico asociado a la cardiomiopatía inducida por terapia de cáncer, ha promovido el desarrollo de protocolos de tratamiento preventivo utilizando los agentes cardiovasculares disponibles y el desarrollo de nuevos agentes. Dexrazoxane, un agente quelante intracelular, ha demostrado una reducción significativa de fallo cardíaco, pero su utilidad ha sido limitada por su reducción en el efecto antitumoral de los tratamientos. Los betabloqueadores que han demostrado mayor beneficio en estos pacientes han sido el carvedilol y nebivolol. La evidencia del uso de estatinas como prevención para cardiomiopatía es limitada, pero se ha recomendado su consideración en pacientes de alto riesgo. El uso rutinario de terapia preventiva para cardiotoxicidad debe ser considerado en pacientes con un índice de riesgo alto según se establezca al evaluar sus factores preexistentes y el tipo de terapia a recibirse.

En conclusión, los pacientes de cáncer se encuentran en riesgo de desarrollar problemas cardiovasculares signif icativos asociado al tratamiento recibido. Una evaluación temprana y manejo por un equipo multidisciplinario cardiooncológico es una gran herramienta para la detección temprana y manejo apropiado para contribuir a una mejor sobrevida y calidad de vida de los afectados.

Conoce el nuevo

Oncológico de Ponce.

San Cristóbal Cancer Institute Radioterapia Braquiterapia Cirugía Radiocirugía

Nutrición Cuidado Paliativo Medicina Integrativa Psicología

SANCRISTOBALCANCER.COM

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Malignidad en los pacientes trasplantados de corazón,

un peligro subyacente Por: David Bragin Sánchez, MD FACC, FESC, FISC Especialista en fallo cardíaco y trasplante de corazón Jefe de la sección de cardiología Rockwood Heart and Vascular Expresidente de la Sociedad Puertorriqueña de Cardiología Spokane, Washington

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Palabras clave Trasplante de corazón, Cáncer, Malignidades, Tratamiento, Consideraciones

Key words Heart transplant, cancer, malignancies, treatment, considerations

Resumen El trasplante de Corazón es la terapia más efectiva para aquellos pacientes con fallo cardíaco terminal.

Tras el trasplante de corazón hay muchas posibles complicaciones y la malignidad se convierte en la causa más común de muerte según progresa la vida del paciente trasplantado. Este artículo hará una revisión de las publicaciones disponibles para discutir el manejo de medicamentos, cernimiento y educación del paciente trasplantado de corazón para reducir el riesgo de muerte y morbilidad causada por malignidad.

Abstract Heart transplant is the best available therapy for patient with end stage heart disease. After cardiac transplantation there are multiple possible complication and malignancy becomes the leading cause of death as the life of the transplanted patient progresses. This article will review the available literature and will discuss medication management as well as patient follow up and education to reduce the morbidity and mortality of malignancy in the heart transplant patient.

Introducción Al momento, la terapia más efectiva para un paciente con fallo cardíaco terminal es el trasplante de corazón. Esta terapia ofrece no solo una mayor sobrevida sino mejor calidad de vida, pero no es una terapia curativa. Se podría argumentar -en una forma muy objetiva- que se intercambia una patología por otra. Después de un trasplante la intensidad de tratamiento y seguimiento médico se

intensifica. Las causas de mortalidad y morbilidad cambian y entre éstas, el cáncer se ha convertido en una de las patologías más importantes, además asociada a una mayor mortalidad.

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Estadísticas Según las más recientes estadísticas de la Sociedad Internacional de Trasplante de Corazón y Pulmón (ISHLT por sus siglas en ingles) en 2016 a nivel

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Figura 1 Causas de muerte en el paciente trasplantado de corazón seguimiento médico -3.5 veces más que otro tipo de

mundial se hicieron un poco menos de 6000 trasplantes de corazón la mayoría en Estados Unidos, Canadá y Europa1. La supervivencia después de un trasplante de corazón es sobre un 85% a un año y 73% a 5 años (Figura 1). La evolución de la terapia inmunosupresora ha prolongado la vida de los pacientes, pero también juega un rol muy importante en el desarrollo de complicaciones como infección y malignidad. Es claro que según los inmunosupresores usados, la dosis de éstos y el uso de una terapia de inducción al momento de trasplante, la supervivencia de los pacientes ha mejorado desde ese primer trasplante de corazón en 1967.

Malignidad de novo en el paciente trasplantado de corazón Los receptores de trasplantes en general están a mayor riesgo de desarrollar cáncer. Es importante y necesario resaltar que la incidencia de cáncer en los trasplantados de corazón es mayor que la de otros tipos de órganos trasplantados2,3. Los mecanismos moleculares y celulares para desarrollar cáncer son los mismos que en la población general: el crecimiento celular descontrolado y sostenido, resistencia a apoptosis causando inmortalización de líneas celulares, la inhibición de supresores de tumor con la disrupción de material genético y disrupción de los mecanismos para reparar dicho material genético, la disminución en inmunidad viral incluyendo oncogenes y claro está, los mecanismos de invasión local y metástasis4.

No solo la inmunosupresión afecta todos los elementos mencionados. También lo hacen las características del donante y las del receptor del órgano, ya que éstas van a influir en el desarrollo de malignidad (Figura 2). Se cree que la cantidad de radiación médica que reciben los pacientes de trasplante cardíaco como parte de su

trasplantes- está relacionado a la mayor incidencia de cáncer en la población de trasplante cardíaco6. El riesgo de malignidad va de un 2.9% en el primer año a 31.9% a los 10 años de trasplantado. Los tipos de cáncer más comunes en la población trasplantada de corazón son el cáncer de piel de célula escamosa, sarcoma de Kaposi, cáncer de pulmón, linfoma y malignidades urológicas5. Estas malignidades se tienden a portar en una forma más agresiva e invasiva que en los pacientes no trasplantados. La sobrevida de cáncer de pulmón es de solo 21% a los 5 años y el cáncer de próstata teniendo un buen pronóstico con una sobrevida de 86% a los 5 años7. El desorden linfoproliferativo postrasplante es el segundo tipo de cáncer más común en los pacientes trasplantado de corazón y tiene una incidencia de alrededor de 10%, una cifra mayor que en otros tipos de trasplantes. Este desorden está relacionado a un órgano infectado con el virus de Epstein-Barr trasplantado a un receptor no infectado. Por ello, el ajuste de la terapia de inmunosupresión es una forma efectiva de tratar esta condición aunque esta sigue teniendo una pobre sobrevida de un 32% a los 5 años.

Historial de malignidad previa en el paciente trasplantado de corazón En Puerto Rico -donde a diferencia del resto del planeta la primera causa de muerte es cáncer y no la enfermedad cardiovascular- tenemos que considerar dos poblaciones, en especial la población con cáncer previo y la población que desarrolla cardiomiopatía secundaria a quimioterapia. La sobrevida de esta población ha aumentado a tal punto que mucho tienen que ser considerados para trasplante de corazón, más aún con el advenimiento de terapias como los dispositivos de circulación mecánica implantables (LVAD por sus siglas en inglés). La mayoría de los programas de trasplante consideran un paciente de cáncer curado si permanece 5 años libre de la malignidad. Se ha visto que estos pacientes con historial de cáncer previo tienden a desarrollar cáncer 1.8 veces con mayor frecuencia que otros trasplantados de corazón. Además, se caracterizan por desarrollar cáncer a un tiempo más temprano, lo que conlleva a una mayor mortalidad2. El historial de tumores hematológicos conlleva un mayor riesgo de malignidad. Las malignidades más comunes en esta población con historial de cáncer son cáncer de Revista Puertorriqueña de Medicina y Salúd Pública

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Figura 2

“Es importante y necesario resaltar que la incidencia de cáncer en los trasplantados de corazón es mayor que la de otros tipos de órganos trasplantado” reduce el riesgo de linfoma por 50%4. Además se ha visto que el uso de estatinas puede reducir el riesgo de malignidad por un 42% y aumenta la sobrevida de los pacientes trasplantados de corazón 8.

piel tipo no-melanoma seguido por cáncer de pulmón.

Medicamentos Según han evolucionado los medicamentos que se usan para inmunosupresión, inducción y profilaxis se ha visto que hay unos que tienen efectos favorables en la prevención de malignidades.

En la inducción con muromonabCD3 (OKT3) se ha asociado con mayor incidencia de malignidad a diferencia de los anticuerpos del receptor de IL-2, rATG y globulina de anti-timocito se asocian con menor incidencia de cáncer mientras que alemtuzumab tiene un efecto neutro. En la inmunosupresión, el uso de tacrolimus se asocia con menos malignidad que ciclosporina, micofenolato de mofetil (MMF), al igual que sirolimus y everolimus se asocian con menor malignidad e inclusive se prefiere su uso cuando presentan con malignidad los pacientes trasplantados. El uso de aciclovir de forma profiláctica, por los primeros tres meses postrasplantes, 40

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Consideraciones en el manejo del paciente trasplantado de corazón Las consideraciones de prevención de malignidad tienen que incluir planes de cernimiento agresivo que deben tomar en cuenta el historial de malignidad previa, factores de riesgo e historial familiar de cada paciente.

Debemos considerar cómo reducir la exposición a radiación médica de los pacientes trasplantados. Educar al paciente en la importancia del seguimiento médico, dietas altas en fibra y el uso de protector solar y limitar su exposición al sol.

También se debe evaluar el balance apropiado de inmunosupresión con reducción rápida y eliminación de esteroides, donde se hacen ajustes basados en niveles de medicamentos que se correlacionan con el metabolismo de cada paciente de estos medicamentos. No se deben olvidar los factores de riesgo de cada paciente, incluyendo la edad, pues pacientes más ancianos quizás requieren menos inmunosupresión.

Hoy en día, los profesionales de la salud debemos practicar una medicina centrada en el paciente y su educación para que pueda tomar decisiones apropiadas. Es de suma importancia hablar con el

paciente que se está considerando para trasplante cardíaco sobre todo lo que envuelve un trasplante incluyendo el riesgo de malignidad.

Referencias

1. K. K Khush et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth Adult Heart Transplantation Report – 2018; Focus Theme: Multiorgan Transplantation.

The Journal of Heart and Lung Transplantation, Vol 37, No 10 October 2018 1155-68 2. J. F. Delgado et al. Cancer Incidence in Heart Transplant Recipients With Previous Neoplasia History. American Journal of Transplantation 2016; 16; 1569-78 3. JC Youn et al. Temporal Trends of De Novo Malignancy Development After Heart Transplantation. Journal of the American College of Cardiology Vol 71; No 1; 40-49 4. N.Nairet al. Long term immunosuppression and malignancy in thoracic transplantation: Where is the balance. The Journal of Heart and Lung Transplantation, Vol 33, No 5 May 2015; 461-7 5. N. Lateef et al. Malignancies After Heart Transplant. Experimental and Clinical Transplantation (2016) 1:12-16 6. U. N. Vainrib et al. Mediastinal radiation and adverse outcomes after heart transplantation.

The Journal of Heart and Lung Transplantation, Vol 29; 2010; 378-81 7. R. S. Higgins et al. A multi-institutional study of malignancies after heart transplantation and a comparison with the general United States population. The Journal of Heart and Lung Transplantation, Vol 33, No 5 May 2014 478-85 8. G. M. Frohlich et al. Statins and the Risk of Cancer After Heart Transplantation.

Circulation 2012; 126; 440-447

6TO

SIMPOSIO CARDIOVASCULAR

SAN LUCAS CARDIAC OVERVIEW

SAVE THE DATE SÁBADO, 23 DE FEBRERO DE 2019 Complejo Ferial de Ponce

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Descubra todo sobre las nuevas tendencias en este simposio educativo.

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La quimioterapia y el corazón

42

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Por: Luis A. Rosado Carrillo MD, FACC, FISC Cardiólogo Expresidente de la Sociedad Puertorriqueña de Cardiología

Resumen La quimioterapia es una de las formas más utilizadas para tratar el cáncer y algunas condiciones asociadas. Sin embargo, los fármacos utilizados en este procedimiento pueden afectar el funcionamiento del corazón. A este daño provocado por la quimioterapia se le llama toxicidad cardíaca.

Abstract Chemotherapy is one of the most used ways to treat cancer and some associated conditions. However, the drugs used in this procedure can affect the functioning of the heart. This damage caused by chemotherapy is called cardiac toxicity.

Introducción Por décadas, la quimioterapia ha sido el tratamiento más utilizado para tratar un sinnúmero de condiciones relacionadas con el cáncer. Por ello, es importante entender que el beneficio del uso de estos fármacos en la inmensa mayoría de los casos va por encima de los riesgos de toxicidad que estos tratamientos pueden causar en el organismo. En este artículo vamos a hablar específicamente del daño que estos medicamentos pueden causar al corazón y como prevenirlos.

Toxicidad cardíaca, es el daño que ocurre al corazón por quimioterapia. Primero, cabe destacar que no todas las quimioterapias son tóxicas al corazón. Sin embargo, el fármaco más común relacionado a toxicidad cardíaca es la doxorrubicina. La doxorrubicina es un tipo de fármaco de quimioterapia llamado antraciclina. Las antraciclinas se pueden utilizar para tratar leucemia, linfoma, mieloma múltiple y con frecuencia, también en el tratamiento del cáncer de mama.

Signos y síntomas En los pacientes donde ocurre daño por el uso de estos fármacos, lo más frecuente es el desarrollo de fallo cardíaco, lo que significa que el fármaco promueve debilidad al músculo cardíaco. Como consecuencia, esto hace al corazón incapaz de bombear la cantidad suficiente de sangre con oxígeno para suministrarle al cuerpo. Estos pacientes presentan principalmente fatiga al mínimo esfuerzo, debilidad, retención de líquidos, molestia o dolor en el pecho, palpitaciones, arritmias cardíacas, alta presión y en algunos casos infarto cardíaco. También, puede presentar desórdenes de coagulación.

Palabras clave Quimioterapia, toxicidad cardíaca, corazón, problemas cardiovasculares.

Key words Chemot her apy, ca rd iac toxicity, heart, cardiovascular problems.

Tratamiento ¿Cómo se puede prevenir la toxicidad cardíaca? Los problemas cardíacos se pueden prevenir modificando la dosis del fármaco administrado, el método de administración y el tipo de antraciclina. Los predictores de cardiotoxicidad incluyen también los factores de riesgo cardiovasculares previos al tratamiento y la edad del paciente. Es extremadamente importante que antes de ser sometido al tratamiento se sepa qué tan bien o mal se encuentra el corazón del paciente en términos de su función.

Por tal razón, es que frecuentemente el oncólogo envía al paciente a realizarse una evaluación con el cardiólogo para conocer su riesgo antes de comenzar el tratamiento y ofrecerle (en los casos meritorios) terapias que pueden reducir su riesgo de desarrollo de complicaciones, principalmente de fallo cardíaco. Las terapias pueden incluir, pero no limitarse, a inhibidores de la ECA, betabloqueadores y diuréticos. Es también muy común que el cardiólogo continúe el monitoreo cardíaco durante el tratamiento oncológico, dependiendo del tipo de quimioterapia que reciba el paciente. El monitoreo también puede continuar después del tratamiento.

Conclusión Cabe destacar que las terapias oncológicas en la inmensa mayoría de los casos prolongan y/o salvan vidas. La toxicidad cardíaca es algo que es prevenible y muy fácil de cuantificar si se da el seguimiento apropiado. Siguiendo las recomendaciones del oncólogo y el cardiólogo trabajando como equipo, podremos reducir significativamente los riesgos.

Revista Puertorriqueña de Medicina y Salúd Pública

43

MSP ARTÍCULO DE INVESTIGACIÓN

Prevalencia del dolor de cabeza en Puerto Rico Por: Héctor Miranda, MD, Gilberto Ortíz,BS Sandra Figueroa, BS, Diana Peña, BA, Josué Guzmán, PhD

Palabras claves: Key words: Prevalencia, migraña, dolor de cabeza, investigación, Prevalence, migraine, headache, investigation, Puerto Puerto Rico Rico

44

Resumen El dolor de cabeza es una de las quejas más frecuentes reportadas en la población en general.

A pesar del hecho de que esta condición es común, las características epidemiológicas han sido durante mucho tiempo imprecisas y propensas a la interpretación individual. En Puerto Rico, una isla caribeña con una población cercana a los 4 millones, ningún estudio epidemiológico sobre el dolor de cabeza o la migraña en particular, está disponible.

Abstract: Headache is one of the most common complaints reported in the general population. Despite the fact that this condition is common, epidemiological characteristics have long been inaccurate and prone to individual interpretation. In Puerto Rico, a Caribbean island with a population close to 4 million, no epidemiological study about headache or migraine in particular, is available.

Trasfondo: El dolor de cabeza es uno de los desórdenes más reportado frecuentemente en la población adulta general. A pesar del hecho de que esta dolencia es común, no existe un estimado oficial de la prevalencia del dolor de cabeza en Puerto Rico.

Propósito:Examinar la prevalencia del dolor de cabeza y la migraña, específicamente, en Puerto Rico.

Metodología: Se realizó una encuesta telefónica a 1610 individuos. Las llamadas telefónicas se distribuyeron utilizando el censo de 1990 ajustado a la población de Puerto Rico en 1998, de acuerdo al género, área geográfica y edad.

Resultados: La prevalencia del dolor de cabeza en Puerto Rico fue 35.9% y de la migraña en particular, 13.0%. Cuando la prevalencia se fraccionó por edad, género y áreas geográficas, la prevalencia del dolor de cabeza fue similar para todas las edades, con las féminas mostrando una preponderancia de 2:1 sobre los varones.

En la población más joven (entre 20 y 50 años de edad),

la proporción femenino-masculino para la migraña fue de 3:1, y la prevalencia para la migraña fue más baja que en el área metropolitana.

Conclusión: Este estudio, el primero de este tipo en Puerto Rico, demuestra que el dolor de cabeza (y la migraña, específicamente) es una dolencia común en este país.

Background: Headache is one of the most frequently reported disorders in the general adult population.

Despite the fact that this disorder is common, no official estimate of the prevalence of headache exists in Puerto Rico.

Purpose: To examine the prevalence of headache and migraine, specifically, in Puerto Rico.

Methods: A telephone survey of 1610 individuals was conducted. The telephone calls were distributed using the 1990 census adjusted to the population of Puerto Rico in 1998, and according to gender, geographical area, and age.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE INVESTIGACIÓN

Results: The prevalence of headache in Puerto Estimados de prevalencia de migraña por edad y género Rico was 35.9% and migraine, in particular, 13.0%.

Edad Prevalencia por género When prevalence was fractionated by age, gender, Menos de 20 años Hombres 8.7 % Mujeres 19.3% and geographical areas, the prevalence of headache was similar for all ages, with females exhibiting a 2:1 Entre 20 y 29 años Hombres 3.8 % Mujeres 14.1 % preponderance over males. In the younger population Entre 30 y 39 años Hombres 10.8 % Mujeres 20.0 % (between 20 and 50 years of age), the female-male ratio Entre 40 y 49 años Hombres 7.5 % Mujeres 28.6 % for migraine was 3:1, and the prevalence for migraine was lower in the Metropolitans area.

Más de 50 años Hombres 5.9 % Mujeres 12.1 % Conclusion: This study, the first of its type in Tabla 1 Puerto Rico, demonstrates that headache (and migraine specifically) is a common disorder in this country. dividió en 2 clasificaciones utilizando los criterios de la Sociedad Internacional de Dolor de Cabeza (HIS): tanto El dolor de cabeza es una de las quejas más frecuentes dolor de cabeza tipo migraña u otros tipos de dolor de reportadas en la población en general. A pesar del hecho cabeza. Obtuvimos una tasa de entrevista general de de que esta condición es común, las características 4.2 por cada 10000 residentes. Las tasas regionales iban epidemiológicas han sido durante mucho tiempo desde 2.4 (Bayamón) hasta 6.0 (Arecibo). imprecisas y propensas a la interpretación individual.

Para propósitos estadísticos, la muestra fue postEn cambio, muchos de los estudios epidemiológicos han estratificada por región del censo. Por tanto, los cálculos sido realizados en pacientes en busca de tratamiento, en fueron probablemente ponderados en función de lugar de personas de la población general. la población de la muestra en cada región. Este es el En Puerto Rico, una isla caribeña con una población multiplicador de población finita que fue aplicado. Para cercana a los 4 millones, ningún estudio epidemiológico el análisis se utilizó el programa estadístico Stata. sobre el dolor de cabeza o la migraña, en particular, está disponible. Para examinar esta prevalencia, una Resultados encuesta telefónica se realizó a 1610 individuos. Las Dolor de Cabeza – Prevalencia General llamadas telefónicas fueron distribuidas por género, La prevalencia del dolor de cabeza en Puerto Rico, edad y área geográfica, utilizando las estadísticas del basado en una muestra de 1610 entrevistas telefónicas, censo de 1990 y ajustadas a la población de 1998 en fue de 35.9% (con un intérvalo de confianza [CI] de Puerto Rico. metodología 33.4 a 38.3).

Basado en una encuesta sobre dolor de cabeza llevada a cabo por una compañía telefónica local de recopilación Prevalencia por Género de datos, procedimos a estimar varias características de Cuando dividimos la muestra por género, observamos interés para un estudio de prevalencia. Entrevistamos una prevalencia de dolor de cabeza en hombres de 27% a 1610 residentes de Puerto Rico, seleccionados por (CI, 22.6 a 31.0), y una prevalencia de dolor de cabeza municipalidad. Dividimos la muestra entre regiones en mujeres de 40% (CI, 36.9 a 42.9). geográficas de acuerdo al censo de 1990 y la población estimada en 1998.

Prevalencia por Región Una vez la distribución de la muestra fue determinada, La gráfica 1 muestra estimados de prevalencia de los residentes fueron evaluados por un questionario dolor de cabeza por regiones geográficas de Puerto preparado por el Centro de Manejo de Dolor de Rico. La región de Arecibo presentó la más alta Cabeza (CEDOC). El cuestionario preguntaba acerca prevalencia de dolor de cabeza con un 48.9% (CI, 43.1 de la prevalencia del dolor de cabeza durante el pasado a 54.8), mientras que la región metropolitana obtuvo la año. (La encuesta se llevó a cabo durante los meses de más baja prevalencia de dolor de cabeza con un 21.9% abril y mayo del 2000.) Si la respuesta del individuo (CI, 17.5 a 26.4). era positiva, las características y síntomas asociados del dolor de cabeza también eran obtenidas.

Prevalencia por Edad Para propósitos de este estudio, el dolor de cabeza se Los estimados de prevalencia de dolor de cabeza, por Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO DE INVESTIGACIÓN

Estimados de prevalencia de migraña por región y género Arecibo

Hombres 12.8 %

Mujeres 21.4 %

Bayamón

Hombres 0 (0)

Mujeres 18.7%

Caguas

Hombres 6.2 %

Mujeres 7.6 %

Mayagüez

Hombres 5.7 %

Mujeres 15.9 %

Ponce

Hombres 10.7 %

Mujeres 20.3 %

Metropolitana

Hombres 4.2 %

Mujeres 11.4 %

Tabla 2

edad del entrevistado, se muestran en la gráfica 3. La prevalencia más alta de dolor de cabeza se encontró entre las edades de 40- a 49- años (44%; CI, 37.5 a 50.5). Aquellos de 50 años o más se encontraron en el grupo de menor prevalencia (27.3%; CI, 23.8 a 30.8).

Prevalencia por Región y Género La Tabla 2 presenta estimados de la prevalencia de dolor de cabeza dividido por región geográfica y género. Las féminas con la más alta prevalencia de dolor de cabeza residían en la región de Arecibo, 54.8% (CI, 48.0 a 61.5). Los hombres con la prevalencia de dolor de cabeza más alta se encontraron en la región de Caguas, 35.1% (CI, 25.5 a 44.6). Se encontró que la región metropolitana tenía la menor prevalencia de dolor de cabeza en mujeres, 25.5% (CI, 19.9 a 31.1).

Esta región también tuvo la menor prevalencia de dolor de cabeza en hombres, 13.7% (CI, 6.8 a 20.6). En todas las regiones, la prevalencia de dolor de cabeza fue más alta en las mujeres.

Prevalencia por Edad y Género Las mujeres entre 30 y 39 años de edad (51.1%; CI, 43.2 a 59.0) y los hombres entre 20 y 29 años de edad (35.5%; CI, 25.3 a 45.8) tuvieron la más alta prevalencia de dolor de cabeza. La prevalencia de dolor de cabeza más baja se encontró en mujeres (30.3%; CI, 26.1 a 34.5) y hombres (18.6%; CI, 12.4 to 24.7) con edades de 50 años o más. En todos los grupos de edades, la prevalencia más alta de dolor de cabeza fue en las mujeres.

Prevalencia de Migraña por Género Cuando dividimos la muestra por género, observamos una prevalencia de migraña estimada en hombres de 6.0 % (CI, 3.8 a 8.1) y una prevalencia de migraña en mujeres de 16.7% (CI, 11.0 a 19.1).

Prevalencia de Migraña por Región La gráfica 1 reporta los estimados de prevalencia de migraña por región geográfica. La región de Arecibo obtuvo la prevalencia de migraña más alta, la cual fue 19.3% (CI, 14.7 a 23.9), mientras que la región Metropolitana obtuvo la prevalencia más baja 9.2% (CI, 6.1 a 12.3).

Prevalencia de Migraña por Edad Los estimados de prevalencia de migraña, basados en la edad de la persona, se muestran en la gráfica 2.

La prevalencia de migraña más alta se encontró en el grupo de 40- a 49- años de edad (23.0%; CI, 17.4 a 28.7). Aquellos de 50 años o más se encontraron en el grupo con la menor prevalencia (10%; CI, 7.6 a 12.3).

Prevalencia de Migraña por Región y Género Los estimados de prevalencia de migraña por región geográfica y género están presentados en la Tabla 2. La prevalencia de migraña más alta en mujeres (21.4%; CI, 15.9 a 27.0) y hombres (12.9%; CI, 5.0 a 20.7) se encontró en la región de Arecibo. La prevalencia de migraña más baja en mujeres (11.4%; CI, 7.3 a 15.4) se encontró en la región metropolitana. Los hombres en la región de Bayamón reportaron una prevalencia de migraña de cero. En todas las regiones, la prevalencia de migraña fue más alta en mujeres.

Prevalencia de Migraña por Edad y Género La prevalencia de migraña más alta en mujeres se reportó en el grupo de edad de 40- a 49- años (28.6%; CI, 21.6 a 35.7). Los hombres en el grupo de edad de 30- a 39- años obtuvieron la prevalencia de migraña más alta, 10.8% (CI, 3.7 a 17.9).La prevalencia de migraña más baja en mujeres se encontró en el grupo de 50 años o más (12.1%; CI, 9.1 a 15.1) y en hombres, en el grupo de edad entre 20 y 29 años (3.8%; CI, 0.3 a 7.2). En todos los grupos de edades, la prevalencia más alta se encontró en mujeres.

Migraña – Prevalencia GeneralLa prevalencia de migraña en Puerto Rico, basado en una muestra de 1610 entrevistas telefónicas, fue de Comentarios 13.5% (CI, 11.7 a 15.2).

Nuestro estudio muestra que la prevalencia de todos los tipos de dolor de cabeza en Puerto Rico fue 35.9%, 46

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE INVESTIGACIÓN

Estimados de prevalencia de migraña por región

Gráfica 1

Estimados de prevalencia de migraña por edad

Gráfica 2

Estimados de prevalencia de dolor de cabeza por edad

Gráfica 3

Estimados de prevalencia de dolor de cabeza por región

Gráfica 4

lo que es compatible con otros reportes publicados que utilizaron los criterios de HIS. La prevalencia de migraña fue 13.0%, una vez más compatible con las prevalencias reportadas en otros estudios basados en comunidades occidentales.

Cuando la prevalencia se analizó por edades, la diferencia por grupo de edad no fue estadísticamente signif icante, excepto por el paciente mayor de 50 años, cuya prevalencia de dolor de cabeza se redujo extraordinariamente. No se encontró diferencia estadísticamente significante cuando la prevalencia fue dividida por región geográfica.

La proporción de mujeres a hombres fue 1.5:1.

No se encontró un efecto signif icativo por edad en la prevalencia de migraña excepto en el grupo de más de 50 años, cuya prevalencia es estadísticamente menor que en los otros grupos de edades. Se encontró que la prevalencia de migraña es más baja en el área metropolitana de la isla, pero la diferencia no fue estadísticamente significante. Esta proporción más baja probablemente está asociada con la accesibilidad de servicios en esa área.

Nuestro estudio, el primero de su tipo en Puerto Rico con respecto a la prevalencia de dolor de cabeza en la isla, es compatible con otros estudios publicados en países occidentales. Este estudio revela que el dolor de cabeza (y la migraña, en particular) es más común en mujeres que en hombres con una proporción de 3:1. Similar a otros estudios, encontramos una prevalencia menor en el grupo de edad entre 20 a 50 años.

En conclusión, nuestro estudio demuestra la prevalencia de dolor de

cabeza y migraña en Puerto Rico y le proporciona a las autoridades de la salud una base confiable para el mejor uso de los recursos educativos y de tratamiento.

Referencias

1. Lipton RB, Silberstein SD, Stewart WF. An update on the epidemiology of migraine. Headache. 1994;34:319-328.

2. Sillanpaa M. Prevalence of headache in prepuberty. Headache. 1983;23:10-14.

3. Mortimer MJ, Kay J, Jaron A. Epidemiology of headache and childhood migraine in an urban general practice using Ad Hoc, Vahlquist and IHS criteria. Dev Med Child Neurol. 1992;34:1095-1101.

4. Gobel H, Petersen-Braun M, Soyka D. Headache in Germany. A nationwide survey of a representative sample on the basis of the headache classification of the International Headache Society. In: Olesen J, ed. Headache Classification and Epidemiology. New York, NY: Raven Press; 1994:255-261.

5. Rasmussen BK, Jensen R, Schroll M. Olesen J. Epidemiology of headache in a general population- a prevalence study. J Clin Epidemiol. 1991;44:1147-1157.

6. Sheffield RE. Migraine prevalence: a literature review. Headache. 1998;38:595-601.

7. Abduljabbar M, Ogunniyi A, al Balla S, Alballaa S, al-Dalaan A. Prevalence of primary headache syndrome in adults in the Qassim region of Saudi Arabia.

Headache. 1998;36:385-388.

8. Rasmussen BK, Breslau N. Migraine, epidemiology. In: Olesen J, Tfelt-Hansen P, Welch KMA, eds. The Headaches. New York, NY: Raven Press; 1993:169-173.

9. Silberstein SD, Lipton RB. Epidemiology of migraine. Neuroepidemiology.

1993;12:179-194.

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See more of what Emgality can do for patients at EmgalityEfficacy.com

Now Approved For the Preventive Treatment of Migraine in Adults Emgality™ is a once-monthly, self-administered, subcutaneous injection that binds calcitonin gene-related peptide (CGRP) to prevent migraine1 For people who suffer from 4-14 migraine headache days (MHDs) per month,

New Emgality delivered significantly more migraine-free days vs placebo1 • Emgality prevented 4.7 and 4.3 mean MHDs per month vs 2.8 and 2.3 mean MHDs per month with placebo in EVOLVE-1 and EVOLVE-2, respectively, over Months 1 to 6 (baseline mean for EVOLVE-1: 9.2 vs 9.1; EVOLVE-2: 9.1 vs 9.2) (p<0.001)

Emgality demonstrated significant response rates in the reduction of mean monthly MHDs in any given month vs placebo in EVOLVE-1 and EVOLVE-21 1 Mean Patients Meeting Defi ned Levels of Reduction in Monthly MHDs MeanPercentage Percentageofof Patients Meeting Defined Levels of Reduction in Monthly MHDs

EVOLVE-1 (over Months 1 to 6)

EVOLVE-2 (over Months 1 to 6) 100

80

60

40

62%a 39% 39%a

19%

20

0

≥50%

16%a 6%

80

60

59%a 36% 34%a

40

18%

20

0

100%

≥75%

Mean Percentage of Patients

Mean Percentage of Patients

100

≥50%

Level of Reduction Emgality 120 mg (N=210)

100%

≥75%

Level of Reduction

Placebo (N=425) a

Up to 62% of patients had a ≥50% reduction of monthly MHDs in any given month, on average (p<0.001)1

12%a 6%

Emgality 120 mg (N=226)

Placebo (N=450)

p<0.001 vs placebo.

Up to 39% of patients achieved a ≥75% reduction of monthly MHDs in any given month, on average (p<0.001)1

Up to 1 in 7 patients (16%) were 100% migraine headache-free in any given month, on average (p<0.001)1

Emgality was also evaluated in patients with ≥15 headache days per month1 • Emgality prevented 4.8 mean MHDs per month in REGAIN vs 2.7 mean MHDs per month with placebo, on average (baseline mean: 19.4 vs 19.6) (p<0.001)b • With Emgality, 28% of patients achieved a ≥50% reduction of monthly MHDs vs 15% with placebo (p<0.001)b In REGAIN, Emgality 120 mg was not significantly better than placebo for the proportion of patients with 75% and 100% reduction from baseline in the number of monthly MHDs over the 3-month treatment period.1 b

Emgality (N=273), placebo (N=538).1

Study designs1 EVOLVE-1 and EVOLVE-2 were 6-month, double-blind, placebo-controlled studies that enrolled adult patients with episodic migraine (defined as 4-14 MHDs per month) (N=1773). REGAIN was a 3-month, double-blind, placebo-controlled study that enrolled adult patients with chronic migraine (defined as ≥15 headache days per month with ≥8 migraine days per month) (N=1113). In all 3 studies, patients were randomized to receive once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg.c In EVOLVE-1 and EVOLVE-2, treatments for prevention were not allowed. In REGAIN, a subset of patients (15%) continued one concomitant migraine preventive medication. EVOLVE-1 and EVOLVE-2 excluded patients with medication overuse headache. All 3 studies excluded patients with electrocardiogram (ECG) abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.

For each study, the primary endpoint was the mean change from baseline in the number of monthly MHDs over the double-blind treatment period in the intent-to-treat population. c

240 mg is an unapproved dose.

INDICATION Emgality is a calcitonin gene-related peptide antagonist indicated for the preventive treatment of migraine in adults.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Emgality is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (e.g., rash, urticaria, and dyspnea) have been reported with Emgality in clinical studies. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Emgality and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration and may be prolonged.

ADVERSE REACTIONS The most common adverse reactions (incidence ≥2% and at least 2% greater than placebo) in Emgality clinical studies were injection site reactions.

Please see Brief Summary of Prescribing Information for Emgality on adjacent pages.

Please see Instructions for Use included with the device.

GZ HCP ISI 27SEP2018 Reference: 1. Emgality [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC. Emgality™ is a trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

PP-GZ-US-0053 09/2018 ©Lilly USA, LLC 2018.

All rights reserved.

EmgalityTM (galcanezumab-gnlm) injection, for subcutaneous use Brief Summary: Consult the Package Insert for complete Prescribing Information.

INDICATIONS AND USAGE Emgality is indicated for the preventive treatment of migraine in adults.

CONTRAINDICATIONS Emgality is contraindicated in patients with serious hypersensitivity to galcanezumab-gnlm or to any of the excipients.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (e.g., rash, urticaria, and dyspnea) have been reported with Emgality in clinical studies. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Emgality and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration and may be prolonged.

ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

In placebo-controlled clinical studies (2 studies in patients with episodic migraine and 1 study in patients with chronic migraine), 705 patients received at least one dose of Emgality 120 mg once monthly and 1451 patients received placebo, during 3 months or 6 months of double-blind treatment. Of the Emgality-treated patients, approximately 85% were female, 77% were white, and the mean age was 41 years at study entry.

The most common adverse reaction was injection site reactions (18% for Emgality vs 13% for placebo). In the studies, 1.8% of patients discontinued double-blind treatment because of adverse events. Injection site reactions include multiple related adverse event terms, such as injection site pain, injection site reaction, injection site erythema, and injection site pruritus.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to galcanezumab-gnlm in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In controlled studies with Emgality up to 6 months (EVOLVE-1, EVOLVE-2, and REGAIN), the incidence of anti-galcanezumab-gnlm antibody development was 4.8% (33/688) in patients receiving Emgality once monthly (32 out of 33 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, up to 12.5% (16/128) of Emgality-treated patients developed anti-galcanezumab-gnlm antibodies, most of whom tested positive for neutralizing antibodies.

Although anti-galcanezumab-gnlm antibody development was not found to affect the pharmacokinetics, safety or efficacy of Emgality in these patients, the available data are too limited to make definitive conclusions.

Geriatric Use Clinical studies of Emgality did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

DRUG INTERACTIONS Galcanezumab-gnlm is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

DOSING The recommended dosage of Emgality is 240 mg (two consecutive subcutaneous injections of 120 mg each) once as a loading dose, followed by monthly doses of 120 mg injected subcutaneously.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of Emgality in pregnant women. Administration of galcanezumab-gnlm to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at plasma exposures greater than that expected clinically did not result in adverse effects on development.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/ Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

If a dose of Emgality is missed, administer as soon as possible. Thereafter, Emgality can be scheduled monthly from the date of the last dose.

Emgality is for subcutaneous use only. Emgality is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer Emgality using the single-dose prefilled pen or single-dose prefilled syringe, including aseptic technique: • Protect Emgality from direct sunlight • Prior to subcutaneous administration, allow Emgality to sit at room temperature for 30 minutes. Do not warm by using a heat source such as hot water or a microwave • Do not shake the product • Inspect Emgality visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use Emgality if it is cloudy or there are visible particles • Administer Emgality in the abdomen, thigh, back of the upper arm, or buttocks subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard • Both the prefilled pen and prefilled syringe are single-dose and deliver the entire contents

Animal Data When galcanezumab-gnlm was administered to female rats by subcutaneous injection (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout organogenesis, no adverse effects on embryofetal development were observed. The highest dose tested (250 mg/kg) was associated with a plasma exposure (Cave, ss) 38 times that in humans at the recommended human dose (RHD) of 120 mg.

Administration of galcanezumab-gnlm (0, 30, or 100 mg/kg) by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma Cave, ss 64 times that in humans at the RHD.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Administration of galcanezumab-gnlm (0, 30, or 250 mg/kg) by subcutaneous injection to rats throughout pregnancy and lactation produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma Cave, ss 34 times that in humans at the RHD.

Additional information can be found at www.Emgality.com/hcp.

Lactation Risk Summary There are no data on the presence of galcanezumab-gnlm in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Emgality and any potential adverse effects on the breastfed infant from Emgality or from the underlying maternal condition.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Instructions on Self-Administration: Provide guidance to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the prefilled pen or prefilled syringe correctly. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Emgality.

Hypersensitivity Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.

Eli Lilly and Company, Indianapolis, IN 46285, USA ©Lilly USA, LLC 2018.

All rights reserved.

GZ HCP BS 28SEP2018 PP-GZ-US-0053 Emgality™ is a trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

MSP ARTÍCULO ORIGINAL

Trabajo en equipo: clave para el manejo exitoso de infecciones de pie diabético Por: Michelle M. González Ramos, MD Catedrática Asociada, Programa de Entrenamiento en Enfermedades Infecciosas Escuela de Medicina de la Universidad de Puerto Rico Carmen Rita Ballesté Frank, MD, FIDSA

Palabras claves Pie diabético, antibiótico, infección, diabetes, úlcera, osteomielitis

Keywords Diabetic foot, antibiotic, infection, diabetes, ulcer, osteomyelitis

Resumen Diabetes mellitus es un problema de salud que ha ido en aumento global en la última década, convirtiéndose en la causa principal de amputaciones no traumáticas en los Estados Unidos. Aproximadamente el 15 % o de los pacientes que padecen de diabetes desarrollan una úlcera de pie, dando paso a la entidad conocida como pie diabético. Una gran cantidad de estos pacientes desarrollan infecciones contiguas al área de la úlcera, las cuales pueden tener una variedad de presentaciones clínicas, desde celulitis superficial hasta osteomielitis.

El tratamiento de antibióticos para el paciente con pie diabético varía dependiendo de la severidad de la presentación. Existe una variedad de tratamientos adjuvantes para el manejo del paciente de pie diabético, los cuales se utilizan en combinación con antibióticos con el fin de salvar la extremidad. El paciente diabético que presenta ulceración del pie debe recibir un manejo integral por un equipo multidisciplinario de profesionales de la salud, incluyendo un especialista en enfermedades infecciosas que ayude a escoger el tratamiento adecuado de antibióticos. El trabajo en equipo es la clave del éxito y la educación al paciente como a todos los involucrados en el cuidado primario es la base para un desenlace positivo, preservación de la extremidad y mejor calidad de vida.

Abstract Diabetes mellitus has been in increasing trend during the past decade, becoming the main cause of nontraumatic amputations in the US. Approximately 15 % of patients who suffer from diabetes will develop a foot ulcer.

Associated infections are seen in a considerable amount of patients with diabetic foot, which can vary in severity from a superficial cellulitis to osteomyelitis.

Treatment for patients with diabetic foot infections depends on clinical presentation and severity of disease.

Other adjuvant therapies can be used in conjunction with antibiotics in patients with limb threatening infections. Patients with diabetic foot infections need a multidisciplinary approach from a team composed of several healthcare professionals, including an Infectious Disease specialist, who should be in charge of choosing adequate antibiotic therapy. Team work is the key to the successful management of patients with diabetic foot infections and has demonstrated to have a direct impact on quality of life through preservation of the affected extremity.

Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

D

iabetes mellitus es un problema de salud que ha ido en aumento global en la última década, convirtiéndose en la causa principal de amputaciones no traumáticas en los Estados Unidos. Se estima que el riesgo de amputaciones en esta población de pacientes es 15 veces mayor y que 20 por ciento de los pacientes que padecen de úlcera de pie a consecuencia de la diabetes sufrirán una amputación en una extremidad inferior durante el transcurso de su enfermedad.

Los pacientes que padecen de diabetes tienen mayor frecuencia de infecciones asociadas a su desbalance metabólico, pues tienen el sistema inmunológico comprometido por disminución en la función de los glóbulos blancos. Las infecciones en esta población siguen en aumento pues los pacientes tienen una duración de vida más larga, lo cual conlleva a un aumento en la incidencia de complicaciones a largo plazo. Aproximadamente el 15 % de los pacientes que padecen de diabetes desarrollan una úlcera de pie, dando paso a la entidad conocida como pie diabético. El pie diabético es el resultado del efecto combinado de las malformaciones óseas, la angiopatía, la neuropatía y el mayor riesgo de infecciones, los cuales provocan alteraciones tisulares o úlceras secundarias a microtauma. La neuropatía periférica, la cual es la complicación más prevalente de la diabetes, junto con la insuficiencia periferovascular, son factores importantes asociados a un resultado pobre, ya que afecta la respuesta inflamatoria a infección. Entre los factores de riesgo para desarrollar úlcera de pie diabético se encuentra

52

Revista Puertorriqueña de Medicina y Salúd Pública

el ser de sexo masculino, padecer de diabetes por un término de más de 10 años, padecer de neuropatía diabética, anormalidades en la estructura del pie, ser fumador, pobre control de diabetes, insuficiencia renal, utilizar calzado no adecuado, caminar descalzo, pobre higiene y tener historial de una úlcera o amputación previa. La incidencia de amputaciones secundarias en los pacientes que han padecido de una úlcera diabética puede ser hasta un 85%, siendo el aspecto plantar del pie el área más comúnmente afectada.

Las infecciones en pie diabético son frecuentemente difíciles de diagnosticar cuando no se presentan de manera típica, pues pueden ocurrir sin signos clásicos como rubor, calor, tumor o dolor. Las que no amenazan la integridad de la extremidad son aquellas que se presentan como una celulitis superficial sin síntomas sistémicos. La mayor parte de estas infecciones son causadas por organismos gram positivos y su manejo consiste en antibióticos por boca por siete a catorce días.

Alternativas de tratamiento para manejo de infecciones en pacientes que no requieren hospitalización incluyen amoxicilina-clavulanato, trimetropin sulfa, doxiciclina, clindamicina, cefalosporinas (cefalexina o cefpodoxima) y las quinolonas (ciprof loxacina, levof loxacina y moxif loxacina). Por otra parte, aquellas que sí amenazan la integridad de la extremidad del paciente son las que se manifiestan con una celulitis más profunda y extensa, muchas veces con complicaciones como abscesos profundos, gangrena, necrosis de tejidos blandos u osteomielitis. Estos pacientes pueden presentar manifestaciones de toxicidad sistémica como

MSP ARTÍCULO ORIGINAL

fiebre, escalofríos, taquicardia, hipotensión, confusión, vómitos, hiperglicemia severa y acidosis. El tratamiento recomendado para este tipo de presentación consiste en hospitalización y antibióticos intravenosos de amplio espectro que cubran flora polimicrobiana. Alternativas de tratamiento empírico para pacientes con criterios para hospitalización incluyen las penicilinas (ampicilina- sulbactam o piperacilina-tazobactam), cefalosporinas (ceftazidima, cefepime), aztreonam y los carbapenems (ertapenem, imipenem, meropenem o doripenem) en combinación con vancomicina en lo que se obtiene cultivo del área afectada para ayudar a diseñar una terapia dirigida al organismo causando la infección. La presencia de organismos resistentes a terapia convencional de antibióticos, como los estafilococos aureus resistentes a meticilina y los bacilos gram negativos con beta lactamasas de espectro extendido, han ido en aumento en los últimos años y tienen un impacto al momento de escoger tratamiento empírico en algunas poblaciones de pacientes que están a alto riesgo de desarrollar estos tipos de infecciones, como aquellos que han tenido estos organismos anteriormente o los que provienen de un área de alta prevalencia.

Otras alternativas para cubierta para estafilococo aureus resistente a meticilina incluyen daptomicina y linezolid.

Los organismos anaeróbicos son patógenos infrecuentes y no se toman en consideración de manera rutinaria al momento de escoger terapia de antibióticos para pacientes de pie diabético en ausencia de gangrena.

La penetración de antibióticos en tejido es otro factor importante a considerar al momento de decidir tratamiento paraestos pacientes. Las fluoroquinolonas, algunas tetraciclinas, clindamicina, y linezolid son antibióticos que tienen una excelente biodisponibilidad oral y penetración a hueso, sinovio y tejido necrótico. El largo de tratamiento para las infecciones amenazantes a la integridad de la extremidad consiste de dos a cuatro semanas.

Osteomielitis, o infección de hueso en el área contigua a la úlcera, es una complicación a tomar en consideración cuando ésta es profunda o grande en tamaño, máximo enpresenciade isquemia, visibilidad del hueso, fetidez, tejido friable o anormalidad en el color de la piel. Osteomielitis también puede estar presente en un número considerable de pacientes con úlcera en ausencia de signos de infección. El riesgo de osteomielitis en pacientes hospitalizados por pie diabético puede fluctuar entre 20 y 66 por ciento.

El manejo del paciente con osteomielitis consiste en seis semanas de antibióticos, el cual debería ser guiado preferiblemente por un cultivo profundo de tejido o de una biopsia de hueso antes de comenzar tratamiento.

Se ha confirmado en varios estudios que el relapso de osteomielitis es mayor en pacientes que se manejan de manera conservadora sin intervención quirúrgica. Los marcadores de inflamación en sangre, como la proteína C reactiva y la velocidad de sedimentación globular, son herramientas importantes en el diagnóstico de Revista Puertorriqueña de Medicina y Salúd Pública

53

MSP ARTÍCULO ORIGINAL

“EL MANEJO QUIRÚRGICO PARA LA REMOCIÓN DE ESFACELOS Y TEJIDO NECRÓTICO DEBERÍA OCURRIR DENTRO DE LAS PRIMERAS 48 HORAS DE ADMISIÓN” osteomielitis en combinación con estudios de imagen. Gran cantidad de los pacientes con osteomielitis tienen una velocidad de sedimentación globular de 70mm/h o mayor. Los marcadores de inflamación también se utilizan de manera seriada para monitorear respuesta a antibióticos a lo largo del tratamiento de osteomielitis. El estudio de imagen preferido para diagnóstico de osteomielitis es la resonancia magnética, pero muchas veces una placa sencilla puede dar información suficiente para hacer el diagnostico de manera costoefectiva si la úlcera del paciente es crónica.

El uso de productos tópicos con enzimas proteolíticas, alginato o hidrogeles son de utilidad enpacientes que no son candidatos a cirugía. Las esponjas de gentamicina son otro instrumento que ha demostrado mejorar la tasa de curación en combinación con antibióticos sistémicos. Varios estudios han examinado el uso de factores de generación de colonias de granulocitos como tratamiento adjuvante en pacientes de pie diabético y han demostrado que hay una disminución en el riesgo de intervenciones quirúrgicas y amputaciones. Las terapias de células madres también han sido utilizadas exitosamente 54

Revista Puertorriqueña de Medicina y Salúd Pública

en la revascularización de úlceras isquémicas a través del trasplante de células de médula ósea y la estimulación de angiogénesis, pero no han demostrado tener un impacto en la mejoría de procesos infecciosos. Los tratamientos de cámara hiperbárica, durante los cuales se incrementa la cantidad de oxígeno a los tejidos favoreciendo cicatrización, junto con los sistemas de cicatrización asistida por vacío, son otras modalidades que han sido utilizadas con éxito pero no han sido clínicamente probadas como alternativas para el manejo de los pacientes con osteomielitis.

La mayoría de los pacientes con ulceración de pie diabético toman alrededor de 20 semanas de sanación completa.

El paciente diabético que presenta ulceración del pie debe recibir un manejo integral por un equipo multidisciplinario de profesionales de la salud, compuesto porun cirujano, el médico primario, especialistas en cuidado de la piel, un especialista en endocrinología y un especialista en enfermedades infecciosas que ayude a escoger el tratamiento adecuado de antibióticos. El manejo quirúrgico para la remoción de esfacelos y tejido necrótico debería ocurrir dentro de las primeras 48 horas de admisión para evitar el riesgo de que la infección continúe expandiéndose, además de ayudar a determinar la extensión de la destrucción de tejido y la posibilidad de extensión a hueso. El cirujano también es responsable de evaluar la vascularización arterial de la extremidad para que el tratamiento sea exitoso, ya que se estima que la mitad de estos pacientes tienen enfermedad periferovascular y la revascularización es clave para el proceso de sanación. El tratamiento óptimo para estos pacientes incluye prevención mediante la

identificación de aquellos que están a alto riesgo de desarrollar úlceras y educación en medidas preventivas, tales como el examen rutinario del pie, inspección e higiene diaria, evitar auto tratamiento de lesiones, eliminación de presión en el área afectada y buscar ayuda médica de manera temprana.

La tasa en aumento en casos de diabetes mellitus a nivel mundial trae nuevos retos para los profesionales de la salud que a diario trabajan con esta población de pacientes. La utilización adecuada de antibióticos en el manejo de infecciones de pie diabético es esencial para el bienestar del paciente, prevención de complicaciones asociadas y la preservación de los mismos como herramientas de tratamiento. El trabajo en equipo es la clave del éxito y la educación al paciente como a todos los involucrados en el cuidado primario es la base para un desenlace positivo, preservación de la extremidad y mejor calidad de vida.

Referencias:

1. Braunwald, E., Fauci, A., Kasper, D., Hauser, S., Longo, D., and Larry, J. Harrison’s Principles of Internal Medicine, 2001: 2007,2125-6.

2. Del Castillo Tirado, R.A. et al. Guía de práctica clínica en el pie diabético. Archivos de Medicina 2014; Vol 10 No 2:1.

3. Frykberg, R. Diabetic foot ulcers: pathogenesis and management. American Family Physician,2002 ; 66:1655-62.

4. Kuhna, B. Diabetic foot infections. E medicine, June 2004.

5. Lipsky, B., et al. 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. CID, 2012;54(12):132–173.

6. Mandell, G., Bennet, J. and Dolin, R. Principles and Practice of Infectious Diseases, 2000:1046-8,1184-5, 1188-9,1191-2.

7. Uçkay, I., et al. Diabetic Foot Infections: What have we learned in the last 30 years?

IJID 2015 Nov;40:81-91

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© 2018 Sanofi and Regeneron Pharmaceuticals, Inc. All Rights Reserved.

US-ILF-14192

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Indication for Humulin® R U-500

Please see Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

•

Humulin R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and children with diabetes mellitus requiring more than 200 units of insulin per day.

•

Limitation of Use: The safety and efficacy of Humulin R U-500 used in combination with other insulins has not been determined. The safety and efficacy of Humulin R U-500 delivered by continuous subcutaneous infusion has not been determined.

Please see Instructions for Use included with the pen.

Select Safety Information for Humulin R U-500 â&#x20AC;˘

Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

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Dosing Errors: Extreme caution must be observed in measuring the dose of Humulin R U-500 because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia.

Important Safety Information for Humulin® R U-500 Contraindications • Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

Warnings and Precautions Dosing Errors: Extreme caution must be observed in measuring the dose of Humulin R U-500 because inadvertent overdose may result in serious adverse reaction or lifethreatening hypoglycemia.

•

•

Hyperglycemia, Hypoglycemia, or Death Due to Dosing Errors in the Vial Presentation: Medication errors associated with the Humulin R U-500 vial resulting in patients experiencing hyperglycemia, hypoglycemia, or death have been reported.

Dispensing - Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct brand and concentration.

- For the Humulin R U-500 vial, particular attention should be paid to the 20-mL vial size, prominent “U-500” and warning statements on the vial label, and distinctive coloring on the vial and carton.

Prescribing - Dosing errors have occurred when Humulin R U-500 was administered with syringes other than a U-500 insulin syringe. Patients should be prescribed U-500 syringes for use with Humulin R U-500 vials. The dose of Humulin R U-500 should always be expressed in units of insulin.

Administration - Instruct patients to always check the insulin label before each injection.

- Use only a U-500 insulin syringe with Humulin R U-500 to avoid administration errors. Do not use any other type of syringe to administer Humulin R U-500. Adhere to administration instructions.

- Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R U-500 prescribed.

•

If using the Humulin® R U-500 KwikPen®, patients should be counseled to dial and dose the prescribed number of units of insulin (NO dose conversion is required).

•

DO NOT transfer Humulin R U-500 from the Humulin R U-500 KwikPen into any syringe for administration. Overdose and severe hypoglycemia can occur.

•

Never Share a KwikPen or U-500 Syringe Between Patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens.

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Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in insulin, manufacturer, type, or method of administration should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased.

PP-HM-US-1088

05/2018

©Lilly USA, LLC 2018. All rights reserved.

Warnings and Precautions, continued Hypoglycemia: Hypoglycemia is the most common adverse reaction associated with insulin, including Humulin R U-500. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of Humulin R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important, such as driving or operating other machinery.

- Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.

- Early warning symptoms of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system, or in patients who experience recurrent hypoglycemia.

- The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulin preparations, the glucose lowering effect time course of Humulin R U-500 may vary in different individuals or at different times in the same individual and depends on many conditions.

- Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

•

•

Hypersensitivity and Allergic Reactions: Severe, lifethreatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U-500.

If hypersensitivity reactions occur, discontinue Humulin R U-500; treat per standard of care and monitor until symptoms and signs resolve.

•

Hypokalemia: Insulin use can lead to hypokalemia that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

•

Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are PPAR-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin.

Fluid retention may lead to or exacerbate heart failure.

Observe patients for signs and symptoms of heart failure.

If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

Important Safety Information for Humulin R U-500, continued Adverse Reactions • Adverse reactions include hypoglycemia, allergic reactions, lipodystrophy, injection site reactions, weight gain, peripheral edema, and immunogenicity.

Dosage and Administration, continued Advise the patient to read the Patient Information and Instructions for Use.

• •

Drug Interactions • Some medications may alter glucose metabolism and may necessitate insulin dose adjustment. Signs of hypoglycemia may be reduced or absent in patients taking antiadrenergic drugs. Particularly close monitoring may be required.

Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used.

•

Inspect Humulin R U-500 visually and only use if the solution appears clear and colorless.

Use in Specific Populations • Pregnancy Category B: While there are no adequate and well-controlled studies in pregnant women, evidence from published literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal benefits.

•

Administer Humulin R U-500 subcutaneously two or three times daily approximately 30 minutes before a meal. Rotate injection sites to reduce the risk of lipodystrophy.

•

Individualize the dose of Humulin R U-500 based on metabolic needs, blood glucose monitoring results, and glycemic control goal.

Pediatric Use: There are no well-controlled studies of use of Humulin R U-500 in children. Standard precautions as applied to use of Humulin R U-500 in adults are appropriate for use in children.

•

Do NOT administer Humulin R U-500 intravenously or intramuscularly.

•

Do NOT mix Humulin R U-500 with other insulins.

Geriatric Use: There are no well-controlled studies of use of Humulin R U-500 in geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

•

•

•

•

Dosage and Administration Prescribe Humulin R U-500 ONLY to patients who require more than 200 units of insulin per day.

•

Humulin R U-500 is available as a KwikPen or a multiple dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors.

•

DO NOT perform dose conversion when using the Humulin R U-500 KwikPen. The dose window of the KwikPen shows the number of units of Humulin R U-500 to be injected and NO dose conversion is required.

•

•

Humulin R U-500 Vials: Unopened vials of Humulin R U-500 should be kept in a refrigerator. Opened (in-use) vials of Humulin R U-500 should be kept in the refrigerator or at room temperature and used within 40 days of opening.

Throw away any opened vial after 40 days of use, even if there is insulin left in the vial.

•

Humulin R U-500 KwikPen: Unopened Humulin R U-500 KwikPens should be kept in a refrigerator. Opened (inuse) Humulin R U-500 KwikPens should be kept at room temperature and used within 28 days of opening. Do not refrigerate opened KwikPens. Throw away any opened KwikPen after 28 days of use, even if there is insulin left in the pen.

Renal or Hepatic Impairment: Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.

•

•

Storage Protect from heat and light. Do not freeze. Do not use Humulin R U-500 after the expiration date stamped on the label.

DO NOT perform dose conversion when using a U-500 insulin syringe. The markings on the syringe show the number of units of Humulin R U-500 to be injected. Each marking represents 5 units of insulin.

Instruct patients using the vial to use only a U-500 insulin syringe and on how to correctly draw the prescribed dose into the syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose with their syringe.

Please see Brief Summary of Prescribing Information on adjacent pages. See Instructions for Use included with the pen.

HM U500 HCP ISI 27SEP2016 Humulin® and KwikPen® are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. Humulin® R U-500 is available by prescription only.

Humulin R U‑500 (insulin human injection) Brief Summary: Consult the package insert for complete prescribing information.

reactions occur, discontinue Humulin R U‑500; treat per standard of care and monitor until symptoms and signs resolve.

INDICATIONS AND USAGE Humulin® R U‑500 is a concentrated human insulin indicated to improve glycemic control in adults and children with diabetes mellitus requiring more than 200 units of insulin per day.

Limitation of Use: The safety and efficacy of Humulin R U‑500 used in combination with other insulins has not been determined. The safety and efficacy of Humulin R U‑500 delivered by continuous subcutaneous infusion has not been determined.

Hypokalemia: Insulin use can lead to hypokalemia, that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium‑lowering medications, patients taking medications sensitive to serum potassium concentrations).

CONTRAINDICATIONS Humulin R U‑500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U‑500 or any of its excipients.

WARNINGS AND PRECAUTIONS Dosing Errors: Extreme caution must be observed in measuring the dose of Humulin R U‑500 because inadvertent overdose may result in serious adverse reaction or life threatening hypoglycemia.

Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with the Vial Presentation: Medication errors associated with the Humulin R U‑500 vial presentation resulting in patients experiencing hyperglycemia, hypoglycemia or death have been reported. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to details at all levels may prevent these errors.

Dispensing • Instruct patients to always inspect insulin vials or pens to confirm that the correct insulin is dispensed including the correct insulin brand and concentration.

• With the Humulin R U‑500 vial, particular attention should be paid to the 20‑mL vial size, prominent “U‑500” and warning statements on the vial label, and distinctive coloring on the vial and carton.

Prescribing • Dosing errors have occurred when Humulin R U‑500 was administered with syringes other than a U‑500 insulin syringe. Patients should be prescribed U‑500 syringes for use with Humulin R U‑500 vials. The dose of Humulin R U‑500 should always be expressed in units of insulin.

Administration • Instruct patients to always check the insulin label before each injection.

• Use only a U‑500 insulin syringe with Humulin R U‑500 to avoid administration errors. Do not use any other type of syringe to administer Humulin R U‑500. Adhere to administration instructions.

• Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R U‑500 prescribed.

If using the Humulin R U‑500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of insulin (NO dose conversion is required).

DO NOT transfer Humulin R U‑500 from the Humulin R U‑500 KwikPen into any syringe for administration. Overdose and severe hypoglycemia can occur.

Never Share a KwikPen or U‑500 Syringe Between Patients, even if the needle is changed.

Sharing poses a risk for transmission of blood‑borne pathogens.

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in insulin, manufacturer, type, or method of administration should be made cautiously and only under medical supervision and the frequency of blood glucose monitoring should be increased.

Hypoglycemia: Hypoglycemia is the most common adverse reaction associated with insulin, including Humulin R U‑500. Severe hypoglycemia can cause seizures, may be life‑threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of Humulin R U‑500. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important, such as driving or operating other machinery.

• Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual.

• Early warning symptoms of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system, or in patients who experience recurrent hypoglycemia.

• The timing of hypoglycemia usually reflects the time‑action profile of the administered insulin formulation. As with all insulin preparations, the glucose lowering effect time course of Humulin R U‑500 may vary in different individuals or at different times in the same individual and depends on many conditions.

• Patients and caregivers must be educated to recognize and manage hypoglycemia.

Self‑monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Fluid Retention and Heart Failure with Concomitant Use of PPAR‑gamma Agonists: Thiazolidinediones (TZDs), which are PPAR‑gamma agonists, can cause dose‑related fluid retention, particularly when used in combination with insulin, including Humulin R U‑500. Fluid retention may lead to or exacerbate heart failure. Observe patients for signs and symptoms of heart failure and consider discontinuation or dose reduction of the PPAR‑gamma agonist.

ADVERSE REACTIONS Adverse Reactions include hypoglycemia, allergic reactions, lipodystrophy, injection site reactions, weight gain, peripheral edema, and immunogenicity.

DRUG INTERACTIONS Some medications may alter glucose metabolism and may necessitate insulin dose adjustment.

Signs of hypoglycemia may be reduced or absent in patients taking antiadrenergic drugs.

Particularly close monitoring may be required.

USE IN SPECIFIC POPULATIONS Pregnancy Category B: While there are no adequate and well‑controlled studies in pregnant women, evidence from published literature suggests that good glycemic control in patients with diabetes during pregnancy provides significant maternal and fetal benefits.

Pediatric Use: There are no well‑controlled studies of use of Humulin R U‑500 in children. Standard precautions as applied to use of Humulin R U‑500 in adults are appropriate for use in children.

Geriatric Use: There are no well‑controlled studies of use of Humulin R U‑500 in geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

Renal or Hepatic Impairment: Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.

DOSAGE AND ADMINISTRATION Dosing Instructions • Prescribe Humulin R U‑500 ONLY to patients who require more than 200 units of insulin per day.

• Humulin R‑U500 is available as a KwikPen or a multiple dose vial. Patients using the vial must be prescribed the U‑500 insulin syringe to avoid medication errors.

• DO NOT perform dose conversion when using the Humulin R U‑500 KwikPen. The dose window of the KwikPen shows the number of units of Humulin R U‑500 to be injected and NO dose conversion is required.

• DO NOT perform dose conversion when using a U‑500 insulin syringe. The markings on the syringe show the number of units of Humulin R U‑500 to be injected. Each marking represents 5 units of insulin.

• Instruct patients using the vial to use only a U‑500 insulin syringe and on how to correctly draw the prescribed dose into the syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose with their syringe.

• Advise the patient to read the Patient Information and Instructions for Use. • Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used.

• Inspect Humulin R U‑500 visually and only use if the solution appears clear and colorless.

• Administer Humulin R U‑500 subcutaneously two or three times daily approximately 30 minutes before a meal. Rotate injection sites to reduce the risk of lipodystrophy.

• Individualize the dose of Humulin R U‑500 based on metabolic needs, blood glucose monitoring results, and glycemic control goal.

• Do NOT administer Humulin R U‑500 intravenously or intramuscularly.

• Do NOT mix Humulin R U‑500 with other insulins.

HOW SUPPLIED Humulin R U‑500 (500 units per mL) is available as: • 2 x 3 mL Humulin R U‑500 KwikPen (prefilled) • 20 mL multiple dose vials

NDC 0002‑8824‑27 NDC 0002‑8501‑01

PATIENT COUNSELING INFORMATION: See FDA‑approved patient labeling.

Additional information can be found at www.humulin.com Humulin® R U‑500 and Humulin® R U‑500 KwikPen® are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Hypersensitivity and Allergic Reactions: Severe, life‑threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U‑500. If hypersensitivity

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2016, Eli Lilly and Company. All rights reserved.

HI U500 HCP BS 27SEP2016

Humulin R U-500 (insulin human injection)

Humulin R U-500 (insulin human injection)

HI U500 HCP BS 27SEP2016

Humulin RU500, HI U500 HCP BS 27SEP2016, Brief Summary 7 x 10

53690_elhumu_PP-HM-US-1067_cvr_wrp_tlde_fa.indd 49565_elhumu_PP-HM-US-0721_TLDE_cvr_wrp_fa.indd3 3

HI U500 HCP BS 27SEP2016

PRINTER VERSION 1 OF 3/29/18 1 5/24/17

10:38 11:58 AM AM

MSP ARTÍCULO ORIGINAL

ENFRENTANDO

COMPLEJIDADES EN EL TRATAMIENTO DE LA PIEL DEL PACIENTE DIABÉTICO Por: José M. García Mateo, MD, FACE Endocrinólogo y Lipidólogo. Certificado por American Board of Endocrinology Diabetes and Metabolism y American Board of Clinical Lipidology Presidente de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED)

Resumen La piel en el paciente diabético también puede mostrar los efectos de la enfermedad. Los pacientes diabéticos están expuestos a problemas en la pie de diferentes tipos. Hasta un 33% de las personas con diabetes presentan manifestaciones cutáneas. Hay un gran número de alteraciones en la pie que se asocian en mayor o menor grado con la presencia de la diabetes.

De hecho, estas manifestaciones cutáneas pueden ser expresión de la enfermedad o, simplemente, predecirla.

Algunas manifestaciones cutáneas podrían no parecer importantes, sin embargo, deben recibir atención médica inmediata. Mantener la diabetes bajo control es lo más importante para prevenir complicaciones en la piel asociadas a la enfermedad.

Palabras claves: diabetes, manifestaciones cutáneas, enfermedades de la piel, infecciones en el paciente diabético

Abstrat The skin in diabetic patients may also indicate the effects of the disease. Many people with diabetes are exposed to skin problems of different types.

Sometimes skin problems can be the first sign that a person has diabetes. In fact, up to 33% of people with diabetes have cutaneous manifestations. Keeping your diabetes under control is the most important factor in preventing the skin-related complications of diabetes. It is important to be able to recognize these signs in order to treat them appropriately. Some skin manifestations may not seem important, however, they should receive immediate medical attention.

Keywords: diabetes, skin manifestations, skin diseases, infections in diabetic patients.

Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

“La diabetes puede afectar cualquier parte del cuerpo, incluida la piel. Hasta 33% de las personas con diabetes tienen en algún momento de la vida una afección en la piel causada por la enfermedad. De hecho, a veces tales problemas son el primer indicio de que la persona padece la condición” La diabetes puede afectar cualquier parte del cuerpo, incluida la piel. Hasta 33% de las personas con diabetes tienen en algún momento de la vida una afección en la piel causada por la diabetes. De hecho, a veces tales problemas son el primer indicio de que la persona padece la condición. Afortunadamente, es posible prevenir o tratar fácilmente la mayoría de las afecciones de la piel si se detectan a tiempo. Algunos de estos problemas son trastornos de la piel que cualquier persona puede tener, pero son más comunes en las personas que sufren la enfermedad. Incluyen infecciones con bacterias y con hongos, y picazón. Otros problemas de piel se presentan particular o solamente en personas con diabetes.

Incluyen dermopatía diabética, necrobiosis lipoídica diabética, ampollas diabéticas y xantomatosis eruptiva.

Infecciones con hongos Las infecciones micóticas o con hongos en personas con diabetes a menudo se deben a Cándida albicans.

Este hongo tipo levadura puede causar erupciones que causan picazón en áreas húmedas, rojizas, rodeadas de pequeñas ampollas y escamas. Estas infecciones a menudo surgen en los pliegues calientes y húmedos de la piel. Las áreas problemáticas son debajo de los senos, alrededor de las uñas, entre los dedos, en las comisuras de la boca, debajo del prepucio (en los hombres sin circuncisión) y en las axilas y la ingle. Las infecciones fúngicas comunes incluyen tiña inguinal, pie de atleta, tiña e infección vaginal que causa comezón. Si cree que tiene una infección de hongos, llame a su médico.

Afecciones de la piel relacionadas con la diabetes: Enfermedades de la piel en general acantosis nigricans Infecciones con bacterias Es una afección en la que se presentan parches Se presentan varios tipos de infecciones con bacterias elevados de apariencia bronceada o marrón en los lados en las personas con diabetes: • Orzuelos (infecciones de las glándulas del del cuello, las axilas y la ingle. A veces, también salen en las manos, codos y rodillas. La acantosis nigricans párpado) • Forúnculos foliculitis (infección de los folículos del generalmente afecta a las personas que tienen mucho pelo) sobrepeso. El mejor tratamiento es perder peso. Algunas • Carbuncos (infecciones más profundas de la piel cremas pueden ayudar a que las manchas mejoren. y el tejido debajo de ésta) Dermopatía diabética • Infecciones alrededor de las uñas.

La diabetes puede causar cambios en los vasos Por lo general, los tejidos inf lamados están sanguíneos más pequeños. Estos cambios pueden calientes, hinchados, rojizos y duelen. Las bacterias causar problemas de la piel llamados dermopatía más comunes son los estafilococos. Anteriormente, las diabética. A menudo, la dermopatía se presenta como infecciones bacterianas eran potencialmente mortales, manchas escamosas marrones. Estas manchas pueden especialmente para las personas con diabetes. Hoy en ser ovaladas o circulares. Algunas personas piensan día, este tipo de muerte es poco común gracias a los que son manchas por la edad. Este trastorno ocurre antibióticos y mejores métodos de control de la glucosa más a menudo en la parte frontal de las piernas. Pero en la sangre. Pero incluso ahora, las personas con es posible que las piernas no se vean afectadas al mismo diabetes tienen más infecciones bacterianas que otras grado. Las manchas no duelen, ni se abren ni pican. La personas. Los médicos consideran que personas sanas dermopatía es inofensiva y no requiere tratamiento. o con otras enfermedades con diabetes pueden reducir la posibilidad de estas infecciones mediante un buen Necrobiosis lipoídica diabética Esta produce manchas similares a la dermopatía cuidado de la piel.

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Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

“Todas estas afecciones deben ser evaluadas y tratadas adecuadamente para prevenir complicaciones” diabética, pero en menor cantidad, más grandes y más profundas. La necrobiosis a menudo surge como una zona opaca, rojiza y elevada.

Después de un tiempo, parece una cicatriz brillante con borde violeta.

Es posible ver los vasos sanguíneos debajo de la piel más fácilmente.

A veces, causa picazón y dolor y en otras ocasiones las manchas se abren. La necrobiosis es poco común. Las mujeres adultas son más propensas a ella. Mientras las llagas no se abran, no necesita tratamiento. Pero si tiene llagas abiertas, vaya al médico para que le haga un tratamiento.

las personas con diabetes les salen ampollas. Las ampollas diabéticas pueden salir en el dorso de las manos, dedos, pies y a veces en las piernas o antebrazos. Estas llagas parecen ampollas debidas a quemaduras y a menudo les salen a personas con neuropatía diabética.

A veces son grandes, pero no duelen ni causan enrojecimiento a su alrededor. Se curan solas, generalmente sin causar cicatrices, en aproximadamente tres semanas.

El único tratamiento es controlar el nivel de glucosa en la sangre.

la sangre. Al igual que las ampollas diabéticas, estas protuberancias desaparecen cuando se restablece el control de la diabetes.

Esclerosis digital A veces, las personas con diabetes tienen la piel apretada, gruesa y cerosa en el revés de las manos.

La piel en los dedos de los pies y la frente también suele engrosarse. Las articulaciones de los dedos se ponen rígidas y no pueden moverse como deberían. En pocas ocasiones, las rodillas, tobillos o codos también se ponen tiesos. Esta afección se presenta en, aproximadamente, un tercio de las personas que tienen diabetes de tipo 1. El único tratamiento es controlar el nivel de glucosa en la sangre.

Todas estas afecciones deben ser evaluadas y tratadas adecuadamente para prevenir complicaciones, unas son más comunes que otras.

Su médico evaluará y decidirá si necesita la intervención de un especialista en condiciones de la piel (dermatólogo).

Xantomatosis eruptiva Es otra afección causada por la diabetes no controlada. Consiste en dilataciones de la piel que se ven firmes, amarillentas y parecen guisantes o arvejas. Cada bulto tiene un halo rojo y quizá pique.

Esta afección ocurre con mayor frecuencia en el dorso de las manos, pies, brazos, piernas y glúteos. El trastorno generalmente ocurre en Reacciones alérgicas Pueden ocurrir como reacción a hombres jóvenes con diabetes de tipo medicamentos como las pastillas de 1. A menudo, la persona tiene un insulina o para la diabetes. Si piensa alto nivel de triglicéridos y grasa en que está teniendo una reacción a un medicamento, debe consultar con su médico. Esté atento a erupciones, Referencias: depresiones o protuberancias en los 1. ADA Practice Guidelines 2015 2. AACE / ACE Comprehensive Diabetes Management Algorithm 2015. Endocrine Practice puntos donde se inyecta insulina.

Vol. 21 No 4. April 2015

3. ADA Standards of Medical Care in Diabetes 2015. Supp Diabetes Care. January 2015 Ampollas diabéticas En ocasiones poco frecuentes, a 4. Clinical Diabetes. V Fonseca. Textbook. Saunders. 2006 Revista Puertorriqueña de Medicina y Salúd Pública

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No-see,no-handle no-handleneedle needle No-see, Noreconstitution reconstitutionrequired required No Noneed needto todial dialaadose dose No 1,21,2

ÂŽ ÂŽ (dulaglutide) is a Indication: Trulicity Indication: Trulicity (dulaglutide) is a glucagon-like peptide-1 receptor agonist glucagon-like peptide-1 receptor agonist (GLP-1 RA) that is indicated adjunct (GLP-1 RA) that is indicated as as anan adjunct to to diet and exercise improve glycemic control diet and exercise to to improve glycemic control in adults with type 2 diabetes. in adults with type 2 diabetes.

Limitations Use: Not recommended Limitations of of Use: Not recommended as as first-line therapy patients inadequately first-line therapy forfor patients inadequately controlled diet and exercise because controlled onon diet and exercise because of of thethe uncertain relevance rodent C-cell tumor uncertain relevance of of rodent C-cell tumor findings humans.

Prescribe only if potential findings to to humans.

Prescribe only if potential benefits outweigh potential risks.

Has been benefits outweigh potential risks.

Has notnot been studied in patients with a history pancreatitis; studied in patients with a history of of pancreatitis; consider another antidiabetic therapy.

Not consider another antidiabetic therapy.

Not forfor treatment type 1 diabetes mellitus thethe treatment of of type 1 diabetes mellitus or or diabetic ketoacidosis.

Not a substitute diabetic ketoacidosis.

Not a substitute forfor insulin.

Has been studied in patients with insulin.

Has notnot been studied in patients with severe gastrointestinal disease, including severe severe gastrointestinal disease, including severe gastroparesis.

Not patients with pre-existing gastroparesis.

Not forfor patients with pre-existing severe gastrointestinal disease. severe gastrointestinal disease.

Select Important Safety Information Select Important Safety Information WARNING: RISK THYROID C-CELL TUMORS WARNING: RISK OFOF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence thyroid treatment-duration-dependent increase in the incidence of of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure.

C-cell tumors (adenomas and carcinomas) after lifetime exposure. is unknown whether Trulicity causes thyroid C-cell tumors, It isIt unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans human including medullary thyroid carcinoma (MTC), in humans as as human relevance dulaglutide-induced rodent thyroid C-cell tumors relevance of of dulaglutide-induced rodent thyroid C-cell tumors hashas not been determined. not been determined.

Trulicity is contraindicated in patients with a personal family Trulicity is contraindicated in patients with a personal or or family history MTC and in patients with Multiple Endocrine Neoplasia history of of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN Counsel patients regarding potential syndrome type 2 (MEN 2).2).

Counsel patients regarding thethe potential risk of MTC with the use of Trulicity and inform them of symptoms risk of MTC with the use of Trulicity and inform them of symptoms thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, of of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring serum calcitonin persistent hoarseness).

Routine monitoring of of serum calcitonin or or using thyroid ultrasound is of uncertain value early detection using thyroid ultrasound is of uncertain value forfor early detection of of MTC in patients treated with Trulicity.

MTC in patients treated with Trulicity.

Please see Important Safety Information Trulicity, including Boxed Warning about possible thyroid tumors including Please see Important Safety Information forfor Trulicity, including Boxed Warning about possible thyroid tumors including thyroid cancer, following pages and accompanying Brief Summary Prescribing Information.

Please see Instructions thyroid cancer, onon following pages and accompanying Brief Summary of of Prescribing Information.

Please see Instructions forfor Use included with pen.

Use included with thethe pen.

Preparation2 •

Check the pen to be sure it is not expired, damaged, cloudy, discolored, or has particles in it

•

Choose an area for injection (abdomen or thigh), being sure to choose a different site (even within area) each week

The key administration steps

Disposal2

2

•

1

Uncap the pen

2

Place and unlock

Dispose of the pen in a closable punctureresistant container and not in household trash

3

Press and hold

Please review the full Instructions for Use with your patients to ensure they understand how to properly administer Trulicity.

Select Important Safety Information •

Trulicity is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2, and in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components.

•

Cases of medullary thyroid carcinoma (MTC) in patients treated with liraglutide, another GLP-1 RA, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 RA use in humans. If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.

Yes, I think I can do this

*

In a study, 99% of patients reported that overall, the Trulicity Pen was easy or very easy to use3

•

Patients with type 2 diabetes who were naïve to self-injection and injecting others (n=214) participated in a phase 3b, multicenter, open-label, single-arm, outpatient study on the safe and effective use of the Trulicity single-dose pen

•

The primary objective was to achieve a final injection success rate (proportion of patients who successfully complete injection) significantly greater than 80%

•

Patients were trained at baseline on proper self-injection technique with the pen

•

Final injection (4th weekly injection) success was observed in 99.1% [95% CI: 96.6% to 99.7%] (n=209) of patients (primary objective met). Success determined by evaluation of patients’ ability to accurately complete each step in the sequence of drug administration

•

After the final self-injection, patients completed a 12-item ease of use module (secondary endpoint). 209 (99%) out of 210 patients reported that overall, the single dose pen was “easy” or “very easy” to use

To see how Trulicity can help your patients start injectable therapy, visit Trulicity.com/yesican

*Patient will need additional assistance from their healthcare professional as well as to review the full Instructions for Use included with the Trulicity Pen. Please see Important Safety Information for Trulicity, including Boxed Warning about possible thyroid tumors including thyroid cancer, on following pages and accompanying Brief Summary of Prescribing Information.

Please see Instructions for Use included with the pen.

Important Safety Information WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether Trulicity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Trulicity and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Trulicity.

Trulicity is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with a prior serious hypersensitivity reaction to dulaglutide or any of the product components.

Risk of Thyroid C-cell Tumors: Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist (GLP-1 RA), have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 RA use in humans. If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.

Pancreatitis: Has been reported in clinical trials. Observe patients for signs and symptoms including persistent severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, discontinue Trulicity promptly. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis.

Hypoglycemia: The risk of hypoglycemia is increased when Trulicity is used in combination with insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylactic reactions and angioedema) in patients treated with Trulicity. Instruct patients who experience symptoms to discontinue Trulicity and promptly seek medical advice. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist as it is unknown whether they will be predisposed to anaphylaxis with TRULICITY. Acute Kidney Injury: In patients treated with GLP-1 RAs, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In patients with renal impairment, use caution when initiating or escalating doses of Trulicity and monitor renal function in patients experiencing severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease: Use of Trulicity may be associated with gastrointestinal adverse reactions, sometimes severe. Trulicity has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Trulicity.

The most common adverse reactions (excluding hypoglycemia) reported in ≥5% of Trulicity-treated patients in placebo-controlled trials (placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg) were nausea (5.3%, 12.4%, 21.1%), diarrhea (6.7%, 8.9%, 12.6%), vomiting (2.3%, 6.0%, 12.7%), abdominal pain (4.9%, 6.5%, 9.4%), decreased appetite (1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), and fatigue (2.6%, 4.2%, 5.6%).

Gastric emptying is slowed by Trulicity, which may impact absorption of concomitantly administered oral medications. Use caution when oral medications are used with Trulicity. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with Trulicity. In clinical pharmacology studies, Trulicity did not affect the absorption of the tested, orally administered medications to a clinically relevant degree.

Pregnancy: Limited data with Trulicity in pregnant women are not sufficient to determine a drug associated risk for major birth defects and miscarriage. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide. Use only if potential benefit justifies the potential risk to the fetus.

Lactation: There are no data on the presence of dulaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Trulicity and any potential adverse effects on the breastfed infant from Trulicity or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of Trulicity have not been established and use is not recommended in patients less than 18 years of age.

Please see Brief Summary of Prescribing Information, including Boxed Warning about possible thyroid tumors including thyroid cancer, and Medication Guide on following pages.

Please see Instructions for Use included with the pen.

DG HCP ISI 15JAN2019 Trulicity® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Trulicity is available by prescription only.

Other product/company names mentioned herein are the trademarks of their respective owners.

References 1. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC. 2. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC. 3. Matfin G, Van Brunt K, Zimmermann AG, et al. Safe and effective use of the once weekly dulaglutide single-dose pen in injection-naïve patients with type 2 diabetes. J Diabetes Sci Technol.

2015;9(5):1071-1079.

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TRULICITY® (dulaglutide)

ADVERSE REACTIONS

Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE

Clinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Pool of Placebocontrolled Trials: These data reflect exposure of 1670 patients to TRULICITY and a mean duration of exposure to TRULICITY of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73 m2 ) in 96.0% of the pooled study populations. Adverse Reactions in PlaceboControlled Trials Reported in ≥5% of TRULICITY-Treated Patients: Placebo (N=568), TRULICITY 0.75mg (N=836), TRULICITY 1.5 mg (N=834) (listed as placebo, 0.75 mg, 1.5 mg): nausea (5.3%, 12.4%, 21.1%), diarrheaa (6.7%, 8.9%, 12.6%), vomitingb (2.3%, 6.0%, 12.7%), abdominal painc (4.9%, 6.5%, 9.4%), decreased appetite (1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), fatigued (2.6%, 4.2%, 5.6%). (a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise.) Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving TRULICITY than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively.

In addition to the adverse reactions ≥5% listed above, the following adverse reactions were reported more frequently in TRULICITY-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%; 3.9%; 3.7%), flatulence (1.4%; 1.4%; 3.4%), abdominal distension (0.7%; 2.9%; 2.3%), gastroesophageal reflux disease (0.5%; 1.7%; 2.0%), and eructation (0.2%; 0.6%; 1.6%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of TRULICITY as monotherapy and add-on therapy to oral medications or insulin.

In this pool, a total of 3342 patients with type 2 diabetes were treated with TRULICITY for a mean duration 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 ml/min/1.73 m2) in 95.7% of the TRULICITY population. In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed as ≥5% above. Other Adverse Reactions: Hypoglycemia: Incidence (%) hypoglycemia in placebo-controlled clinical studies : episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Add-on to Metformin at 26 weeks, Placebo (N=177), TRULICITY 0.75 mg (N=302), TRULICITY 1.5 mg (N=304), Hypoglycemia with a glucose level <54 mg/dL: Placebo: 0; 0.75 mg: 0.3; 1.5 mg: 0.7; Severe hypoglycemia: all 0.

Add-on to Metformin + Pioglitazone at 26 weeks, Placebo (N=141), TRULICITY 0.75 mg (N=280), TRULICITY 1.5 mg (N=279), Hypoglycemia with a glucose level <54 mg/dL: Placebo: 1.4; 0.75 mg: 2.1; 1.5 mg: 0; Severe hypoglycemia: all 0. Add-on to Glimepiride at 24 weeks, Placebo (N=60), TRULICITY 1.5 mg (N=239), Hypoglycemia with a glucose level <54 mg/dL: Placebo: 0; 1.5 mg: 3.3; Severe hypoglycemia: all 0. Add-on to Insulin Glargine with or without Metformin at 28 weeks, Placebo (N=150), TRULICITY 1.5 mg (N=150), Hypoglycemia with a glucose level <54 mg/dL: Placebo: 9.3; 1.5 mg: 14.7; Severe hypoglycemia: Placebo: 0; 1.5 mg: 0.7. Add-on to SGLT2i with or without Metformin at 24 weeks, Placebo (N=140), TRULICITY 0.75mg (N=141) TRULICITY 1.5 mg (N=142), Hypoglycemia with a glucose level <54 mg/dL: Placebo: 0.7; 0.75 mg: 0.07; 1.5 mg: 0.7; Severe hypoglycemia: Placebo: 0; 0.75mg 0.7; 1.5 mg: 0.

TRULICITY® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use: Not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans.

Prescribe TRULICITY only to patients for whom the potential benefits outweigh the potential risk. Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. It is not a substitute for insulin. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. Not recommended in patients with pre-existing severe gastrointestinal disease.

WARNING: RISK OF THYROID C-CELL TUMORS • In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

• TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. CONTRAINDICATIONS Do not use in patients with a personal or family history of MTC or in patients with MEN 2. Do not use in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components.

WARNINGS AND PRECAUTIONS Risk of Thyroid C-cell Tumors: In male and female rats, dulaglutide causes a dose-related and treatmentduration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including MTC, in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Pancreatitis: In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years). After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, promptly discontinue TRULICITY. If pancreatitis is confirmed, TRULICITY should not be restarted. TRULICITY has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TRULICITY is used in combination with insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting. Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with TRULICITY. If a hypersensitivity reaction occurs, the patient should discontinue TRULICITY and other suspected medications and promptly seek medical advice. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY. Acute Kidney Injury: In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal failure, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. Severe Gastrointestinal Disease: Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe. TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRULICITY. TRULICITY® (dulaglutide)

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Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagoques. In a 78-week clinical trial hypoglycemia (glucose level<54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-week clinical trial, hypoglycemia (glucose level <54mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg, and 1.5 mg, respectively, were co-administered with prandial insulin. Heart Rate Increase and Tachycardia Related Adverse Reactions: TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm).

The long-term clinical effects of the increase in HR have not been established. Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4%, and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3%, and 2.2% of patients treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. Hypersensitivity: Systemic hypersensitivity adverse reactions sometimes severe (eg, severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on TRULICITY in the four Phase 2 and Phase 3 studies. Injection-site Reactions: In the placebo-controlled studies, injection-site reactions (eg, injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First Degree Atrioventricular (AV) Block: A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7%, and 2.3% for placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR TRULICITY® (dulaglutide)

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interval increase to at least 220 milliseconds was observed in 0.7%, 2.5%, and 3.2% of patients treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. Amylase and Lipase Increase: Patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%. Immunogenicity: Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) TRULICITY-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in TRULICITY (ie, dulaglutide). Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products. Postmarketing Experience: The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Anaphylactic reactions, angioedema • Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis DRUG INTERACTIONS TRULICITY slows gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TRULICITY. Drug levels of oral medications with a narrow therapeutic index should be adequately monitored when concomitantly administered with TRULICITY. In clinical pharmacology studies, TRULICITY did not affect the absorption of the tested, orally administered medications to any clinically relevant degree.

USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary Limited data with TRULICITY in pregnant women are not sufficient to determine a drug associated risk for major birth defects and miscarriage. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy. TRULICITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered dulaglutide during organogenesis, early embryonic deaths, fetal growth reductions, and fetal abnormalities occurred at systemic exposures at least 14-times human exposure at the maximum recommended human dose (MRHD) of 1.5 mg/week. In pregnant rabbits administered dulaglutide during organogenesis, major fetal abnormalities occurred at 13-times human exposure at the MRHD. Adverse embryo/fetal effects in animals occurred in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide.

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an HbA1c >10%.

The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations: Disease-associated maternal and/or embryo/fetal risk; Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia- related morbidity.

Data: Animal Data: Pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide every 3 days during organogenesis had systemic exposures 4-, 14-, and 44-times human exposure at the maximum recommended human dose (MRHD) of 1.5 mg/week, respectively, based on plasma area under the time-concentration curve (AUC) comparison. Reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg. Irregular skeletal ossifications and increases in post- implantation loss also were observed at 4.89 mg/kg.

In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide every 3 days during organogenesis, systemic exposures in pregnant rabbits were 1-, 4-, and 13-times human exposure at the MRHD, based on plasma AUC comparison. Fetal visceral malformation of lung lobular agenesis and skeletal malformations of the vertebrae and/or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg.

In a prenatal-postnatal study in F0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, systemic exposures in pregnant rats were 2-, 4-, and 16-times human exposure at the MRHD, based on plasma AUC comparison. F1 pups from F0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through postnatal day 63 for males and postnatal day 84 for females. F1 offspring from F0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balanopreputial separation. Females had decreased startle response. These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment. F1 female offspring of the F0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg. The human relevance of these memory deficits in the F1 female rats is not known.

Lactation: Risk Summary There are no data on the presence of dulaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRULICITY and any potential adverse effects on the breastfed infant from TRULICITY or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of TRULICITY have not been established in pediatric patients.

TRULICITY is not recommended for use in pediatric patients younger than 18 years.

Geriatric Use: In the pool of placebo- and active-controlled trials, 620 (18.6%) TRULICITY-treated patients were 65 years of age and over and 65 TRULICITY-treated patients (1.9%) were 75 years of age and over.

TRULICITY® (dulaglutide)

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No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment: There is limited clinical experience in patients with mild, moderate, or severe hepatic impairment. Therefore, TRULICITY should be used with caution in these patient populations. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed.

Renal Impairment: In four Phase 2 and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) TRULICITY-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m2), 171 (4.3%) TRULICITY-treated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m2),) and no TRULICITY-treated patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). In a 52-week clinical trial, 270 (71%) TRULICITY-treated patients had moderate renal impairment (eGFR ≥ 30 but <60 mL/min/1.73 m2) and 112 (29%) TRULICITY-treated patients had severe renal impairment (eGFR ≥ 15 but < 30 mL/min/1.73 m2). No overall differences in safety or effectiveness were observed in this study. In a clinical pharmacology study in subjects with renal impairment, including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide PK was observed. In the 52-week Phase 3 study in patients with type 2 diabetes and moderate to severe renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies.No dose adjustment is recommended in patients with renal impairment including end-stage renal disease (ESRD). Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. There is limited clinical experience in patients with severe renal impairment or ESRD. TRULICITY should be used with caution in patients with ESRD. Gastroparesis: Dulaglutide slows gastric emptying. TRULICITY has not been studied in patients with pre-existing gastroparesis.

OVERDOSAGE :Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (eg, nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient’s clinical signs and symptoms.

PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide • Inform patients that TRULICITY causes benign and malignant thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (eg, a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their physician.

• Inform patients that persistent severe abdominal pain, that may radiate to the back and which may (or may not) be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TRULICITY promptly, and to contact their physician, if persistent severe abdominal pain occurs.

• The risk of hypoglycemia may be increased when TRULICITY is used in combination with a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and reinforce instructions for hypoglycemia management when initiating TRULICITY therapy, particularly when concomitantly administered with a sulfonylurea or insulin. • Patients treated with TRULICITY should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients treated with TRULICITY of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs. • Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of TRULICITY and other GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking TRULICITY and seek medical advice promptly. • Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant. • Prior to initiation of TRULICITY, train patients on proper injection technique to ensure a full dose is delivered. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inform patients of the potential risks and benefits of TRULICITY and of alternative modes of therapy. Inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and advise patients to seek medical advice promptly. • Each weekly dose of TRULICITY can be administered at any time of day, with or without food. The day of once-weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before. If a dose is missed and there are at least 3 days (72 hours) until the next scheduled dose, it should be administered as soon as possible. Thereafter, patients can resume their usual once-weekly dosing schedule.

If a dose is missed and the next regularly scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and instead resume TRULICITY with the next regularly scheduled dose. • Advise patients treated with TRULICITY of the potential risk of gastrointestinal side effects. • Instruct patients to read the Medication Guide and the Instructions for Use before starting TRULICITY therapy and review them each time the prescription is refilled. • Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. • Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is especially useful for evaluating longterm glycemic control.

Additional information can be found at www.TRULICITY.com

Eli Lilly and Company, Indianapolis, IN 46285, USA US License Number 1891 Copyright © 2014, 2015, 2017, Eli Lilly and Company. All rights reserved.

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MSP ARTÍCULO ORIGINAL

El cáncer gástrico:

una perspectiva global Por: Marcia Cruz Correa MD, PhD, AGAF, FASGE Michelle Cruz-Badía BS Research Assistant and Laboratory Technician at UPR Comprehensive Cancer Center María González Pons, PhD Afiliaciones: Universidad de Puerto Rico. Centro Comprensivo de Cáncer, San Juan, PR; Universidad of Puerto Rico Recinto de Ciencias Médicas, San Juan, P.R.

Resumen Summary En este artículo se discute la epidemiología, los In this article we discuss gastric cancer epidemiology, factores de riesgo, la carcinogénesis, y la prevención de risk factors, carcinogenesis, and prevention. cáncer gástrico.

Palabras claves: Cáncer gástrico, Helicobacter pylori, disparidades en cáncer gástrico,metaplasia gastrointestinal, quimio prevención.

Keywords: Gastric cancer, Helicobacter pylori, gastric cancer disparities, gastrointestinal metaplasia, chemoprevention.

Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

Carcinogénesis de CG Progresión de lesiones en estómago según la “Cascada de Correa” 1. La inflamación gástrica prolongada que resulta de la infección crónica por H. pylori causa daño epitelial que conduce a la atrofia gástrica, caracterizada por la pérdida de células parietales y células principales y atrofia glandular. El epitelio gástrico se reemplaza por metaplasia intestinal, seguida de focos de displasia de bajo grado, que luego pueden desarrollar displasia de alto grado que luego puede convertirse en adenocarcinoma.

Mucosa normal

gastritis crónica

gastritis atrófica

cáncer gástrico

Metaplasia intestinal

Displasia

figura 1

Epidemiologia El cáncer gástrico (CG) es el 5to cáncer más común y la 3ra causa de muerte por cáncer a nivel mundial2.

Se estimó que en el 2012 habrían 952,000 nuevos casos de cáncer gástrico a nivel mundial, de las cuales, cerca del 75% de las personas diagnosticadas morirán a causa de esta enfermedad3. Sin embargo, las tasas de incidencia de CG varían dramáticamente entre los diferentes países, siendo más altas en los países menos desarrollados3. El CG es más común en Asia Oriental, Europa y América del Sur y Central, mientras que las tasas de incidencia más bajas se observan en África y América del Norte4. Según el Registro Central de Cáncer de Puerto Rico, durante el periodo de 20112015, el CG estuvo entre las 10 malignidades de cáncer más comunes en hombres. Durante el mismo periodo, el CG fue la 6ta causa de muerte por cáncer en hombres y la 8va causa de muerte por cáncer en mujeres3. El riesgo promedio de que una persona desarrolle CG en su vida es de aproximadamente 1 en 111, con un riesgo de 2 a 3 veces mayor en hombres que en mujeres.

Aunque casi el 60% de los nuevos casos de CG se diagnostican en Asia6 , se han notado mejores resultados de sobrevida entre los individuos asiáticos en comparación con los diagnosticados en los países occidentales7. Las tasas de supervivencia de CG a cinco años de diagnóstico son un 40% más bajas en EE.UU. 72

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y Europa en comparación con Japón8. Además, de las disparidades en la incidencia y la mortalidad, también se han observado diferencias en la presentación clínica de la enfermedad y la ubicación anatómica. Las disparidades con respecto a la distribución geográfica del cáncer gástrico se atribuyen principalmente a las diferencias en los factores de riesgo, como los patrones dietéticos, el nivel socioeconómico y la prevalencia de infección con Helicobacter pylori entre las personas afectadas9. Las infecciones crónicas con H. pylori representan alrededor del 90% de los casos de CG noncardia en todo el mundo10, y por lo tanto, juega un papel importante en las variaciones regionales del CG. Otros factores de riesgo para el CG incluyen la disponibilidad de frutas y verduras frescas y métodos de conservación de alimentos, también aporta a variaciones regionales de la incidencia esta malignidad11.

Factores de riesgo para el cáncer gástrico Los factores de riesgo para el desarrollo de cáncer gástrico incluyen: sexo masculino, edad avanzada, infección con H. pylori, fumar tabaco, ciertos patrones dietéticos y bajo nivel socioeconómico. Haber sido infectado con H. pylori es uno de los principales factores de riesgo para CG, específicamente CG non-cardia (cáncer en todas las áreas del estómago, excepto en la parte superior cerca del estómago) 12, 13. H. pylori es la

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‘‘El cáncer gástrico es el quinto cáncer más común y la tercera causa de muerte por cáncer a nivel mundial. Cerca del 75% de las personas diagnosticadas morirán a causa de esta enfermedad” infección bacteriana crónica más común en humanos y se cree que induce gastritis en casi todos los individuos expuestos a la bacteria. La gastritis progresa a lo largo de un proceso llamado la "Cascada de Correa", que comienza con gastritis y progresa hasta etapas precancerosas de gastritis atrófica multifocal y metaplasia intestinal; sub-siguientemente la lesión progresa a ser displasia y adenocarcinoma gástrico (Figura 1).

La prevalencia de infección con H. pylori también está influenciada por factores socioeconómicos, demográficos y étnicos14. Entre los adultos de mediana edad, la prevalencia es mayor de 80% en países en desarrollo, en comparación con 20-50% en los países industrializados15. La prevalencia estimada de H. pylori en EE.UU. es de 30.7% y varía entre los grupos raciales y/o étnicos: 21% en blancos, 52% en afroamericanos, y 64% en mexicano-estadounidenses16.

Sin embargo, se han encontrado diferencias marcadas en la incidencia de infecciones con H. pylori entre individuos hispanos de diferentes regiones de Centroamérica y Sudamérica14, 17. En Puerto Rico, la seroprevalencia de H. pylori es de 33.0%, la cual es comparable con la seroprevalencia reportada en EE.UU. Según nuestro estudio, las infecciones con H. pylori son comunes, y se observan tasas más altas de infecciones con H. pylori en individuos que viven en municipios con baja densidad poblacional y aquellos con bajo nivel socioeconómico, representando una disparidad en salud18. La prevalencia de infecciones con H. Pylori en Puerto Rico puede tener un impacto en la incidencia de neoplasia gástrica y puede contribuir a una disparidad en cuanto a la incidencia de CG entre las personas con bajo nivel socioeconómico en la isla. En adición, cuando se toma en consideración que la población puertorriqueña presentó limitaciones en cuanto al acceso a alimentos y bebidas seguras, falta de agua potable, posible hacinamiento en refugios, malas prácticas higiénicas y limitaciones en cuanto al acceso de asistencia médica tras el huracán María19, todos estos factores podrían afectar la cantidad de personas expuestas a infecciones con H. pylori y con más riesgo a desarrollar neoplasia gástrica luego de este desastre natural. Sin embargo, el efecto del huracán María en la incidencia de H. pylori y un posterior aumento en las tasas de incidencia de CG en la población puertorriqueña debe ser evaluado en estudios epidemiológicos futuros.

Disparidades raciales y/o étnicas en cáncer gástrico Aunque el número de muertes por CG ha disminuido a través de los años, se siguen observando importantes disparidades geográficas y raciales en la incidencia y mortalidad a causa de esta malignidad. La disminución observada en la incidencia de CG se ha producido más en los tumores de tipo non-cardia, que son atribuibles principalmente a infección con H. pylori, el uso del tabaco y a las dietas altas en sodio20. Se ha observado una incidencia significativamente mayor de CG entre los asiáticos, seguido por negros e hispanos en comparación con los blancos21-23. Curiosamente, la incidencia de CG es similar en todos los grupos raciales y/o étnicos en los Estados Unidos hasta los 60-64 años, donde las tasas de incidencia entre individuos asiáticos aumentan drásticamente. De 1992 a 2009, la sobrevida a 3 años del diagnóstico de CG fue más alta entre asiáticos (26%), seguida por individuos afroamericanos, hispanos y blancos, los cuales tenían tasas de sobrevida comparables (~ 19%)23.

Las factores que contribuyen a las disparidades geográficas y raciales y/o étnicas del CG aún no se conocen por completo y pueden deberse a una combinación de factores que incluyen: diferencias en cuanto a acceso a cuidado médico, factores ambientales y/o factores genéticos24. América Latina tiene una alta incidencia de CG, con una concentración mayor de casos en las regiones montañosas25-27, donde la relación entre mortalidad-incidencia es extremadamente alta. En los EE.UU., el CG representa una gran disparidad de salud donde individuos no caucásicos, incluyendo a los hispanos, tienen tasas de incidencia de CG casi dos veces más altas comparadas a la población caucásica21, 22. Es importante tomar en consideración esta disparidad en salud en la población hispana en EE.UU. ya que se pronostica que este grupo formará el 25% de la población estadounidense para 2040-2050 y representan una población en riesgo para desarrollar CG, particularmente entre inmigrantes de áreas de alta incidencia, como América Central.

Debido a que se han reportado diferencias marcadas en la prevalencia de H. pylori entre los hispanos de diferentes países de Centroamérica y Sudamérica17, 20, el riesgo de CG entre los hispanos de EEUU puede variar según el país del cual provengan.

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Cardia

Non - Cardia

Sin embargo, cuando se evalúan los factores de susceptibilidad a cáncer en los Estados Unidos los hispanos de diferentes poblaciones generalmente se agrupan. El agrupar los pacientes hispanos como una sola categoría nos limita la capacidad de evaluar los factores biológicos, hereditarios y ambientales que influyen en el riesgo a desarrollar CG y que pueden variar de acuerdo al sub-grupo hispano. Por esta razón, se diseñó un estudio en Puerto Rico para describir y comparar las características epidemiológicas de los hispanos puertorriqueños diagnosticados con CG. En nuestro estudio se observó que el 60% de los casos totales de CG entre los años 1998-2007 ocurrian en hombres. En este mismo periodo, la mayoría de los tumores fueron diagnosticados en individuos con 60 años o más (80%). En cuanto a sobrevida, al comparar los periodos del 1998-2002 y 2003-2007, se observó un aumento leve de 22% a 28% en la sobrevida relativa 5 años luego del diagnóstico (Figura 2). La sobrevivencia relativa a 5 años es mayor en mujeres que en hombres.

Durante el periodo 2003-2007 la sobrevida relativa de acuerdo al estadio del tumor fue de 45% para tumores localizados, 19% para tumores regionales, y 7% para tumores avanzados.

carcinoma gástrico en etapas tempranas se define como tumores malignos limitados a la mucosa o submucosa, independientemente de la invasión de los ganglios linfáticos. El carcinoma gástrico en etapa avanzada se clasifica de acuerdo con la extensión de la invasión y la apariencia endoscópica (lesiones polipoides, ulceradas con bordes bien definidos, ulceradas con bordes mal definidos o infiltrantes difusas sin evidencia de masa o úlceras).

La ubicación del tumor dicta la clasificación anatómica como cardia o non-cardia (Figura 3). Los adenocarcinomas presentan diferentes características clínicas y epidemiológicas de acuerdo a su clasificación anatómica. CG localizado en la cardia afecta a poblaciones predominantemente caucásicas y se asocia con la enfermedad por reflujo gastroesofágico, pero no con infecciones con H. pylori. Los adenocarcinomas en el cardia son agresivos, se caracterizan por su invasión rápida de las paredes gástricas y esofágicas, metastizan a los ganglios linfáticos locales y tienen un mal pronóstico.

Debido a su agresividad, la Clasificación Conjunta Americana de Cáncer (AJCC) decidió utilizar el sistema de estadio del cáncer esofágico para todos los CG que surgen en la unión esofagogástrica y cualquier cáncer que surja en los 5 cm proximales del estómago que afecten la unión esofagogástrica. A diferencia de los tumores en la región Clasificación del cáncer gástrico del cardia, los tumores localizados distales esta región El CG se clasifica en dos grupos principales: estados (non-cardia) han disminuido en las últimas décadas. El tempranos o avanzados. El pronóstico depende en gran CG non-cardia se asocia con infecciones con H. pylori y medida de la etapa del tumor al momento de diagnóstico. comprende más del 60% de todos los casos de GC a nivel La tasa de supervivencia a 5 años en pacientes con CG mundial. temprano se encuentra entre el 85-100%, mientras que para la CG avanzado es de solo 5-20%. El grado de Clasificación histológica invasión define si el tumor es temprano o avanzado. El El CG se clasifica como intestinal (con uniones 74

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intercelulares) o difuso (sin uniones intercelulares). Los adenocarcinomas de tipo intestinal forman glándulas o túbulos revestidos por epitelio que se asemeja a la mucosa intestinal.

Aunque la incidencia de CG de tipo intestinal ha disminuido recientemente, sigue siendo el tipo más frecuente de CG encontrado en poblaciones con alta incidencia de esta malignidad. Este tipo de CG por lo general ocurre en una proporción de 2 hombres por cada mujer y en individuos entre 55-80 años de edad.

Los adenocarcinomas gástricos de tipo difuso son más agresivos y tienen un peor pronóstico. No se ha observado diferencias en incidencia en este tipo de CG entre géneros y generalmente se diagnostican en pacientes más jóvenes (40-60 años de edad). Las células del CG tipo difuso carecen de cohesión e invaden los tejidos de forma independiente o en pequeños grupos. El CG de tipo difuso puede estar asociado a infecciones con H. pylori, con la pérdida de expresión de E-cadherina y hasta la fecha, no se han definido lesiones pre-cancerosas.

Prevención del cáncer gástrico L a pr e venc ión pr i m a r i a tiene como objetivo prevenir la enfermedad antes de que ocurra, evitando así la exposición a factores de riesgo, cambiando las conductas no saludables, y actuando para prevenir el desarrollo de la enfermedad. Los cambios de estilo de vida recomendados para prevenir la CG incluyen limitar la exposición al tabaco y mantener un índice de masa corporal saludable.

En términos de dieta, el consumo de frutas y hortalizas frescas uno o más días por semana reduce significativamente el riesgo de CG. La erradicación de la infección con H. pylori es esencial en la prevención del CG23, 24. Individuos de grupos

raciales y/o étnicos con alto riesgo de CG deben de ser evaluados para la presencia de la infección y recibir antibióticos para su erradicación.

Metaplasia gastrointestinal y quimioprevención Las lesiones gástricas precancerosas, como la metaplasia gastrointestinal (GIM, por sus siglas en inglés) son frecuentes tanto en las regiones de alta como de baja incidencia en el mundo. GIM es el reemplazo de la mucosa gástrica por un epitelio que se parece histológicamente a la mucosa intestinal y es un evento clave en el proceso de la carcinogénesis gástrica. La prevalencia de GIM varía según la tasa de infección por H. pylori en la población28. La metaplasia intestinal está presente en aproximadamente el 20% de todas las biopsias gástricas29, un 10% de los pacientes con GIM desarrollan CG30. En nuestro estudio evaluando la prevalencia de GIM en patologías gástricas en Puerto Rico durante el periodo de 2012-2014, se observó que GIM estaba presente en 10.7% de los tejidos analizados. La mayoría de los casos de GIM se observaron en biopsias de la incisura angularis y el antro. Infecciones con H. pylori se detectaron en el 26.9% de los casos.

A las personas con síntomas de GIM se les recomienda una endoscopía de vigilancia cada 3 años 31. Sin embargo, ya que los métodos para erradicar H. pylori son limitados, se necesitan otros métodos de intervención farmacológica para prevenir el desarrollo de CG 16 . El uso de medicamentos anti-inf lamatorios no esteroidales ( NSA I D) y aspirina se han investigado como agentes quimiopreventivos de CG31. La cúrcuma, un polifenol cualidades antiinf lamatorias y

Figura 3: Clasificación anatómica e histopatológica del cáncer gástrico.

A. Clasificación anatómica del CG (cardia vs. non-cardia).

B. Clasificación histológica demostrando cáncer gástrico tipo intestinal.

C. Imagen demostrando la histología del cáncer gástrico tipo difuso.

antioxidantes, se ha evaluado en estudios de celulares como agente de prevención de cáncer gástrico.

Nuestro grupo de investigación en el Centro Comprensivo de Cáncer de la UPR y el Recinto de Ciencias Médicas, en conjunto con la Universidad de Vanderbilt estamos llevando a cabo un estudio clínico para evaluar la cúrcuma como agente de quimioprevención para el CG (número de ensayo clínico: NCT02782949). Ya que más de la mitad de los individuos diagnosticados con CG mueren a causa de esta malignidad, es importante seguir investigando maneras de prevenir la progresión de lesiones pre-cancerosas como GIM, para así salvar vidas y eliminar las disparidades de salud en cuanto al CG en nuestra población.

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11. 11. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.

Cancer Epidemiol Biomarkers Prev 2014; 23(5):700-713.

12. Machida-Montani A, Sasazuki S, Inoue M, Natsukawa S, Shaura K, Koizumi Y, et al.

Association of Helicobacter pylori infection and environmental factors in non-cardia gastric cancer in Japan. Gastric Cancer 2004; 7(1):46-53.

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13. Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study.

Scand J Gastroenterol 1999; 34(4):353-360.

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17. Bonequi P, Meneses-Gonzalez F, Correa P, Rabkin CS, Camargo MC. Risk factors for gastric cancer in Latin America: a metaanalysis. Cancer causes & control : CCC 2013; 24(2):217-231.

18. Gonzalez-Pons M, Soto-Salgado M, Sevilla J, Marquez-Lespier JM, Morgan D, Perez CM, et al. Seroprevalence of Helicobacter pylori in Hispanics living in Puerto Rico: A population-based study.

Helicobacter 2017.

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THESE ARE PATIENTS WITH

METASTATIC GASTRIC,

NON-SMALL CELL LUNG, OR COLORECTAL CANCER. PATIENTS WHOSE DISEASE HAS PROGRESSED ON PRIOR TREATMENT.* PATIENTS WHO KNOW THEIR SITUATION, BUT ARE NOT SURRENDERING TO IT.

PATIENTS WHO, IN THE FACE OF ADVERSITY,

REMAIN DETERMINED.

LEARN MORE ABOUT THE APPROPRIATE PATIENTS FOR CYRAMZA AT CYRAMZAHCP.COM *Hypothetical patient example.

SELECT IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing.

Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Please see additional Important Safety Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing, on adjacent page.

Also see the Brief Summary of Prescribing Information for CYRAMZA on subsequent pages.

”We have some unfinished business.”

METASTATIC GASTRIC OR GEJ ADENOCARCINOMA INDICATION CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

”Whatever’s next, I want to be all in.”

METASTATIC NON-SMALL CELL LUNG CANCER INDICATION CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

”I ’m ready to do

what it takes.”

METASTATIC COLORECTAL CANCER INDICATION

CYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

INDICATIONS

3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo. metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients vs placebo in study 1 were: metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease thromboembolic events (1.7% vs 0%). progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reCYRAMZA, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of patients with metaported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, static colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients.

Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate IMPORTANT SAFETY INFORMATION FOR CYRAMZA of infusion-related reactions was 0.4%.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Most Common Adverse Reactions—Combination With Paclitaxel Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia severe bleeding.

(54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage gastrointestinal perforation. events (10% vs 6%; 4% vs 2%).

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutroDiscontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. penia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more Warnings and Precautions patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

Hemorrhage • Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were • In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel in advanced gastric cancer, the CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel). incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2. In study 3, Most Common Adverse Reactions—Combination With Docetaxel • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoag- docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/ asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs ulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3. In study 4, which evaluated CYRAMZA plus FOLFIRI in metastatic colorectal cancer, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

• The most common serious adverse events with CYRAMZA plus docetaxel in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated Arterial Thromboembolic Events (ATEs) patients versus 37% in patients who received placebo plus docetaxel.

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia • In patients ≥65 years of age, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE. docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or Hypertension within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), and in patients • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Monitor blood pressure every 2 weeks or more frequently as indicated CYRAMZA in study 3 were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of grade ≥3 during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertenhemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage sive crisis or hypertensive encephalopathy. was 10% and the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall Infusion-Related Reactions (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel.

(16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA in- • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus fusion. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. docetaxel versus 0.8% placebo plus docetaxel).

Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs. Most Common Adverse Reactions—Combination With FOLFIRI Gastrointestinal Perforations • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus • Four of 570 patients (0.7%) who received CYRAMZA as a single agent in advanced gastric cancer clinical trials experienced FOLFIRI and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea (60% vs 51%; 11% vs 10%), neutropenia (59% vs gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo plus paclitaxel. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus 46%; 38% vs 23%), decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%; 0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28% vs 14%; 3% vs <1%), hypertension (26% vs 9%; 11% vs 3%), peripheral edema (20% vs docetaxel as compared to 0.3% for placebo plus docetaxel. In study 4, the incidence of gastrointestinal perforation was 1.7% 9%; <1% vs 0%), proteinuria (17% vs 5%; 3% vs <1%), palmar-plantar erythrodysesthesia syndrome (13% vs 5%; 1% vs <1%), for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal hemorrhage events (12% vs 7%; 2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty percent of gastrointestinal perforation. patients treated with CYRAMZA plus FOLFIRI received granulocyte colony-stimulating factors.

Impaired Wound Healing • The most common serious adverse events with CYRAMZA plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA has the potential to adversely affect febrile neutropenia (2.8%). wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops • Treatment discontinuation of any study drug due to adverse reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated patients (29%) than in placebo plus FOLFIRI-treated patients (13%). The most common adverse reactions leading to disconwound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. tinuation of any component of CYRAMZA plus FOLFIRI as compared to placebo plus FOLFIRI were neutropenia (12.5% versus Clinical Deterioration in Child-Pugh B or C Cirrhosis 5.3%) and thrombocytopenia (4.2% versus 0.8%). The most common adverse reactions leading to treatment discontinuation of • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in CYRAMZA were proteinuria (1.5%) and gastrointestinal perforation (1.7%). patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus FOLFIRI-treated patients in study 4 consisted of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) gastrointestinal perforation (1.7% CYRAMZA plus FOLFIRI versus 0.6% for placebo plus FOLFIRI).

• RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Discontinue CYRAMZA in patients who develop RPLS. Symp• Thyroid-stimulating hormone (TSH) was evaluated in 224 patients (115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo toms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. plus FOLFIRI-treated patients) with normal baseline TSH levels. Increased TSH was observed in 53 (46%) patients treated with Proteinuria Including Nephrotic Syndrome CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with placebo plus FOLFIRI. • In study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including Drug Interactions 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by • No pharmacokinetic interactions were observed between ramucirumab and paclitaxel, between ramucirumab and docetaxel, or between ramucirumab and irinotecan or its active metabolite, SN-38. urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy.

Use in Specific Populations Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine • Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF, and protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. the setting of nephrotic syndrome.

There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have Thyroid Dysfunction been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive • Monitor thyroid function during treatment with CYRAMZA. In study 4, the incidence of hypothyroidism reported as an adverse potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and pediatric development, and to event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and 0.9% in the placebo plus FOLFIRI-treated patients. use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. Embryofetal Toxicity • Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that • Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link breastfeeding is not recommended during treatment with CYRAMZA. angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use • Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Please see Brief Summary of Prescribing Information for CYRAMZA, including Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs wound healing, on adjacent pages.

RB-P-HCP ISI 16FEB2017 CYRAMZA® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

PP-RB-US-1524 07/2018 PRINTED IN USA © Lilly USA, LLC 2018. All rights reserved.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidineor platinum-containing chemotherapy.

Non-Small Cell Lung Cancer CYRAMZA in combination with docetaxel, is indicated for treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. Colorectal Cancer CYRAMZA in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.

In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel.

Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event.

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation.

In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

CYRAMZA® (ramucirumab) injection

CYRAMZA RB-P HCP BS 27MAR2017 - 9.5 x 11.5

RB-P HCP BS 27MAR2017

Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Gastric Cancer Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.

CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1 provides the frequency and severity of adverse reactions in Study 1.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA (8 mg/kg) N=236

Placebo N=115

All Grades (Frequency %)

Grade 3-4 (Frequency %)

All Grades (Frequency %)

Grade 3-4 (Frequency %)

14

1

9

2

6

3

2

1

9

0

3

0

16

8

8

3

Gastrointestinal Disorders Diarrhea Metabolism and Nutrition Disorders Hyponatremia Nervous System Disorders Headache Vascular Disorders Hypertension

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 61 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.

In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2 provides the frequency and severity of adverse reactions in Study 2.

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 Adverse Reactions (MedDRA) System Organ Class Blood and Lymphatic System Disorders Neutropenia Thrombocytopenia Gastrointestinal Disorders Diarrhea Gastrointestinal hemorrhage events Stomatitis CYRAMZA® (ramucirumab) injection

CYRAMZA plus Paclitaxel (N=327) All Grades Grade ≥3 (Frequency %) (Frequency %)

Placebo plus Paclitaxel (N=329) All Grades Grade ≥3 (Frequency %) (Frequency %)

54 13

41 2

31 6

19 2

32 10 20

4 4 1

23 6 7

2 2 1 RB-P HCP BS 27MAR2017

PRINTER VERSION 1 OF 3

Table Table2: 2:Adverse AdverseReactions ReactionsOccurring OccurringatatIncidence IncidenceRate Rate≥5% ≥5%and anda ≥2% a ≥2% Difference DifferenceBetween BetweenArms Armsin inPatients PatientsReceiving ReceivingCYRAMZA CYRAMZAplus plusPaclitaxel Paclitaxelin inStudy Study2 (Cont.)

2 (Cont.)

Clinically Clinicallyrelevant relevantadverse adversedrug drugreactions reactionsreported reportedin in≥1% ≥1%and and<5% <5%of ofthetheCYRAMZA CYRAMZAplus plusdocetaxel-treated docetaxel-treatedpatients patients in inStudy Study3 were 3 werehyponatremia hyponatremia(4.8% (4.8%CYRAMZA CYRAMZAplus plusdocetaxel docetaxelversus versus2.4% 2.4%forforplacebo placeboplus plusdocetaxel) docetaxel)and andproteinuria proteinuria (3.3% CYRAMZA (3.3% CYRAMZAplus plusdocetaxel docetaxelversus versus0.8% 0.8%placebo placeboplus plusdocetaxel). docetaxel).

CYRAMZA CYRAMZAplus plusPaclitaxel Paclitaxel Placebo Placeboplus plusPaclitaxel Paclitaxel (N=327) (N=327) (N=329) (N=329) AllAllGrades Grades Grade Grade≥3≥3 AllAllGrades Grades Grade Grade≥3≥3 (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%) General GeneralDisorders Disordersand andAdministration AdministrationSite SiteDisorders Disorders Adverse AdverseReactions Reactions (MedDRA) (MedDRA)System System Organ OrganClass Class

Fatigue/Asthenia Fatigue/Asthenia Peripheral Peripheraledema edema

5757 2525

Metabolism Metabolismand andNutrition NutritionDisorders Disorders Hypoalbuminemia Hypoalbuminemia 1111 Renal Renaland andUrinary UrinaryDisorders Disorders Proteinuria Proteinuria 1717 Respiratory, Respiratory, Thoracic, Thoracic, and andMediastinal MediastinalDisorders Disorders Epistaxis Epistaxis 3131 Vascular VascularDisorder Disorder Hypertension Hypertension 2525

1212 22

4444 1414

66 11

11

55

11

11

66

00

00

77

00

1515

66

33

Clinically Clinicallyrelevant relevantadverse adversereactions reactionsreported reportedin in≥1% ≥1%and and<5% <5%of ofthetheCYRAMZA CYRAMZAplus pluspaclitaxel paclitaxeltreated treatedpatients patientsin inStudy Study2 2 were weresepsis sepsis(3.1% (3.1%CYRAMZA CYRAMZAplus pluspaclitaxel paclitaxelversus versus1.8% 1.8%placebo placeboplus pluspaclitaxel) paclitaxel)and andgastrointestinal gastrointestinalperforations perforations(1.2% (1.2% CYRAMZA CYRAMZAplus pluspaclitaxel paclitaxelversus versus0.3% 0.3%forforplacebo placeboplus pluspaclitaxel). paclitaxel).

Non-Small Non-SmallCell CellLung LungCancer Cancer CYRAMZA CYRAMZA Administered Administeredin inCombination Combinationwith withDocetaxel Docetaxel Study Study3 was 3 wasa multinational, a multinational, randomized, randomized, double-blind double-blindstudy studyconducted conductedin inpatients patientswith withNSCLC NSCLCwith withdisease diseaseprogression progressiononon or orafter afterone oneplatinum-based platinum-basedtherapy therapyforforlocally locallyadvanced advancedor ormetastatic metastaticdisease. disease.

Patients Patientsreceived receivedeither eitherCYRAMZA CYRAMZA1010mg/kg mg/kg 2 2 2 2 intravenouslyevery every3 weeks 3 weeksor orplacebo placeboplus plusdocetaxel docetaxel7575mg/m mg/mintravenously intravenouslyevery every intravenously intravenouslyplus plusdocetaxel docetaxel7575mg/m mg/mintravenously 3 weeks.

3 weeks.

Due Dueto toananincreased increasedincidence incidenceof ofneutropenia neutropeniaand andfebrile febrileneutropenia neutropeniain inpatients patientsenrolled enrolledin inEast East Asian Asiansites, sites, Study Study3 3 was wasamended amendedand and2424patients patients(11 CYRAMZA (11 CYRAMZAplus plusdocetaxel, docetaxel, 1313placebo placeboplus plusdocetaxel) docetaxel)at atEast East Asian Asiansites sitesreceived receiveda starting a starting 2 2 every every3 weeks.

3 weeks.

Study Study3 excluded 3 excludedpatients patientswith withananECOG ECOGPSPSof of2 or 2 orgreater, greater, bilirubin bilirubingreater greater dose doseof ofdocetaxel docetaxelat at6060mg/m mg/m than thanthetheupper upperlimit limitof ofnormal normal(ULN), (ULN), uncontrolled uncontrolledhypertension, hypertension, major majorsurgery surgerywithin within28 days, 28 days, radiographic radiographicevidence evidenceof ofmajor major airway airwayor orblood bloodvessel vesselinvasion invasionbybycancer, cancer, radiographic radiographicevidence evidenceof ofintra-tumor intra-tumorcavitation, cavitation, or orgross grosshemoptysis hemoptysiswithin withinthethe preceding preceding2 months, 2 months, and andpatients patientsreceiving receivingtherapeutic therapeuticanticoagulation anticoagulationor orchronic chronicanti-platelet anti-platelettherapy therapyother otherthan thanonce oncedaily daily aspirin. aspirin.

The Thestudy studyalso alsoexcluded excludedpatients patientswhose whoseonly onlyprior priortreatment treatmentforforadvanced advancedNSCLC NSCLCwas wasa tyrosine a tyrosinekinase kinase(epidermal (epidermal growth growthfactor factorreceptor receptor[EGFR] [EGFR]or oranaplastic anaplasticlymphoma lymphomakinase kinase[ALK]) [ALK])inhibitor. inhibitor.

The Thedata datadescribed describedbelow belowreflect reflectexposure exposure to toCYRAMZA CYRAMZAplus plusdocetaxel docetaxelin in627 627patients patientsin inStudy Study3. 3.

Demographics Demographicsand andbaseline baselinecharacteristics characteristicswere weresimilar similarbetween between treatment treatmentarms. arms.

Median Medianage agewas was6262years; years;67% 67%of ofpatients patientswere weremen; men;84% 84%were were White Whiteand and12% 12%were were Asian; Asian;33% 33%had had ECOG ECOGPSPS0; 0;74% 74%had hadnon-squamous non-squamoushistology histologyand and25% 25%had hadsquamous squamoushistology. histology.

Patients Patientsreceived receiveda median a medianof of4.54.5doses dosesof of CYRAMZA; CYRAMZA;thethemedian medianduration durationof ofexposure exposurewas was3.53.5months, months, and and195 195(31% (31%of of627) 627)patients patientsreceived receivedCYRAMZA CYRAMZAforforat atleast least sixsixmonths. months.

In InStudy Study3, 3, thethemost mostcommon commonadverse adversereactions reactions(all(allgrades) grades)observed observedin inCYRAMZA CYRAMZAplus plusdocetaxel-treated docetaxel-treatedpatients patientsat ata rate a rateof of ≥30% ≥30%and and≥2% ≥2%higher higherthan thanplacebo placeboplus plusdocetaxel docetaxelwere wereneutropenia, neutropenia, fatigue/asthenia, fatigue/asthenia, and andstomatitis/mucosal stomatitis/mucosalinflammation. inflammation.

Treatment Treatmentdiscontinuation discontinuationdue dueto toadverse adversereactions reactionsoccurred occurredmore morefrequently frequentlyin inCYRAMZA CYRAMZAplus plusdocetaxel-treated docetaxel-treatedpatients patients (9%) (9%)than thanin inplacebo placeboplus plusdocetaxel-treated docetaxel-treatedpatients patients(5%).

(5%).

The Themost mostcommon commonadverse adverseevents eventsleading leadingto totreatment treatment discontinuation discontinuationof ofCYRAMZA CYRAMZAwere wereinfusion-related infusion-relatedreaction reaction(0.5%) (0.5%)and andepistaxis epistaxis(0.3%).

(0.3%).

ForForpatients patientswith withnon-squamous non-squamous histology, histology, thetheoverall overallincidence incidenceof ofpulmonary pulmonaryhemorrhage hemorrhagewas was7%7%and andthetheincidence incidenceof of≥Grade ≥Grade3 pulmonary 3 pulmonaryhemorrhage hemorrhagewas was 1%1%forforCYRAMZA CYRAMZAplus plusdocetaxel docetaxelcompared comparedto to6%6%overall overallincidence incidenceand and1%1%forfor≥Grade ≥Grade3 pulmonary 3 pulmonaryhemorrhage hemorrhageforforplacebo placebo plus plusdocetaxel. docetaxel.

ForForpatients patientswith withsquamous squamoushistology, histology, thetheoverall overallincidence incidenceof ofpulmonary pulmonaryhemorrhage hemorrhagewas was10% and 10% andthethe incidence incidenceof of≥Grade ≥Grade3 pulmonary 3 pulmonaryhemorrhage hemorrhagewas was2%2%forforCYRAMZA CYRAMZAplus plusdocetaxel docetaxelcompared comparedto to12% overall 12% overallincidence incidenceand and 2%2%forfor≥Grade ≥Grade3 pulmonary 3 pulmonaryhemorrhage hemorrhageforforplacebo placeboplus plusdocetaxel. docetaxel.

The Themost mostcommon commonserious seriousadverse adverseevents eventswith withCYRAMZA CYRAMZA plus plusdocetaxel docetaxelwere werefebrile febrileneutropenia neutropenia(14%), (14%), pneumonia pneumonia(6%), (6%), and andneutropenia neutropenia(5%).

(5%).

The Theuseuseof ofgranulocyte granulocytecolonycolonystimulating stimulatingfactors factorswas was42% 42%in inCYRAMZA CYRAMZAplus plusdocetaxel-treated docetaxel-treatedpatients patientsversus versus37% 37%in inpatients patientswho whoreceived receivedplacebo placeboplus plus docetaxel. docetaxel.

In Inpatients patients≥65 ≥65years, years, there therewere were1818(8%) (8%)deaths deathsonontreatment treatmentor orwithin within3030days daysof ofdiscontinuation discontinuationforforCYRAMZA CYRAMZA plus plusdocetaxel docetaxeland and9 (4%) 9 (4%)deaths deathsforforplacebo placeboplus plusdocetaxel. docetaxel.

In Inpatients patients<65 <65years, years, there therewere were1313(3%) (3%)deaths deathsonontreatment treatment or orwithin within30 days 30 daysof ofdiscontinuation discontinuationforforCYRAMZA CYRAMZAplus plusdocetaxel docetaxeland and2626(6%) (6%)deaths deathsforforplacebo placeboplus plusdocetaxel. docetaxel.

Table Table3 provides 3 providesthethefrequency frequencyand andseverity severityof ofadverse adversereactions reactionsin inStudy Study3. 3.

1616 4949 33

1010 4646 55

1010 4040 <1<1

77

1919

22

<1<1

55

00

1414 00

5050 99

1111 <1<1

<1<1

77

<1<1

66

55

22

®® CYRAMZA CYRAMZA (ramucirumab) (ramucirumab)injection injection

CYRAMZA CYRAMZARB-P RB-PHCP HCPBS BS27MAR2017 27MAR2017- -9.5 9.5x x11.5 11.5

AdverseReactions Reactions Adverse (MedDRA)System System (MedDRA) OrganClass Class Organ

CYRAMZAplus plusFOLFIRI FOLFIRI CYRAMZA N=529 N=529

Placeboplus plusFOLFIRI FOLFIRI Placebo N=528 N=528

Grades Grade≥3≥3 Grades Grade≥3≥3 AllAllGrades Grade AllAllGrades Grade (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency

Bloodand andLymphatic LymphaticSystem SystemDisorders Disorders Blood Neutropenia Neutropenia

5959

3838

4646

2323

Thrombocytopenia Thrombocytopenia

2828

33

1414

<1<1

GastrointestinalDisorders Disorders Gastrointestinal Decreasedappetite appetite Decreased

3737

22

2727

22

Diarrhea Diarrhea

6060

1111

5151

1010

Gastrointestinalhemorrhage hemorrhageevents events Gastrointestinal

1212

22

77

11

Stomatitis Stomatitis

3131

44

2121

22

2020

<1<1

99

00

66

11

22

00

1717

33

55

<1<1

3333

00

1515

00

1313

11

55

<1<1

2626

1111

99

33

GeneralDisorders Disordersand andAdministration AdministrationSite SiteDisorders Disorders General Peripheraledema edema Peripheral Metabolismand andNutrition NutritionDisorders Disorders Metabolism Hypoalbuminemia Hypoalbuminemia Renaland andUrinary UrinaryDisorders Disorders Renal a a Proteinuria Proteinuria

Respiratory, Respiratory, Thoracic, Thoracic, and andMediastinal MediastinalDisorders Disorders Epistaxis Epistaxis Skin Skinand andSubcutaneous SubcutaneousTissue TissueDisorders Disorders

Vascular VascularDisorders Disorders

CYRAMZA Placebo CYRAMZAplus plusdocetaxel docetaxel Placeboplus plusdocetaxel docetaxel (N=627) (N=618) (N=627) (N=618) AllAllGrades Grade AllAllGrades Grade Grades Grade3-43-4 Grades Grade3-43-4 (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%) (Frequency (Frequency%)%)

Blood Bloodand andLymphatic LymphaticSystem SystemDisorders Disorders Febrile 1616 Febrileneutropenia neutropenia Neutropenia 5555 Neutropenia Thrombocytopenia 1313 Thrombocytopenia Gastrointestinal GastrointestinalDisorders Disorders Stomatitis/Mucosal 3737 Stomatitis/Mucosalinflammation inflammation Eye EyeDisorders Disorders Lacrimation 1313 Lacrimationincreased increased General GeneralDisorders Disordersand andAdministration AdministrationSite SiteDisorders Disorders Fatigue/Asthenia 5555 Fatigue/Asthenia Peripheral 1616 Peripheraledema edema Respiratory, Thoracic, and Respiratory, Thoracic, andMediastinal MediastinalDisorders Disorders Epistaxis 1919 Epistaxis Vascular VascularDisorders Disorders Hypertension 1111 Hypertension

Table Table4: 4:Adverse AdverseReactions ReactionsOccurring OccurringatatIncidence IncidenceRate Rate≥5% ≥5%and anda ≥2% a ≥2%Difference Difference Between BetweenArms Armsin inPatients PatientsReceiving ReceivingCYRAMZA CYRAMZAin inStudy Study4 4

Palmar-plantar Palmar-plantarerythrodysesthesia erythrodysesthesia syndrome syndrome

Table Table3: 3:Adverse AdverseReactions ReactionsOccurring OccurringatatIncidence IncidenceRate Rate≥5% ≥5%and anda ≥2% a ≥2% Difference DifferenceBetween BetweenArms Armsin inPatients PatientsReceiving ReceivingCYRAMZA CYRAMZAin inStudy Study3 3

Adverse AdverseReactions Reactions(MedDRA) (MedDRA) System SystemOrgan OrganClass Class

Colorectal ColorectalCancer Cancer CYRAMZA Administered CYRAMZA Administeredin inCombination Combinationwith withFOLFIRI FOLFIRI Study randomized, double-blind Study4 was 4 wasa multinational, a multinational, randomized, double-blindstudy studyconducted conductedin inpatients patientswith withmetastatic metastaticcolorectal colorectalcancer cancer with oxaliplatin, and Patients withdisease diseaseprogression progressionononor orafter aftertherapy therapywith withbevacizumab, bevacizumab, oxaliplatin, anda fluoropyrimidine. a fluoropyrimidine.

Patientsreceived received either eitherCYRAMZA CYRAMZA8 mg/kg 8 mg/kgintravenously intravenouslyplus plusFOLFIRI FOLFIRIintravenously intravenouslyevery every2 weeks 2 weeksor orplacebo placeboplus plusFOLFIRI FOLFIRIintravenously intravenously every 2 weeks. every 2 weeks.

Study uncontrolled major Study4 excluded 4 excludedpatients patientswith withananECOG ECOGPSPSof of2 or 2 orgreater, greater, uncontrolledhypertension, hypertension, majorsurgery surgerywithin within28 days, 28 days, and anan andthose thosewho whoexperienced experiencedanyanyof ofthethefollowing followingduring duringfirst-line first-linetherapy therapywith witha bevacizumab-containing a bevacizumab-containingregimen: regimen: arterial arterialthrombotic/thromboembolic thrombotic/thromboembolicevent; event;Grade Grade4 hypertension; 4 hypertension;Grade Grade3 proteinuria; 3 proteinuria;a Grade a Grade3-43-4bleeding bleedingevent; event;or or bowel perforation. bowel perforation.

Demographics Median Demographicsand andbaseline baselinecharacteristics characteristicsforforthethetreated treatedpopulation populationwere weresimilar similarbetween betweentreatment treatmentarms arms(n=1057). (n=1057).

Median age White Asian; agewas was6262years; years;57% 57%of ofpatients patientswere weremen; men;76% 76%were were Whiteand and20% 20%were were Asian;48% had 48% hadECOG ECOGPSPS0. 0.

The Patients Thedata datadescribed describedin inthisthissection sectionreflect reflectexposure exposureto toCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIin in529 529patients patientsin inStudy Study4. 4.

Patientsreceived received a median and a medianof of8 doses 8 doses(range (range1-68) 1-68)of ofCYRAMZA; CYRAMZA;thethemedian medianduration durationof ofexposure exposurewas was4.44.4months, months, and169 169(32% (32%of of529) 529) patients The patientsreceived receivedCYRAMZA CYRAMZAforforat atleast leastsixsixmonths. months.

Themost mostcommon commonadverse adversereactions reactions(all(allgrades) grades)observed observedin inCYRAMZA CYRAMZA plus neutropenia, plusFOLFIRI-treated FOLFIRI-treatedpatients patientsat ata rate a rateof of≥30% ≥30%and and≥2% ≥2%higher higherthan thanplacebo placeboplus plusFOLFIRI FOLFIRIwere werediarrhea, diarrhea, neutropenia, decreased epistaxis, and Twenty decreasedappetite, appetite, epistaxis, andstomatitis. stomatitis.

Twentypercent percentof ofpatients patientstreated treatedwith withCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIreceived received granulocyte Treatment granulocytecolony-stimulating colony-stimulatingfactors. factors.

Treatmentdiscontinuation discontinuationof ofanyanystudy studydrug drugdue dueto toadverse adversereactions reactionsoccurred occurredmore more frequently frequentlyin inCYRAMZA CYRAMZAplus plusFOLFIRI-treated FOLFIRI-treatedpatients patients(29%) (29%)than thanin inplacebo placeboplus plusFOLFIRI-treated FOLFIRI-treatedpatients (13%). patients (13%).

The Themost mostcommon commonadverse adversereactions reactionsleading leadingto todiscontinuation discontinuationof ofanyanycomponent componentof ofCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIasascompared compared to toplacebo were The placeboplus plusFOLFIRI, FOLFIRI, wereneutropenia neutropenia(12.5% (12.5%versus versus5.3%) 5.3%)and andthrombocytopenia thrombocytopenia(4.2% (4.2%versus versus0.8%).

0.8%).

Themost most common commonadverse adversereactions reactionsleading leadingto totreatment treatmentdiscontinuation discontinuationof ofCYRAMZA CYRAMZAwere wereproteinuria proteinuria(1.5%) (1.5%)and andgastrointestinal gastrointestinal perforation (1.7%). perforation (1.7%).

The intestinal Themost mostcommon commonserious seriousadverse adverseevents eventswith withCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIwere werediarrhea diarrhea(3.6%), (3.6%), intestinalobstruction obstruction(3.0%), (3.0%), and andfebrile febrileneutropenia neutropenia(2.8%).

(2.8%).

Table Table4 provides 4 providesthethefrequency frequencyand andseverity severityof ofadverse adversereactions reactionsin inStudy Study4. 4.

Hypertension Hypertension a a

Includes Includes3 patients 3 patientswith withnephrotic nephroticsyndrome syndromein inthetheCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRItreatment treatmentgroup. group.

Clinically Clinicallyrelevant relevantadverse adversereactions reactionsreported reportedin in≥1% ≥1%and and<5% <5%of ofCYRAMZA CYRAMZAplus plusFOLFIRI-treated FOLFIRI-treatedpatients patientsin inStudy Study4 4 consisted consistedof ofgastrointestinal gastrointestinalperforation perforation(1.7% (1.7%CYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIversus versus0.6% 0.6%forforplacebo placeboplus plusFOLFIRI).

FOLFIRI).

Thyroid Thyroidstimulating stimulatinghormone hormone(TSH) (TSH)levels levelswere wereevaluated evaluatedin in224 224patients patients(115 (115CYRAMZA CYRAMZAplus plusFOLFIRI-treated FOLFIRI-treatedpatients patientsand and 109 109placebo placeboplus plusFOLFIRI-treated FOLFIRI-treatedpatients) patients)with withnormal normalbaseline baseline TSH TSHlevels. levels.

Patients Patientsunderwent underwentperiodic periodic TSH TSHlaboratory laboratory assessments assessmentsuntil until3030days daysafter afterthethelastlastdose doseof ofstudy studytreatment. treatment.

Increased Increased TSH TSHlevels levelswere wereobserved observedin in5353(46%) (46%)patients patients treated treatedwith withCYRAMZA CYRAMZAplus plusFOLFIRI FOLFIRIcompared comparedwith with4 (4%) 4 (4%)patients patientstreated treatedwith withplacebo placeboplus plusFOLFIRI. FOLFIRI. Immunogenicity Immunogenicity AsAswith withallalltherapeutic therapeuticproteins, proteins, there thereis isthethepotential potentialforforimmunogenicity. immunogenicity.

In In2323clinical clinicaltrials, trials, 86/2890 86/2890(3.0%) (3.0%)of ofCYRAMZACYRAMZAtreated treatedpatients patientstested testedpositive positiveforfortreatment-emergent treatment-emergentanti-ramucirumab anti-ramucirumabantibodies antibodiesbybyananenzyme-linked enzyme-linkedimmunosorbent immunosorbent assay assay(ELISA).

(ELISA).

Neutralizing Neutralizingantibodies antibodieswere weredetected detectedin in1414of ofthethe8686patients patientswho whotested testedpositive positiveforfortreatment-emergent treatment-emergent anti-ramucirumab anti-ramucirumabantibodies. antibodies.

The Thedetection detectionof ofantibody antibodyformation formationis ishighly highlydependent dependentononthethesensitivity sensitivityand andspecificity specificityof ofthetheassay. assay.

Additionally, Additionally, thethe observed observedincidence incidenceof ofantibody antibody(including (includingneutralizing neutralizingantibody) antibody)positivity positivityin inananassay assaymay maybebeinfluenced influencedbybyseveral severalfactors factors including includingassay assaymethodology, methodology, sample samplehandling, handling, timing timingof ofsample samplecollection, collection, concomitant concomitantmedications, medications, and andunderlying underlyingdisease. disease.

ForForthese thesereasons, reasons, comparison comparisonof ofincidence incidenceof ofantibodies antibodiesto toCYRAMZA CYRAMZAwith withthetheincidences incidencesof ofantibodies antibodiesto toother otherproducts productsmay may bebemisleading. misleading.

DRUG DRUGINTERACTIONS INTERACTIONS NoNopharmacokinetic pharmacokineticinteractions interactionswere wereobserved observedbetween betweenramucirumab ramucirumaband andpaclitaxel, paclitaxel, between betweenramucirumab ramucirumaband anddocetaxel, docetaxel, or orbetween betweenramucirumab ramucirumaband andirinotecan irinotecanor oritsitsactive activemetabolite, metabolite, SN-38.

SN-38.

®® RB-P RB-PHCP HCPBSBS27MAR2017 27MAR2017 CYRAMZA CYRAMZA (ramucirumab) (ramucirumab)injection injection

RB-P RB-PHCP HCPBSBS27MAR2017 27MAR2017

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USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA plus FOLFIRI in Study 4, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.

Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

Table 5: CYRAMZA Dose Reductions for Proteinuria Initial CYRAMZA Dose 8 mg/kg 10 mg/kg

First Dose Reduction to: 6 mg/kg 8 mg/kg

Second Dose Reduction to: 5 mg/kg 6 mg/kg

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, docetaxel, or the components of FOLFIRI, refer to the current prescribing information.

PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event.

• Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment.

• Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAHCP.com.

DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and Schedule Gastric Cancer The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.

Non-Small Cell Lung Cancer The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity.

Colorectal Cancer The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. Continue CYRAMZA until disease progression or unacceptable toxicity.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride).

For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose (see Table 5) once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose (see Table 5) once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

CYRAMZA® (ramucirumab) injection

CYRAMZA RB-P HCP BS 27MAR2017 - 9.5 x 11.5

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OBESIDAD Y CÁNCER DE PRÓSTATA EN PUERTO RICO Por Ricardo Sánchez Ortiz, MD FACS Especialista en Urología Oncológica Director de Cirugía Robótica, Hospital HIMA San Pablo Bayamón Catedrático Auxiliar de Urología de la Universidad de Puerto Rico Adjunct Assistant Profesor of Urology, MD Anderson Cancer Center Robotic Urologic Oncology Institute, San Juan

Según la Sociedad Americana del Cáncer, en el año 2017 se diagnosticaron cerca de 230,000 hombres con cáncer de próstata en EE.UU. y cerca de 2,500 en Puerto Rico.

Estas cifras convirtieron al cáncer de próstata en el cáncer sólido más común y en la causa de muerte de 515 millones de hombres alrededor del mundo.

En cifras: de los diagnósticos en Puerto Rico son por cáncer de próstata.

En 2017 se diagnosticó cáncer de próstata a 180.000 hombres en Estados Unidos.

de todas las muertes por cáncer en la isla del 2008 - 2012, estuvieron asociadas al cáncer de próstata.

El cáncer de próstata es el tipo de cáncer más común en hombres. Le siguen el cáncer de vejiga y cáncer de riñón, respectivamente.

39 %

17,6 %

En promedio, cada año mueren 515 hombres a causa de la enfermedad.

Prevalencia de la condición en la isla De los casos detectados, 6 de cada 10 son diagnosticados a hombres mayores de 65 años, siendo los 50 años la edad más común de detección de la anomalía.

Este tipo de cáncer corresponde al 33% de diagnósticos de esta enfermedad y está asociado al 17,6% de fallecimientos durante 2008 - 2012.

Agentes infecciosos

Causantes del cáncer de próstata La causa del cáncer de próstata se desconoce, pero hay factores que se asocian con su padecimiento:

Bacteria

Determinados virus

Agentes infecciosos

Hongos

Virus

Hongos

Factores genéticos

Pacientes con un familiar de primer grado afectado (padre, hijo o hermano) tienen de un 18 a 40% de probabilidad de desarrollar cáncer en su vida.

Etapa I

Etapa III

Diagnóstico de esta patología Si el paciente afectado fue diagnosticado con cáncer a temprana edad, los riesgos aumentan en el caso de sus familiares.

En estos pacientes, la detección solo se realiza cuando se manifiestan síntomas contundentes como:

Sangrado al orinar

Dificultad para conseguir una erección

Pérdida total del control de esfínteres

Necesidad de orinar con mayor frecuencia

Dolor / ardor al orinar o eyacular

Factores de riesgo Recientes investigaciones han evidenciado que la población con mayor riesgo son los hombres expuestos a factores como: Procedencia: africanos o nacidos en el Caribe Residencia: Norteamérica e islas del Caribe Exposición a agentes químicos: cadmio Estilo de vida: ingesta de grasas, harinas y poco consumo de frutas y verduras

Dato: Expertos creen que el cáncer de próstata, que se manifiesta en

hombres puertorriqueños, es mucho más agresivo que el desarrollado por la población masculina estadounidense.

Relación entre obesidad y cáncer de próstata El riesgo de ser diagnosticados con tumores agresivos también se vio aumentado en hombres con:

Obesidad moderada: 2.17 veces Obesidad severa: 3.95 veces

En los últimos años se encontró una relación directa entre la obesidad y el riesgo de desarrollar cáncer de próstata.

Un estudio publicado por el grupo de Johns Hopkins reveló que de 787 hombres que se sometieron a biopsias de próstata, aquellos con obesidad tenían una probabilidad 2.36 veces mayor de tener esta patología.

Tratamiento para el cáncer de próstata Un diagnóstico temprano puede alargar considerablemente la vida del paciente.

El factor más importante es la detección temprana con visitas anuales al urólogo desde los 40 años.

El riesgo de desarrollar cáncer de próstata se puede reducir bajando de peso e implementando una dieta baja en grasa.

Estadísticas actuales reportan una tasa de supervivencia del 99% tras 5 años de la enfermedad.

Sometidos o no a tratamiento, luego de 10 años, el 98% de afectados siguen con vida casi que normal.

El 95% logra sobrevivir más de 15 años, sin complicaciones de salud asociadas a la enfermedad.

*El autor tiene una práctica limitada al manejo de cáncer de próstata y cirugía robótica.

Etapa IV

Etapa II

Diseño y fuente: Revista Medicina y Salud Pública (MSP)

BACK ON PROGRESSION

FOR PATIENTS WITH NON-METASTATIC CRPC On ADT With a rapidly rising PSA*

In the SPARTAN study†: ERLEADA™ (apalutamide) + ADT improved median metastasis-free

And no radiographically detectable metastases

(40.5 months vs 16.2 months; HR=0.28; 95% CI: 0.23, 0.35; P<0.0001)

survival (MFS) by 2 YEARS (24.3 months) vs placebo + ADT 1

��INTRODUCING��

• An androgen receptor inhibitor indicated for the treatment of patients with non-metastatic CRPC1 • Once-daily oral dosing with no additional laboratory monitoring requirements 1

*PSA doubling time ≤10 months.

Study Design: SPARTAN was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with non-metastatic CRPC (N=1207). Patients had a PSA doubling time to be ≤10 months and serum testosterone levels <50 ng/dL. All patients in the SPARTAN trial received a concomitant GnRH analog or ha non-metastatic by blinded central imaging review. Patients were randomized 2:1 to receive ERLEADA™ 240 mg orally once daily + ADT or placebo orally once daily + ADT. The primary endpoint was oft 1-3 tissue lesions or enlarged lymph nodes above the iliac bifurcat ADT = androgen-deprivation therapy; CRPC = castration-resistant prostate cancer; GnRH = gonadotropin-releasing hormone; HR = h e Prostate Androgen Receptor Targeting with ARN-509.

3. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN Investigators.

References: 1. ERLEADA™ [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. 2.

Apalutamide treatment and metastasis-free survival in prostate cancer [published online February 8, 2018]. N Engl J Med. doi:10.1056/NEJMoa1715546.

†

Please see brief summary of full Prescribing Information for ERLEADA™ on subsequent pages.

Visit erleadahcp.com

MSP ARTÍCULO ORIGINAL

Radiografía del manejo y tratamiento de la dermatitis atópica Por: Francisco Colón Fontánez, MD, FAAD Dermatólogo Pediátrico, Catedrático Asociado de Dermatología Universidad de Puerto Rico, Recinto de Ciencias Médicas Hospital de Niños San Jorge

Resumen La dermatitis atópica es una condición inflamatoria crónica de la piel caracterizada por picor y enrojecimiento. Es más prevalente durante la niñez. El 70% de los pacientes tiene un historial familiar de atopia (asma, rinitis alérgica y/o dermatitis. Los alérgenos pueden ser sustancias en contacto con la piel (fragancias, químicos, fibras de ropa, etc), partículas ambientales por vía aérea (polvo, polen, hongo, contaminantes) y en un menor número de casos, ciertos alimentos (huevo, leche de vaca, maní, soya, mariscos, trigo, entre otros).

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Abstract Atopic dermatitis is a chronic inflammatory skin condition characterized by itching and redness. It is more prevalent during childhood. The 70% of patients have a family history of atopy (asthma, allergic rhinitis and / or dermatitis. Allergens can be substances in contact with skin (fragrances, chemical, textile fibers, etc.), environmental particles by air (dust, pollen, mushroom, contaminants) and in fewer cases, certain foods (egg, cow's milk, peanuts, soybeans, shellfish, wheat, among others).

MSP ARTÍCULO ORIGINAL

“Las probabilidades de desarrollar dermatitis atópica son de 2 a 3 veces más alta en niños con uno de los padres con la condición, y ésta aumenta de 3 a 5 veces si ambos padres padecen la condición”

Palabras claves Fibrilación Auricular o atrial, Arritmia, Accidente cerebrovascular, Stroke Coagulo, Anticoagulantes Key Words Fibrilación Auricular o atrial, Arritmia, Accidente cerebrovascular, Stroke Coagulo, Anticoagulantes

Introducción La dermatitis atópica es más prevalente durante la niñez.

Aproximadamente, el 60% de los pacientes desarrolla la condición durante el primer año de edad y el 90% para los 5 años. El 70% de los pacientes tiene un historial familiar de atopia (asma, rinitis alérgica y/o dermatitis. La piel de estos pacientes responde de forma exagerada a diferentes estímulos (alérgenos). Los alérgenos pueden ser sustancias en contacto con la piel (fragancias, químicos, fibras de ropa, etc), partículasambientales por vía aérea (polvo, polen, hongo, contaminantes) y en un menor número de casos, ciertos alimentos (huevo, leche de vaca, maní, soya, mariscos, trigo, entre otros).

Los términos dermatitis atópica y eczema atópico son sinónimos. La prevalencia de la dermatitis atópica en niños en los Estados Unidos es aproximadamente un 10.7%. En algunos estados puede llegar a ser un 18.1%.

Patogénesis La dermatitis atópica tiene una patogénesis compleja que envuelve factores genéticos, inmunológicos y ambientales que llevan a una barrera de piel disfuncional y a una desregulación del sistema inmunológico. Dos factores de riesgo parecen estar consistente y fuertemente asociados al desarrollo de dermatitis atópica: un historial familiar de atopia y mutaciones en el gen FLG. Las probabilidades de desarrollar dermatitis atópica son de 2 a 3 veces más alta en niños con uno de los padres con la condición, y ésta aumenta de 3 a 5 veces si ambos padres padecen la condición. El gen FLG codifica la proteína profilagrina que se degrada en monómeros de filagrina. Casi el 50% de los pacientes con dermatitis atópica tienen al menos un gen FLG mutado. En el estrato córneo la filagrina se incorpora a la envoltura lipídica, interacciona con la queratina y se procesa aún más, degradándose en amino ácidos que asisten en la retencíon de agua.

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"La dermatitis atópica se diagnostica clínicamente utilizando el historial médico, los signos asociados y la morfología/distribución de las lesiones en piel"

La filagrina es entonces esencial para la homeostasis y función de barrera epidermal, regulando la permeabilidad de la piel al agua y partículas externas como lo son los alérgenos. Las ceramidas (esfingolípidos) 1 y 3 están reducidas significativamente en los pacientes con dermatitis atópica afectando de igual forma la función de barrera epidermal y por ende sus respuestas inf lamatorias.

En las lesiones activas de dermat it is atópica se han encontrado alteraciones en todas las células envueltas en los procesos inf lamatorios. Hay un número aumentado de células de Langerhans que tienen a su vez niveles elevados del receptor de alta afinidad para inmunoglobulina E. Esto contribuye a un estado hiperreactivo en donde las linfocitos T se activan con concentraciones bien bajas de antígenos. Los linfocitos T activados en las lesiones agudas de dermatitis atópica son predominantemente T ayudantes tipo 2 (Th2). Los Th2 producen interleuquinas 4, 5 y 13, que a su vez inducen a los linfocitos B (productores de anticuerpos) a producir niveles elevados de inmunoglobulina E (IgE). Los macrófagos de pacientes con dermatitis atópica tienen niveles aumentados del receptor de alta afinidad IgE causando una sobreproducción de prostaglandina.

E2 e interleuquina 10. El AMP 92

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cíclico produce una modulación negativa de las respuestas inf lamatorias e inmunes. En la dermatitis atópica parece haber niveles aumentados de la enzima fosfodiesterasa (inhibe AMP cíclico), ocasionando una hipereactividad inmunológica que lleva a inflamación.

Tanto las células cebadas como los basófilos son estimulados por la IgE liberando histamina en exceso lo que explica en parte el picor en estos pacientes. Otros mediadores de picor deben estar envueltos ya que en la mayoría de los pacientes, el uso de antihistamínicos orales no es suficiente para controlar el picor.

La interleuquina 5 es crítica para la sobrevivencia, diferenciación y activación de los eosinófilos y los basóf ilos. Los mismos queratinocitos contribuyen al estado de hiper-reactividad produciendo un sinnúmero de citoquinas y quimioquinas. Los eosinóf ilos humanos producen interlequina 12 que lleva a un eventual cambio hacia lesiones crónicas de dermatitis atópica. En estas lesiones crónicas hay una presencia aumentada de los linfocitos T ayudantes tipo 1 (Th1) e interferón gamma.

piel. En el año 2003 la Academia A mericana de Dermatolog ía llegó a un consenso acerca de los criterios que son diagnósticos de la condición. Existen dos hallazgos esenciales que tienen que estar presentes: el prurito y la presencia de lesiones eczematosas crónicas en distribución típica para la edad del paciente (cara, cuello y áreas extensoras en infantes /niños y áreas flexurales en cualquier edad).

Existen a su vez unos hallazgos importantes que se observan en la mayoría de los casos y dan apoyo al diagnóstico, a saber: comienzo a temprana edad, historial personal o familiar de atopia, xerosis y reactividad de la inmunoglobulina E. No existe al presente un marcador bioquímico confiable o específico que pueda distinguir la condición de otras condiciones médicas. La elevación de inmunoglobulina E está presente en un 80% de los casos pero no es un hallazgo específico.

Hasta un 55% de la población normal tiene niveles elevados de algún IgE alérgeno-específ ico.

Otras condiciones médicas como lo son las infecciones parasíticas, ciertos cánceres y enfermedades autoinmunes pueden tener niveles Diagnóstico de IgE elevados. Además, el nivel La der mat it is atópica se de la IgE no correlaciona con la diagnostica clínicamente utilizando severidad clínica entre los pacientes. el historial médico, los signos asociados y la mor folog ía/ Tratamientos rutinarios distribución de las lesiones en El tratamiento básico de la

MSP ARTÍCULO ORIGINAL

"La dermatitis atópica tiene una patogénesis compleja que envuelve factores genéticos, inmunológicos y ambientales que llevan a una barrera de piel disfuncional y a una desregulación del sistema inmunológico"

condición consiste en evitar el contacto con los alérgenos antes mencionados lo más posible y establecer un régimen de hidratación agresiva en toda la piel, combinado con el uso de corticosteroides sobre las áreas enrojecidas y con picor. Es bien frecuente utilizar antihistamínicos orales para controlar el picor. El rascado crónico puede llevar al desarrollo de excoriaciones y laceraciones que se impetiginizan, requiriendo el uso de antibióticos tópicos, orales y en casos severos intravenosos. En ciertas ocasiones en donde la respuesta al tratamiento tópico ha fallado, cursos cortos de esteroides orales ó intravenosos son necesarios para alcanzar una mejoría.

Tratamientos selectivos Los inhibidores de la calcineurina tópicos fueron una opción terapeútica innovadora y bien esperanzadora cuando salieron al mercado hace más de 10 años atrás. El tacrolimus ungüento (0.03 y 0.1%) y el pimecrolimus en crema (1%) fueron aprobados por la Administración Federal de Drogas (FDA en inglés) en los años 2000 y 2001 respectivamente. Los inhibidores de la calcineurina, inhiben la transcripción y liberación de citoquinas inflamatorias y otros mediadores de los linfocitos T. En el 2005, la FDA hizo pública una alerta sobre el posible riesgo de cáncer (especialmente linfoma), con

el uso de ambos medicamentos.

Desde el 2006, los productos tienen un recuadro negro dentro de su literatura. Esta acción ha causado una disminución significativa en su uso desde entonces. Los estudios a largo plazo en pacientes pediátricos luego de lanzados los productos al mercado de hasta 6.5 años de duración, no han mostrado un aumento de cáncer comparados con la población general. Queda por verse si con el tiempo la acumulación de data positiva, puede revertir el estigma negativo sobre ellos. Al presente, tanto el tacrolimus como el pimecrolimus siguen siendo los únicos tratamientos para la dermatitis atópica que tuvieron indicación para uso prolongado en niños de 2 años en adelante. Por el recuadro negro, la indicación actual es como droga de segunda línea y uso a corto plazo en pacientes de 2 años de edad en adelante que no estén inmunocomprometidos y no hayan respondido a tratamientos convencionales. Para el 2014 la Academia Americana de Dermatología publica unas guías para el diagnóstico y manejo de la dermatitis atópica dividida en 4 partes. En estas guías, el uso de los inhibidores de la calcineurina están recomendados tanto para tratamiento agudo como crónico de la condición y son recomendados para evitar el uso prolongado de corticosteroides (con sus ya

conocidas secuelas como lo son la atrofia epidermal, descoloración, estrías y posible supresión del eje hipotalámico-hipofisiario).

Solo 4 inmunosupresores orales han mostrado eficacia y relativa seguridad en el manejo de casos severos de dermatitis atópica, a saber: ciclosporina, metotrexato, azatioprina y micofenolato mofetil. Todos deben ser reservados para casos severos y utilizados por médicos con experiencia y conocimiento en las dosis, tiempo de uso y monitoreo de efectos secundarios. Los biológicos son sustancias o agentes basados en proteínas que son producidos por organismos vivos y usados como terapia en contra de varios desórdenes inflamatorios autoinmunes como lo son la psoriasis y la artritis reumatoidea entre otros. Ejemplos de biológicos lo son los anticuerpos monoclonales, receptores solubles y citoquinas. Al presente no hay ningún biológico aprobado por la FDA para el tratamiento de la dermatitis atópica.

En un artículo pionero sobre el uso de biológicos en dermatitis atópica publicado en el 2009 en la revista de la Academia Americana de Dermatología, quedó demostrado que los inhibidores del factor de necrosis tumoral alfa (siglas TNF en inglés) como lo son el etanercept. adalimumab e inf liximab, no son efectivos en el manejo de la dermatitis atópica. Se evidencia Revista Puertorriqueña de Medicina y Salúd Pública

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también en ese artículo que interferón gama es el que tiene más evidencia científica de efectividad, pero el alto costo y sus reacciones adversas tipo síndrome viral han limitado su uso. Existen al presente dos estudios randomizados con placebo que evaluaron la efectividad de omalizumab en dermatitis atópica mostrando resultados mixtos. Omalizumab es un anticuerpo monoclonal humanizado en contra de la inmunoglobulina E (IgE), aprobado por la FDA para asma severa recalcitrante y urticaria crónica idiopática. Existen en la literatura médica varios reportes de casos mostrando muy buena respuesta clínica con el uso del rituximab. El rituximab es un

de o m a l i z u m a b/r it u x i m a b omalixumab/inmunoglobulinas, también se han reportado en la literatura médica.

Tratamientos en el horizonte Varios biológicos están bajo estudio, a saber: el receptor de interleuquina 31 (IL- 31), IL-22, IL-13 (tralokinumab), IL-12/23 (ustekinumab) e IL-4 (dupilumab).

De todos los anteriores, solo dupilumab está en fase 3 de investigación. El dupilumab es un anticuerpo monoclonal humano que se pega a la subunidad alfa del receptor de IL-4 en los linfocitos T ayudantes, bloqueando así su respuesta inmunológica. Este bloqueo también detiene el efecto

apremilast y el citrato de tofacitinib.

El apremilast es un inhibidor selectivo de la fosfodiesterasa 4 aprobado por la FDA para el tratamiento de la artritis psoriática y la psoriasis en placa en el año 2014.

Existe un estudio piloto que se originó en el 2011 y aún está en fase 2, sobre el uso de apremilast en la dermatitis atópica. Los resultados parciales de este estudio publicados en el 2012 en la revista Archivos de Dermatología son alentadores. El inhibidor de la quinasa de Janus 1 y 3, conocido como citrato de tofacitinib, fue aprobado para el tratamiento de artritis reumatoidea en 2012. En 2015 esta droga no logró que la FDA otorgara la aprobación para su uso en psoriasis, aludiendo carencia de data suficiente

"Solo 4 inmunosupresores orales han mostrado eficacia y relativa seguridad en el manejo de casos severos de dermatitis atópica, a saber: ciclosporina, metotrexato, azatioprina y micofenolato mofetil" anticuerpo monoclonal dirigido en contra del antígeno CD 20 presente en los linfocitos B. El rituximab tiene aprobación de FDA para ciertos tipos de linfomas/leucemias, artritis reumatoidea que falle a tratamiento con anti-TNF y ciertas poliangitis.

Sus posibles efectos secundarios serios como lo son arritmias cardiacas, dolor de pecho, toxicidad renal, reacciones severas en la piel, e inclusive la muerte, han frenado el utilizarlo con frecuencia. Las inmunoglobulinas intravenosas han mostrado muy buena efectividad en el tratamiento de casos severos de dermatitis atópica. Los mejores resultados porcentuales se observan con los niños. Combinaciones 94

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de la IL-13 sobre los linfocitos T ayudantes. Al presente, esta droga parece ser tan o más efectiva que cualquiera de las opciones sistémicas existentes y con un perfil de seguridad bien alto. Es en resumen la droga más esperada y ofrecerá una esperanza de mejor calidad de vida para muchos pacientes. Los estudios son todos en pacientes mayores de 18 años por lo que su uso en niños, que son la mayoría de los casos, tendrá que esperar. La dosis que muy probablemente sea aprobada es de 300 mg semanales.

Existen dos agentes orales que recientemente han recibido mucha atención como posibles alternativas en el manejo de la dermatitis atópica:

en su perfil de seguridad. Este año, en febrero, una nueva fórmula de liberación extendida fue aprobada para la artritis reumatoidea. En la revista de la Academia Americana de Dermatología de septiembre de 2015, se publicaron los resultados del uso de citrato de tofacitinib en 6 pacientes con dermatitis atópica que habían fallado otras terapias convencionales. La mejoría que se observó en esos pacientes fue muy buena, pero definitivamente es muy prematuro predecir si estudios como ese se repetirán y si la droga mostrará igual o mejor efectividad.

En 2015 en el Congreso Mundial de Dermatología se presentó una data preliminar de un estudio fase 2, doble

MSP ARTÍCULO ORIGINAL

“Aún esperamos esa droga maravillosa que logre ofrecer una efectividad terapéutica que raye en la total supresión de las manifestaciones clínicas de la condición. Como sucedió con la psoriasis, la artritis reumatoidea y las enfermedades gastrointestinales autoinmunes, en los últimos 3 años ha surgido un despertar en la búsqueda de nuevos medicamentos...” ciego, randomizado y multicéntrico con citrato de tofacitinib al 2% en ungüento. Este medicamento se le aplicó dos veces al día por 4 semanas a un total de 65 pacientes adultos con dermatitis atópica. Hubo una disminución de un 82% en el índice de área y severidad de la dermatitis comparado con solo un 30% de reducción en el grupo placebo.

Otra droga tópica que parece ser prometedora lo es el crisabarole, que es un inhibidor de la fosfodiesterasa 4. El crisabarole es una molécula pequeña que contiene boro. Esta droga se encuentra en fase 3 de investigación y la data publicada de su efectividad es muy positiva.

Conclusión La mayoría de los tratamientos actuales se basa en el uso de emolientes, esteroides tópicos y antihistamínicos. En muchos pacientes ese tratamiento tradicional y conservador no es efectivo para controlar la condición.

La aprobación de los inhibidores de calcineurina, entrando el siglo 21, fue un avance importante en su manejo, pero se quedaron algo distantes de ser las drogas casi milagrosas que esperábamos. Los inmunosupresores orales se utilizan en casos severos, refractarios a tratamiento convencional y han

sido útiles, pero sus efectos adversos son un detente para su uso en muchos casos. Aún esperamos esa droga maravillosa que logre ofrecer una efectividad terapéutica que raye en la total supresión de las manifestaciones clínicas de la condición. Como sucedió con la psoriasis, la artritis reumatoidea y las enfermedades gastrointestinales autoinmunes, en los últimos 3 años ha surgido un despertar en la búsqueda de nuevos medicamentos para la dermatitis atópica. El biológico que está en fase 3 de investigación y que promete ser de excelente eficacia con pocos efectos secundarios lo es el dupilumab (anticuerpo Humano, que se pega a la subunidad alfa del receptor de IL-4 en los linfocitos T ayudantes).

Otras drogas tópicas con resultados preliminares muy buenos lo son los inhibidores de fosfodiesterasa 4 y de la quinasa de Janus 1 y 3.

Referencias

1. Eichenfield LF, Tom WL, et al. Guidelines of care for the management of atopic dermatitis: section1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014 Feb; 70(2):338-51.

2. Eichenfield LF, Tom WL, et al. Guidelines of care for the management of atopic dermatitis: section2.Management and treatment of atopic dermatitis with topical therapies. J Am

Acad Dermatol. 2014 Jul; 71(1):116-32.

3. Sidbury R, Davis DM, et al. Guidelines of care for the management of atopic dermatitis: section 4. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014 Aug; 71(2):327-49.

5. Sidbury R, Davis DM, et al. Guidelines of care for the management of atopic dermatitis: section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014 Dec; 71(6):1218-33.

6. Bremmer MS, Bremmer SF, et al. Are biologics safe in the treatment of atopic dermatitis? A review with a focus on immediate hypersensitivity reactions. J Am Acad Dermatol. 2009 Oct; 61(4):666-76.

7. Samrao A, Berry TM, et al. A pilot study of an oral phosphoiesterase inhibitor (apremilast) for atopic dermatitis in adults.

Arch Dermatol. 2012 Aug; 148(8):890-7.

8. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013 Jun; 14(3):163-78.

9. Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015 Sept; 73(3):395-9.

10. Beck LA, Hamilton JD, et al. Dupilumab treatment in adults with moderate to severe atopic dermatitis. N Eng J Med. 2014; 371(2):130-9.

11. Fukuyama T, Ehling S, et al. Topically administered Janus-kinase inhibitors tofacitinib and oclacitinib display impressive antipruritic and anti-inflammatory responses in a model of allergic dermatitis.

J Pharmacol Exp Ther. 2015; 354(3):394405.

12. Hanifin JM, Reed ML. A populaton based survey of eczema prevalence in the United States. Dermatitis 2007; 18(2):82-91.

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80 mg/mL

MOVING. TOUCHING. MOMENTS. Taltz is indicated for adults with active psoriatic arthritis (PsA).

Taltz is also indicated for adults with moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

WARNINGS AND PRECAUTIONS Infections Taltz may increase the risk of infection. In clinical trials of patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). A similar increase in risk of infection was seen in placebo-controlled trials of patients with psoriatic arthritis. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during clinical trials in patients with plaque psoriasis.

Immunizations Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz.

ADVERSE REACTIONS Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profile observed in patients with psoriatic arthritis was consistent with the safety profile in patients with plaque psoriasis, with the exception of influenza and conjunctivitis.

Please see Brief Summary of Prescribing Information on the following pages. Please see Instructions for Use included with the device.

IX HCP ISI 01DEC2017 References: 1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018. 2. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet.

2017;389:2317-2327. 3. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30.

IN PATIENTS WITH PSORIATIC ARTHRITIS

Taltz provided powerful improvement in joint symptoms at week 241 EVEN IN THOSE WHO FAILED/WERE INTOLERANT TO 1 OR 2 TNFis SPIRIT-P1 (BIOLOGIC-NAIVE): ACR RESPONSE RATES AT WEEK 24, NRI*

58 ACR20

%

vs 30%

40 ACR50

%

vs 15%

23 ACR70

%

vs 6%

SPIRIT-P2 (TNFi-EXPERIENCED): ACR RESPONSE RATES AT WEEK 24, NRI†

53 ACR20

%

vs 20%

Taltz

Placebo

35 ACR50

%

vs 5%

22 ACR70

%

vs 0%

*Taltz 80 mg every 4 weeks n=107; placebo n=106. †Taltz 80 mg every 4 weeks n=122; placebo n=118.

Primary endpoint=ACR20 response at week 24. Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint. Nonresponder imputation (NRI) of intent-to-treat population through week 24.1

Taltz helped stop the progression of joint damage at week 16 vs placebo1 In SPIRIT-P1 (biologic-naive), adjusted mean change from baseline in mTSS at week 16 was 0.13 for Taltz vs 0.36 for placebo* Inhibition of progression of structural damage was assessed radiographically and expressed as the adjusted mean change in mTSS and its components, the joint space narrowing score and bone erosion score, at week 16 vs baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints.1 SPIRIT-P2 (TNFi-experienced) did not include an assessment of radiographic progression.2 Taltz 80 mg every 4 weeks n=107; placebo n=106.

SPIRIT-P1 AND -P2 TRIAL DESIGN SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)-experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of adalimumab 40 mg every 2 weeks was included. Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and adalimumab arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. Nonresponder imputation (NRI) methods were used for categorical efficacy analyses during the double-blind treatment period.1-3

Learn more about The Taltz Clear Access Program, which helps assure access so your commercially insured patients can confidently get Taltz.‡ Visit taltzsavings.com Government beneficiaries excluded. Terms and conditions apply.

‡

Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries and affiliates.

PP-IX-US-1919 06/2018 ©LILLY USA, LLC 2018. ALL RIGHTS RESERVED.

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Taltz® (ixekizumab) injection Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE Plaque Psoriasis—Taltz is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis— Taltz is indicated for the treatment of adult patients with active psoriatic arthritis.

CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients (Warnings and Precautions).

WARNINGS AND PRECAUTIONS Infections—Taltz may increase the risk of infection. In clinical trials in patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%).

Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Taltz group than in the placebo group. A similar increase in risk of infection was seen in placebo-controlled trials in patients with psoriatic arthritis (Adverse Reactions). Instruct patients treated with Taltz to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Taltz until the infection resolves.

Pre-treatment Evaluation for Tuberculosis—Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Consider anti-TB therapy prior to initiating Taltz in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be conirmed. Patients receiving Taltz should be monitored closely for signs and symptoms of active TB during and after treatment.

Hypersensitivity—Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz (Adverse Reactions). If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inlammatory Bowel Disease— During Taltz treatment, monitor for onset or exacerbation of inlammatory bowel disease. Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than in the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials in patients with plaque psoriasis.

Immunizations—Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz. No data are available on the response to live vaccines.

Table 1: Adverse Reactions Occurring in ≥1% of the Taltz Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 Adverse Reactions Injection site reactions Upper respiratory tract infectionsa Nausea Tinea infections a b

Taltz 80 mg Q2W (N=1167) (n%) 196 (17)

Etanerceptb (N=287) (n%) 32 (11)

Placebo (N=791) (n%) 26 (3)

163 (14)

23 (8)

101 (13)

23 (2) 17 (2)

1 (<1) 0

5 (1) 1 (<1)

Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.

U.S. approved etanercept.

Adverse reactions that occurred at rates less than 1% in the Taltz group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, inluenza, conjunctivitis, inlammatory bowel disease, and angioedema.

Weeks 13 to 60 : A total of 332 subjects received the recommended maintenance regimen of Taltz 80 mg dosed every 4 weeks.

During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Taltz (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Taltz (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.

Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

Immunogenicity—As with all therapeutic proteins there is the potential for immunogenicity with Taltz. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.

Plaque Psoriasis Population

By Week 12, approximately 9% of subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.

Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Taltz at the recommended dosing regimen, had antibodies that were classiied as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of eficacy.

Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed antidrug antibodies, the majority of which were low titer, and 8% had conirmed neutralizing antibodies.

The detection of antibody formation is highly dependent on the sensitivity and speciicity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be inluenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Taltz across indications or with the incidences of antibodies to other products may be misleading.

Postmarketing Experience—The following adverse reactions have been identiied during postapproval use of Taltz. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Taltz exposure.

Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

T:11.25”

ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: t *OGFDUJPOT (Warnings and Precautions) t )ZQFSTFOTJUJWJUZ 3FBDUJPOT (Contraindications and Warnings and Precautions) t *OþBNNBUPSZ #PXFM %JTFBTF (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not relect the rates observed in practice.

Plaque Psoriasis Weeks 0 to 12 : Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Taltz compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Taltz (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Taltz (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.

In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Taltz Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the Taltz group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Taltz group than the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.

Weeks 0 to 60 : Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Taltz (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Taltz (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).

Specific Adverse Drug Reactions: Injection Site Reactions : The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz.

Infections : In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Taltz (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Taltz (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) (Warnings and Precautions).

During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Taltz (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Taltz (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.

Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Taltz (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Taltz (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).

Laboratory Assessment of Cytopenia: Neutropenia—Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Taltz (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Taltz, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.

In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Taltz group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Taltz 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Taltz 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to <2,000 cells/mm3).

Neutropenia in the Taltz group was not associated with an increased rate of infection compared to the placebo group.

Thrombocytopenia—Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Taltz 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3).

Thrombocytopenia in subjects treated with Taltz was not associated with an increased rate of bleeding compared to subjects treated with placebo.

Active Comparator Trials : In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S.-approved etanercept and 2% for Taltz 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Taltz 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Taltz 80 mg Q2W. The rate of serious infections was 0.3% for both Taltz 80 mg Q2W and U.S. approved etanercept.

Psoriatic Arthritis Taltz was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on Taltz and 224 on placebo). A total of 229 patients in these trials received TALTZ 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety proile observed in patients with psoriatic arthritis treated with Taltz Q4W is consistent with the safety proile in patients with plaque psoriasis with the exception of the frequencies of inluenza (1.3%) and conjunctivitis (1.3%).

T:8.5”

DRUG INTERACTIONS Live Vaccinations—Avoid use of live vaccines in patients treated with Taltz (Warnings and Precautions).

Cytochrome P450 Substrates—The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFĮ, IFN) during chronic inlammation. Thus, Taltz, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.

Therefore, upon initiation or discontinuation of Taltz in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modiication of the CYP450 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—There are no available data on Taltz use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Taltz may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical signiicance of these nonclinical indings is unknown.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data—An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week).

Ixekizumab crossed the placenta in monkeys.

In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week).

These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical signiicance of these indings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.

Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health beneits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition.

Pediatric Use—The safety and effectiveness of Taltz in pediatric patients (<18 years of age) have not been evaluated.

Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or eficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not suficient to determine whether they respond differently from younger subjects.

OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know.

Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or preilled syringe correctly (Instructions for Use).

Infection: Inform patients that Taltz may lower the ability of their immune system to ight infections.

Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions).

Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions).

Additional information can be found at www.Taltz.com.

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2016, 2017, Eli Lilly and Company. All rights reserved.

IX HCP BS 01DEC2017 Taltz® (ixekizumab) injection

IX HCP BS 01DEC2017

MSP ARTÍCULO ORIGINAL

Vigilancia terapéutica de drogas en Enfermedad Inflamatoria del Intestino:

ajuste de terapia guiada y resultados clínicos en puertorriqueños con EII

Resumen: La vigilancia terapeútica de drogas (en inglés Therapeutic drug monitoring, TDM) está recomendada para pacientes con enfermedad inf lamatoria del intestino en terapia con medicamentos biológicos. Los niveles de la droga y la presencia y títulos de anticuerpos contra la misma son útiles para evaluar pérdida de respuesta y enfermedad activa durante terapia y sirven de guía en la decisión de ajuste de terapia para lograr una mejor respuesta o remisión. Estas pruebas son costosas y de acceso limitado en Puerto Rico, barreras para implementar el uso en la práctica clínica.

Presentamos la experiencia del Centro para Enfermedades Inflamatorias del Intestino UPR de 2014 a 2016. Se hizo la prueba de niveles de droga y anticuerpos en 106 pacientes en infliximab o

100

Revista Puertorriqueña de Medicina y Salúd Pública

adalimumab. Las indicaciones para la prueba fueron pérdida de respuesta, falta de respuesta primaria, pérdida de dosis, y reacción adversa. 26% tenía anticuerpos y 55% tenían niveles bajos de droga. En 64% se hizo un cambio de terapia.

No se observaron cambios significativos en síntomas o parámetros de laboratorio a los 6 y 12 meses. 88% estaban libres de terapia de corticoesteroides al año, y hubo muy pocas hospitalizaciones y cirugías.

El uso de TDM está apoyado por las guías clínicas y parece ser costo-efectivo en guiar la ajustes y cambios en terapia. El acceso a esta prueba en Puerto Rico debe mejorarse de modo que esta herramienta útil pueda ser incorporada de forma rutinaria en el manejo de biológicos en pacientes con Enfermedad inflamatoria del intestino.

MSP ARTÍCULO ORIGINAL

Por: Sulimar Rodríguez, MD, Natalia Blanco, MD, Esther A. Torres,MD Departamento de Medicina, Centro para Enfermedades Inflamatorias del Intestino,Universidad dePuerto Rico, Recinto de Ciencias Médicas,San Juan, PR

Key words: Inflammatory bowel disease, therapeutic surveillance, treatment, monitoring Palabras claves: Enfermedad Inflamatoria del Intestino, vigilancia terapéutica, tratamiento, monitoreo

Abstract Therapeutic drug monitoring is now recommended for the management of treatment with biologics in patients with Inflammatory Bowel Disease.

Levels of the specific drug and presence and titers of drug antibodies are useful for evaluating loss of response and presence of active disease on therapy and serve as a guide in the decision of adjustment of therapy to better achieve a response or remission. These tests are costly and have limited access in Puerto Rico, which are barriers to implementing theiruse in clinical practice.

We report the experience of the UPR Center for IBD from 2014 to 2016. 106 patients on inf liximab or adalimumab were tested for drug levels and antibodies. Indications for testing were loss of response,

primary non-response, loss of doses, and adverse reaction.

Twenty six percent had antibodies detected and 55% had subtherapeutic drug levels. Sixty-four percent of the patients tested underwent change in therapy. Symptoms and laboratory parameters did not change significantly from baseline levels at 6 and 12 months. However, 88% were steroid free after one year, and there were few hospitalizations and surgeries.

The use of TDM is supported by clinical guidelines and appears to be cost-effective in guiding therapy changes or adjustments. Access to testing for patients in Puerto Rico must be improved so this useful tool can be incorporated routinely into the management of biologics in patients with IBD.

Revista Puertorriqueña de Medicina y Salúd Pública

101

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La enfermedad inf lamatoria intestinal (EII), incluyendo la enfermedad de Crohn (EC) y la colitis ulcerosa (CU), son trastornos inflamatorios crónicos idiopáticos sin cura establecida. La evidencia sugiere que se deben a una respuesta inflamatoria alterada a factores ambientales en individuos genéticamente predispuestos1.

El uso de med icamentos biológicos para el tratamiento de las EII ha cambiado su curso, y estos están indicados como primera línea para EII de moderada a severa y enfermedad perianal. Los antagonistas de Factor de Necrosis Tumoral (anti-TNF) han sido el pilar del tratamiento, siendo infliximab (IFX) y adalimumab (ADA) los más estudiados y utilizados1,2,3 .

Los mencionados antagonistas tienen una farmacocinética y farmacodinámica complejas y 102

Revista Puertorriqueña de Medicina y Salúd Pública

variables, afectadas por el peso corporal, nivel de albúmina, grado de inflamación y la formación de anticuerpos que pueden alterar su eliminación y efectos1,4,5,6,7.

Alrededor de un 30% de los pacientes no responden a los antiTNF (no-respondedores primarios) y cerca de un 50% pierden respuesta al cabo de un año (no-respondedores secundarios)1.

Se han desarrollado pruebas de vigilancia terapéutica de drogas (en inglés Therapeutic drug monitoring, TDM ) para monitorizar los niveles séricos de anti-TNF (y más recientemente de vedolizumab y de ustekinumab también) y la formación de anticuerpos antifármaco, con el objetivo de individualizar la terapia1,3,4. Guías recientes apoyan el uso de éstas. La guía de la Asociación Americana de Gastroenterología (AGA):

“Therapeutic Drug Monitoring in IBD”, recomienda la vigilancia reactiva (cuando hay pérdida o pobre respuesta durante la terapia) en lugar de proactiva y sugiere que el objetivo de concentración valle debe ser >5µg/mL para IFX y >7.5µg/mL para ADA6. La guía clínica del Colegio Americano de Gastroenterología (ACG): “Management of Crohn’s Disease in Adults” plantea que se debe considerar la TDM si se documenta enfermedad activa durante la terapia7. Aunque aún está en debate si debe hacerse TDM de manera proactiva, ésta ayuda a identificar la causa de la falla terapéutica, guiando el ajuste en terapia7.

Enfermedad activa en presencia de niveles séricos terapéuticos y ausencia de anticuerpos, ref leja “fallo mecanístico” (predomina un mediador inf lamatorio diferente

MSP ARTÍCULO ORIGINAL

Tabla 1. Porciento de pacientes con anticuerpos EC

25% (24/94)

CU

36% (4/11) P=0.442

al TNF)5,6,7. El ACG recomienda cambiar a un medicamento con diferente mecanismo de acción (ej. un anti-IL12/23 o antiintegrina). Sin embargo, pacientes asintomáticos con enfermedad endoscópica leve o enfermedad perianal, quienes pueden requerir niveles séricos más altos, podrían beneficiarse de escalar la dosis del anti-TNF primero7.

Niveles séricos subterapéuticos en ausencia de anticuer pos responde a “fallo terapéutico mediado no-inmunológicamente”, que resulta de la eliminación rápida del medicamento, que usualmente acompaña a una carga alta de inflamación. En este caso debe considerarse escalar la dosis o acortar el intervalo de administración7.

Niveles séricos subterapéuticos/ no-detectables en presencia de títulos altos de anticuerpo, apuntan a “fallo terapéutico mediado inmunológicamente”, donde los anticuerpos aumentan la eliminación o neutralizan el efecto del fármaco5,7. No existe consenso en cuanto al dintel para los títulos de anticuerpos y algunas pruebas son muy sensitivas y pueden detectar títulos muy bajos y potencialmente

subclínicos de anticuerpos6,7. Es por esto que, cuando hay títulos bajos de anticuerpos, antes de considerar cambiar de medicamento, debe plantearse optimizar la dosis o añadir un inmunomodulador (i.e. tiopurina) primero. Se ha demostrado que estos aumentan la acción de los anti-TNF y disminuyen la producción de anticuerpos7.

El TDM es de uso reciente en la práctica y no hay estudios descriptivos de la experiencia con esta en puertorriqueños.

Quisimos explorar el valor clínico del uso de TDM para guiar la terapia y mejorar los resultados clínicos en nuestros pacientes con EII. Esto justificaría su uso como una estrategia de manejo costoefectiva y ayudaría a abogar por su cobertura por las aseguradoras médicas. Nuestras hipótesis fueron que usar estas pruebas mejoraría los resultados clínicos, puesto que evitaría la continuación de terapias inefectivas, reduciendo así los retrasos en lograr remisión, y que conllevaría a un uso más efectivo y eficiente de recursos.

En este estudio observacional retrospectivo basado en revisión de expedientes clínicos incluimos a todos los pacientes de nuestra clínica de EII a quienes se le hicieron las pruebas de nivel sérico de antiTNF y de anticuerpos desde marzo de 2014 a diciembre de 2016. Las pruebas fueron ordenadas por sus

Tabla 2. Niveles séricos de medicamento y anticuerpos Pacientes en ADA Nivel sérico promedio= 8.8µg/mL (rango1.6-30µg/mL) 38% (23/60) tuvo nivel sérico <7.58µg/mL De estos, 48%(11/23) tuvo anticuerpos detectados 22% (2/11) tuvo título de anticuerpo>10U/mL Pacientes en IFX Nivel sérico promedio=6.56µg/mL (rango1-32µg/mL) 76% (35/46) tuvo nivel sérico <5µg/mL De estos, 49% (17/35) tuvo anticuerpos detectados37% tuvo título de anticuerpo>10U/mL)

médicos por indicaciones clínicas.

Las pruebas utilizadas fueron la “Prometheus Anser IFX Assay” y la “Prometheus Anser ADA Assay” (Prometheus Laboratories Inc, California). Éstas son un nuevo tipo de ensayo de cambio en la corrida de base fluida, no-radiomarcadas, que tienen varias ventajas sobre los análisis disponibles de ELISA y RIA (ensayos de radio-inmunoprecipitación), puesto que pueden medir ambos el nivel del fármaco y del anticuerpo en la misma muestra sin interferencia significativa y con mayor sensibilidad y especificidad, resultando en menos falsos positivos y negativos y evitando el usar y descartar material radiactivo8.

Los datos r e c o le c t a d o s fueron: edad, sexo, diagnóstico, aseguradora médica, anti-TNF utilizado, indicación para hacer la prueba, resultado de la misma, cambio en terapia que se hizo, y variables clínicas incluyendo: frecuencia de defecación diaria (auto-reportado), dolor abdominal (sí o no), evidencia de enfermedad endoscópica, severidad de está, tasa de sedimentación eritrocítica (ESR), proteína reactiva-C (CRP), hemoglobina (Hgb), albúmina (alb) y hospitalizaciones y cirugías, antes y a los 6 y 12 meses después de las pruebas. También se evaluó el uso de corticoesteroides a los 12 meses después de las pruebas.

El análisis estadístico se realizó con el programa STATA-V14.

Para las estadísticas univariadas, se utilizó estadística descriptiva (para variables continuas) y distribución de frecuencia (para variables categóricas). Para las estadísticas bivariadas se utilizó el Chi-cuadrado y el Test exacto de Fisher para evaluar asociación entre variables categóricas y el test de suma de rangos de Wilcoxon para evaluar la diferencia media de variables Revista Puertorriqueña de Medicina y Salúd Pública

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MSP ARTÍCULO ORIGINAL

"La enfermedad inflamatoria intestinal (EII), incluyendo la enfermedad de Crohn (EC) y la colitis ulcerosa (CU), son trastornos inflamatorios crónicos idiopáticos sin cura establecida" Tabla 3. Hospitalizaciones y cirugías 6 meses (n=90)

12 meses (n=80)

Hospitalización

17%

6%

Cirugía

15%

8%

continuas. El estudio fue aprobado por el Consejo de Revisión Institucional (IRB) del Recinto de Ciencias Médicas de la Universidad de Puerto Rico (protocolo 1250316).

Resultados: Se incluyó un total de 106 pacientes. La edad promedio fue 35 +/- 12 años (rango 10-79). 59% eran hombres, 89% tenía EC. 43% tenía aseguradora médica privada, 49% estaba asegurado por el programa de salud del gobierno y 3.7% por Medicare. 57% estaba en ADA (80% bisemanal, 20% semanal) y 43% en IFX (78% cada 8 semanas, 16% cada 6 y 6% cada 4).

75% tenía documentada una colonoscopía antes de la prueba, 95% (76/80) tenía documentada enfermedad activa. De estos, 57% (44/66) tenía severidad documentada (47% leve, 47% moderada, 6% severa).

La indicación para la prueba fue pérdida de respuesta en 53%, norespuesta primaria en 43%, pérdida de múltiples dosis en 3% y efecto adverso en 1%. La Tabla 1 muestra la prevalencia de anticuerpos para cada enfermedad. En general, 26.3% tuvo anticuerpos detectados (nivel promedio 9U/mL, DS=20, rango 0-100U/mL). La Tabla 2 muestra los niveles séricos de 104

Revista Puertorriqueña de Medicina y Salúd Pública

medicamento y de anticuerpos. 55% tuvo niveles de medicamento por debajo del objetivo, de los cuales 48% tuvo anticuerpos detectados.

No hubo diferencia significativa en cuanto a la presencia de dolor o la frecuencia de eliminación intestinal entre los niveles base y 6 ó 12 meses. Tampoco hubo diferencia en el ESR, CRP, hemoglobina o albúmina. Solo un pequeño número de pacientes tuvo una colonoscopia de seguimiento, lo que no permitió análisis estadístico al respecto.

Luego de tener el resultado de estas pruebas, el 64% de los pacientes tuvo un cambio en su terapia: 4% tuvo aumento de dosis, a 27.5% se le acortó el intervalo de administración, a 10% se le hizo ambos y a 58% se le cambió a otro medicamento. A los 12 meses, 93 (88%) de los pacientes estaba fuera de esteroides. Según muestra la Tabla 3, solo unos pocos pacientes tuvieron hospitalizaciones o cirugías a los 6 y a los 12 meses.

Discusión: Un gran número de nuestros pacientes con EII tuv ieron pruebas de monitoreo terapéutico del fármaco para evaluación de enfermedad activa de leve a moderada a pesar de estar en terapia con anti-TNF. Más de la mitad de estos participantes tuvo niveles séricos bajos, y la mitad tuvo anticuerpos. Se le hizo un cambio en la terapia al 64% de los pacientes evaluados. La terapia convencional sin el uso de estas

pruebas de monitoreo pudo haber resultado en la continuación de una terapia inefectiva o en un ajuste o cambio empírico y potencialmente inefectivo, el cual pudo haber resultado en costos más altos, retraso en la mejoría y complicaciones (ej. hospitalizaciones, cirugías, uso prolongado de esteroides).

Un año luego de las pruebas, cerca del 90% de los pacientes estaba libre de uso de esteroides, un objetivo clínico muy importante de la terapia de las EII. También las hospitalizaciones y las cirugías disminuyeron del mes 6 al 12, sugiriendo un nivel menor de severidad de la actividad de la enfermedad. No hubo diferencias signif icativas para los otros resultados clínicos a los 6 o a los 12 meses (síntomas, laboratorios, actividad endoscópica), ni entre EC y CU. Sin embargo, este fue un estudio observacional retrospectivo sin grupo control, los datos no fueron documentados de manera estandar izada sig uiendo un protocolo, y algunos de los resultados estaban documentados de manera subjetiva en los expedientes médicos (ej. dolor, severidad de actividad endoscópica). Esto se podría evaluar mejor en un estudio prospectivo con una población mayor, recolección de datos estandarizada, evaluación endoscópic a en i nter v a los predispuestos y con comparación con un grupo control (estrategia de manejo empírica).

El manejo actual de las EII requiere la estratif icación del

MSP ARTÍCULO ORIGINAL

riego del paciente, así como del nivel de actividad y el manejo agresivo temprano de los pacientes con riesgo de moderado a alto9,10. La estrategia de “treat-to-target” implica el dar tratamiento con la meta de alcanzar y documentar una remisión completa11. Los altos costos de las terapias biológicas y el aumento en costos médicos asociados a un empeoramiento en la severidad de la actividad de la EII exigen que se desarrollen estrategias para seleccionar el fármacos y la dosis más apropiada para las circunstancias de cada paciente. El monitoreo terapéutico de los niveles de fármaco y anticuerpos se está convirtiendo en una herramienta cada vez más importante para el uso efectivo de los medicamentos biológicos. El hallazgo de niveles subterapéuticos sin anticuerpos enfatiza la utilidad de su uso proactivo para apoyar la utilización de dosis distintas a las aprobadas por la FDA, puesto que permitiría identificar pacientes que se beneficiarían de dosis más altas y estarían a riesgo de mantenerse más tiempo en una dosis inefectiva.

A pesar de estar sustentadas por guías clínicas recientes por parte de las asociaciones más importantes de gastroenterología, incluyendo el AGA y el ACG, estas pruebas no las hacen rutinariamente en la mayoría de los laboratorios, son costosas y no son cubiertas habitualmente por las aseguradoras médicas en Puerto Rico.

El uso de TDM parece ser costo-efectivo, ya que puede prevenir los costos de un tratamiento ineficaz y mejorar los resultados de los pacientes. Las aseguradoras deben ser alentadas a considerar cubrir el costo de estas pruebas, puesto que se han vuelto la práctica recomendada en el tratamiento de las EII. Conflictos de interés: Ninguno que divulgar Reconocimientos: Este estudio fue patrocinado por el Centro Dotal de Investigación de Servicios de Salud de la Escuela de Medicina de la Universidad de Puerto Rico, Subvención 5S21MD000242 y 5S21MD000138, del “National Center for Minority Health and Health Disparities” del “National Institutes of Health” (NCMHDNIH). Su contenido es responsabilidad total de los autores y no necesariamente representa las visiones oficiales del NCMHDNIH. El análisis estadístico fue realizado por Krystel Ruiz Serrano, MS, del Centro Dotal de Investigación de Servicios de Salud de la Escuela de Medicina de la

Universidad de Puerto Rico Estamos agradecidos del programa de asistencia al paciente de Prometheus Laboratories Inc para subsidiar el costo de las pruebas, lo cual facilita el uso de esta herramienta en nuestra práctica clínica de EII. Referencias:

1. Yarur AJ, Rubin DT. Therapeutic drug monitoring of anti-tumor necrosis factor agents in patients with inflammatory bowel disease.

Inflamm Bowel Dis 2015; 21:1709-1718.

2. Peyrin-Biroulet L, Deltenre P, de Suray N, et al. Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008; 6:644-653.

3. Steenholdt C, Bendtzen K, Brynskov J et al. Cut-off levels and diagnostic accuracy of Infliximab trough levels and Infliximab antibodies in Crohn’s Disease. Scand J Gastroenterol, 2001; 46:310-318 4. Adedokun OJ, Sandborborn WJ, Feagan BG, et al. Association of serum concentration of Infliximab and efficacy in adult patients with Ulcerative Colitis. Gastroenterol 2014; 147:1296-1307 5. Maser EA, Villela R, Silverberg MS, et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006; 4:1248-1254.

6. Feurerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S on behalf of AGA Clinical Guidelines Commitee. Therapeutic drug monitoring in Inflammatory bowl disease. Gastroenterol 2017: 153 (3); 827-834 7. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults, Am J Gastroenterol, advance online publication, 27 March 2018, doi:10.1038/ajg.2018.27 8. Wang SL,Ohrmund L,Hauenstein S,et al.Development and validation of a homogenous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012; epub ahead of print.

9. AGA Institute guidelines for the Identification, Assessment and Initial Medical Treatment of Crohn’s Disease, clinical decision support tool, www.gastro.org/IBDcarepathway. 2015.

10. AGA Institute clinical support tool: Identification, Assessment and Initial Medical Treatment of Ulcerative Colitis, clinical care pathway. www.gastro.org/UC. 2015.

11. P eyrin-Biroulet L, Sandborn WJ, Sands,BE., Selecting Therapeutic Targets in In ammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target, Am J Gastroenterol 2015:110; 1325-1338.

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INDICATION1 HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine. The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to anti-TNF agents.

1

IMPORTANT SAFETY INFORMATION

SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue HUMIRA if a patient develops a serious infection or sepsis.

Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease.

Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients: 1. with chronic or recurrent infection, 2. who have been exposed to TB, 3. with a history of opportunistic infection, 4. who resided in or traveled in regions where mycoses are endemic, 5. with underlying conditions that may predispose them to infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

• Do not start HUMIRA during an active infection, including localized infections.

• Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.

• If an infection develops, monitor carefully and initiate appropriate therapy.

• Drug interactions with biologic products: A higher rate of serious infections has been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. An increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no demonstrated added benefit in patients with RA. Concomitant administration of HUMIRA with other biologic DMARDs (e.g., anakinra or abatacept) or other TNF blockers is not recommended based on the possible increased risk for infections and other potential pharmacological interactions.

MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including HUMIRA. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

• Consider the risks and benefits of HUMIRA treatment prior to initiating or continuing therapy in a patient with known malignancy.

• In clinical trials, more cases of malignancies were observed among HUMIRA-treated patients compared to control patients.

• Non-melanoma skin cancer (NMSC) was reported during clinical trials for HUMIRA-treated patients. Examine all patients, particularly those with a history of prolonged immunosuppressant or PUVA therapy, for the presence of NMSC prior to and during treatment with HUMIRA. • In HUMIRA clinical trials, there was an approximate 3-fold higher rate of lymphoma than expected in the general U.S. population. Patients with chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk of lymphoma than the general population, even in the absence of TNF blockers.

• Postmarketing cases of acute and chronic leukemia were reported with TNF blocker use. Approximately half of the postmarketing cases of malignancies in children, adolescents, and young adults receiving TNF blockers were lymphomas; other cases included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents.

HYPERSENSITIVITY • Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If a serious allergic reaction occurs, stop HUMIRA and institute appropriate therapy.

HEPATITIS B VIRUS REACTIVATION • Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.

• Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy.

• Exercise caution in patients who are carriers of HBV and monitor them during and after HUMIRA treatment.

• Discontinue HUMIRA and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming HUMIRA after HBV treatment.

NEUROLOGIC REACTIONS • TNF blockers, including HUMIRA, have been associated with rare cases of new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome.

• Exercise caution when considering HUMIRA for patients with these disorders; discontinuation of HUMIRA should be considered if any of these disorders develop.

• There is a known association between intermediate uveitis and central demyelinating disorders.

HEMATOLOGIC REACTIONS • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with HUMIRA. • Consider stopping HUMIRA if significant hematologic abnormalities occur.

CONGESTIVE HEART FAILURE • Worsening and new onset congestive heart failure (CHF) has been reported with TNF blockers. Cases of worsening CHF have been observed with HUMIRA; exercise caution and monitor carefully.

AUTOIMMUNITY • Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

IMMUNIZATIONS • Patients on HUMIRA should not receive live vaccines.

• Pediatric patients, if possible, should be brought up to date with all immunizations before initiating HUMIRA therapy.

• Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

ADVERSE REACTIONS • The most common adverse reactions in HUMIRA clinical trials (>10%) were: infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc.

Please see Brief Summary of full Prescribing Information on the following pages. ©2017 AbbVie Inc. North Chicago, IL 60064 64E-1932644 October 2017 Printed in U.S.A.

Sophie achieved her goal of controlling her moderate to severe ulcerative colitis (UC) in 8 weeks with HUMIRA.1 Not an actual patient.

Learn more at HUMIRAperspectives.com

HUMIRA® (adalimumab) WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue HUMIRA if a patient develops a serious infection or sepsis.

Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients with chronic or recurrent infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions and Adverse Reactions].

MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including HUMIRA [see Warnings and Precautions].

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis.

It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants [see Warnings and Precautions].

INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. HUMIRA can be used alone or in combination with methotrexate.

Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Adult Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.

Ulcerative Colitis HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning and Warnings and Precautions].

Hidradenitis Suppurativa HUMIRA is indicated for the treatment of moderate to severe hidradenitis suppurativa.

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Uveitis HUMIRA is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers.

Patients have frequently presented with disseminated rather than localized disease.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions].

Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection.

Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating HUMIRA and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating HUMIRA, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille CalmetteGuerin (BCG).

Consider anti-tuberculosis therapy prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with HUMIRA. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. Discontinue HUMIRA if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with HUMIRA, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.

Malignancies Consider the risks and benefits of TNF-blocker treatment including HUMIRA prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNFblocker-treated adult patients compared to control-treated adult patients.

During the controlled portions of 39 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 52 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the most frequently observed malignancies,

other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer During the controlled portions of 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973 HUMIRA-treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population.

Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications.

Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member [see Boxed Warning]. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA [see Boxed Warning]. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered.

Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of HUMIRA and institute appropriate therapy. In clinical trials of HUMIRA in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.

Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus.

In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop HUMIRA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of HUMIRA therapy in this situation and monitor patients closely.

Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of HUMIRA should be considered if any of these disorders

develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Consider discontinuation of HUMIRA therapy in patients with confirmed significant hematologic abnormalities.

Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNFblocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].

Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. HUMIRA has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully.

Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, discontinue treatment [see Adverse Reactions].

Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Similar proportions of patients developed protective levels of anti-influenza antibodies between HUMIRA and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving HUMIRA. The clinical significance of this is unknown. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants [see Use in Specific Populations].

Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions].

ADVERSE REACTIONS The most serious adverse reactions described elsewhere in the labeling include the following: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Infections In the controlled portions of the 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 HUMIRA-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients.

Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions].

Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions].

Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA

titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms.

The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown.

Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of HUMIRA in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of HUMIRA-treated patients and 1.5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. No ALT elevations ≥ 3 x ULN occurred in the open-label study of HUMIRA in patients with polyarticular JIA who were 2 to <4 years.

In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with CD with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In the Phase 3 trial of HUMIRA in pediatric patients with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of controltreated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.

In controlled trials of HUMIRA (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated subjects and 0.6% of control-treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients.

Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed.

With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibodypositive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown.

In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg, adalimumab antibodies were identified in 7% (1 of 15) of HUMIRA-treated patients, and the one patient was receiving concomitant MTX. In patients with AS, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with RA. In patients with PsA, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA. In adult patients with CD, the rate of antibody development was 3%.

In pediatric patients with Crohn’s disease, the rate of antibody development in patients receiving HUMIRA was 3%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 32% of total patients studied), the immunogenicity rate was 10%.

In patients with moderately to severely active UC, the rate of antibody development in patients receiving HUMIRA was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.

In patients with Ps, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.

In subjects with moderate to severe HS, the rate of anti-adalimumab antibody development in subjects treated with HUMIRA was 6.5%.

However, because of the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among subjects who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied), the immunogenicity rate was 28%.

In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab.

However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%. Using an assay which could measure an anti-adalimumab antibody titer in all patients, titers were measured in 39.8% (99/249) of non-infectious uveitis patients treated with adalimumab.

No correlation of antibody development to safety or efficacy outcomes was observed.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers, and are highly dependent on the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration.

The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week.

Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1. Adverse Reactions Reported by ≥5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) HUMIRA 40 mg subcutaneous Every Other Week

Placebo

(N=705)

(N=690)

Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection

17%

13%

Sinusitis

11%

9%

Flu syndrome

7%

6%

Nausea

9%

8%

Abdominal pain

7%

4%

Gastrointestinal

Laboratory Tests* Laboratory test abnormal

8%

7%

Hypercholesterolemia

6%

4%

Hyperlipidemia

7%

5%

Hematuria

5%

4%

Alkaline phosphatase increased

5%

3%

Headache

12%

8%

Rash

12%

6%

Accidental injury

10%

8%

Injection site reaction **

8%

1%

Back pain

6%

4%

Other

Urinary tract infection

8%

5%

Hypertension

5%

3%

* Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated patients in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs.

In Study JIA-I, HUMIRA was studied in 171 patients who were 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis.

Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.

In Study JIA-I, 45% of patients experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment.

The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.

In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash.

In Study JIA-I, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.

Approximately 15% of patients treated with HUMIRA developed mildto-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients.

Most patients were able to continue HUMIRA without interruption.

In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of patients experienced an infection while receiving HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving HUMIRA in the study and included dental caries, rotavirus gastroenteritis, and varicella.

In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Adult Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 adult patients with Crohn’s disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for adult patients with CD treated with HUMIRA was similar to the safety profile seen in patients with RA. Pediatric Crohn’s Disease Clinical Studies HUMIRA has been studied in 192 pediatric patients with Crohn’s disease in one double-blind study (Study PCD-I) and one open-label extension study.

The safety profile for pediatric patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in adult patients with Crohn’s disease.

During the 4 week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (6% and 5%, respectively).

A total of 67% of children experienced an infection while receiving HUMIRA in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis.

A total of 5% of children experienced a serious infection while receiving HUMIRA in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis.

In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions.

Ulcerative Colitis Clinical Studies HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for subjects with Ps treated with HUMIRA was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, HUMIRA-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Hidradenitis Suppurativa Clinical Studies HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study.

The safety profile for subjects with HS treated with HUMIRA weekly was consistent with the known safety profile of HUMIRA. Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from HUMIRA treatment following the primary efficacy timepoint in two studies.

Uveitis Clinical Studies HUMIRA has been studied in 464 patients with uveitis (UV) in placebocontrolled and open-label extension studies. The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA. Postmarketing Experience The following adverse reactions have been identified during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate HUMIRA has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX.

Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

Live Vaccines Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions].

Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HUMIRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Limited clinical data are available from the Humira Pregnancy Registry.

Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups [see Data]. Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant. In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively.

Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to HUMIRA in utero [see Use in Specific Populations].

Data Human Data In a prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Data from the Crohn’s disease portion of the study is in the follow-up phase and the analysis is ongoing.

In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease treated with HUMIRA, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 μg/mL in cord blood, 4.28-17.7 μg/mL in infant serum, and 0-16.1 μg/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: 6 weeks (1.94 μg/mL), 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.

Lactation Risk Summary Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum level. There are no reports of adverse effects of adalimumab on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMIRA and any potential adverse effects on the breastfed child from HUMIRA or from the underlying maternal condition.

Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s disease have not been established. Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to HUMIRA in utero suggest adalimumab crosses the placenta [see Use in Specific Populations]. The clinical significance of elevated adalimumab levels in infants is unknown. The safety of administering live or liveattenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.

Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Precautions].

Juvenile Idiopathic Arthritis In Study JIA-I, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. In Study JIA-II, the safety profile for patients 2 to <4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular JIA [see Adverse Reactions].

HUMIRA has not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

The safety of HUMIRA in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions].

Pediatric Crohn’s Disease The safety and effectiveness of HUMIRA for reducing signs and symptoms and inducing and maintaining clinical remission have been established in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate. Use of HUMIRA in this age group is supported by evidence from adequate and well-controlled studies of HUMIRA in adults with additional data from a randomized, double-blind, 52week clinical study of two dose levels of HUMIRA in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn’s disease. The safety and effectiveness of HUMIRA has not been established in pediatric patients with Crohn’s disease less than 6 years of age.

Geriatric Use A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among HUMIRA treated patients over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.

OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility.

PATIENT COUNSELING INFORMATION Patient Counseling Provide the HUMIRA “Medication Guide” to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.

Advise patients of the potential benefits and risks of HUMIRA. • Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Counsel patients about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the gray needle cap of the 27 gauge HUMIRA pen and prefilled syringe contains natural rubber latex.

• Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

AbbVie Inc. North Chicago, IL 60064, U.S.A. US License Number 1889 Ref: 03-B467-R44/20015346 Revised: 04/2017 64C-1915014 MASTER

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Trasplante de hígado: un gran avance en Puerto Rico Por: Felipe Vélez1, MD Mervin Figueroa 1, MD Víctor Carlo 1.2, MD Rafael Pastrana 1.2, MD Iván Antúnez 1.2, MD José Rivera, MD 1.

Escuela de Medicina de la Universidad de Puerto Rico, Departamento de Medicina,

División de Gastroenterología y Enfermedades de Hígado Centro de Trasplante. Hospital Auxilio Mutuo

La Revista Puertorriqueña de Medicina y Salud Pública (MSP) declara que para la publicación de este artículo no hubo ofrecimiento alguno que pudiera afectar su objetividad y ética. Los trabajos y colaboradores son evaluados por su carácter e interés científico.

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Palabras clave Resumen: Cirrosis, enfermedades crónicas La prevalencia de enfermedades del hígado, trasplante de hígado, crónicas del hígado es elevada y al centro de trasplante de hígado momento no se ha logrado encontrar la cura para muchas de estas condiciones.

Keywords El trasplante de hígado es el mejor Cirrhosis, chronic liver disease, tratamiento disponible para algunos liver transplant, liver transplant de estos pacientes cuando alcanzan center niveles avanzados de severidad en su enfermedad. En Puerto Rico, el acceso a un centro de trasplante de hígado era limitado y los pacientes tenían que emigrar a Estados Unidos para recibir este servicio, haciéndolo inaccesible para muchos. En 2012, todo esto cambió al establecerse el Centro de Trasplante de Hígado en el Hospital Auxilio Mutuo. Sin lugar a dudas, el establecimiento de este centro Doctor Juan del Río, director del Centro en nuestra isla es uno de los avances de Transplante de Hígado del Hospital en el área de gastroenterología más Auxilio Mutuo. importantes en los últimos años.

Abstract: There is a high prevalence of chronic liver disease and for many conditions there has no been success in finding a cure. The best treatment available for some of these patients who reach a severe advanced liver disease is liver transplant. The access to a liver transplant center in Puerto Rico was limited and patients had to migrate to the United States for this service, which made it inaccessible to many. All this changed in 2012 with the establishment of the Liver Transplant Center in the “Hospital Auxilio Mutuo”. The establishment of this center in our island is without any doubt one of the most important advances in the gastroenterology area in recent years.

Introducción: El trasplante de hígado es un procedimiento en el cual se reemplaza un hígado enfermo por uno saludable. Al momento es el único tratamiento definitivo disponible para la enfermedad de hígado terminal, ya que no existen medicamentos que reviertan la cirrosis. Igualmente sirve de tratamiento para otras condiciones como fallo hepático agudo, enfermedades metabólicas avanzadas y cáncer de hígado 1. La prevalencia de cirrosis en Estados Unidos se estima en 0.27% (633.233 adultos) 2 y se realizan aproximadamente 6000 trasplantes de hígado anualmente 3. En Puerto Rico no existen estadísticas pero se estima que la prevalencia es mayor, esto basado en otras condiciones que predisponen el desarrollo de enfermedad crónica del hígado. Anteriormente, todo

Unidos4) de 6.3% por cada 100.000 habitantes fuera del área de San Juan5,6. y 2.3% por cada 100.000 habitantes fuera del área de San Juan. Esta prevalencia es mayor a la de Estados Unidos que se estima en 1% correspondiendo a 2.7 millones

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aquel paciente que fuera candidato a trasplante tenía que ser transferido a algún centro en Estados Unidos, lo cual hacía muy cuesta arriba esta opción para la mayoría de pacientes, dado el alto costo que conlleva todo el proceso. En el año 2012 este panorama cambió al realizarse el primer trasplante de hígado en el Hospital Auxilio Mutuo. Desde entonces se han realizado 129 trasplantes de forma exitosa. Este artículo describe este avance en nuestra isla, el cual ha sido de gran impacto para nuestra sociedad.

Discusión Varios estudios sugieren que existe una alta prevalencia de enfermedades crónicas de hígado en la población puertorriqueña.

En estos estudios se describe la prevalencia de hepatitis C (la causa principal de trasplante en los Estados

“SIRVE DE TRATAMIENTO PARA OTRAS CONDICIONES COMO FALLO HEPÁTICO AGUDO, ENFERMEDADES METABÓLICAS AVANZADAS Y CÁNCER DE HÍGADO”

MSP ARTÍCULO ORIGINAL

“En 2014 se realizaron 6.729 trasplantes de hígado, de los cuales 6.449 (95.8%) fueron de donantes cadavéricos y unos 280 (4.2%) de donantes vivos 14. La lista de espera por un hígado es de aproximadamente 15.000 personas” de adultos no institucionalizados7.

Adicional a esto, una revisión de 332 biopsias de hígado de pacientes puertorriqueños con hepatitis C determinó que un 21.5% de éstos presentaban cirrosis, una cifra elevada en comparación con otros grupos étnicos, como los caucásicos, a froa mer ica nos y asiát ico americanos, los cuales presentan 11% de cirrosis8,9. Durante el 2010, la enfermedad crónica de hígado y cirrosis fueron la decimosexta causa de muerte en Puerto Rico, con una tasa de mortalidad de 5.4 por cada 100.000 habitantes10.

La cirrosis hepática se caracteriza por la distorsión estructural de la arquitectura del hígado y la formulación de nódulos regenerativos.

Estos producen aumento en la presión de la circulación portal y provoca complicaciones como lo son: ascitis, encefalopatía hepática, sangrado por várices esofágicas y/o gástricas, y cáncer hepatocelular.

Todas estas complicaciones afectan la calidad de vida del paciente pero las últimas dos son responsables de una alta mortalidad si no son tratadas a tiempo. Existen guías para la prevención y tratamiento de estas condiciones, las cuales fueron realizadas por la Asociación Americana para el Estudio de las Enfermedades de Hígado (AASLD, por sus siglas en inglés) 11. Sin embargo, cuando estas complicaciones no pueden ser controladas con tratamiento médico o la función del hígado no es adecuada para la sobrevivencia de un paciente

(enfermedad de hígado terminal), el único tratamiento definitivo disponible es el trasplante de hígado.

El primer trasplante de hígado ortotópico exitoso se realizó en Denver, Colorado en 196712. Este procedimiento consiste en remover el hígado saludable de un donante cadavérico para reemplazar el hígado enfermo de un paciente.

Inicialmente este tratamiento se consideraba uno experimental pero luego de décadas de experiencia e investigación, y la introducción de inmunosupresores como el tacrolimus y la ciclosporina, el trasplante de hígado se reconoció como tratamiento clínico estándar.

Desde entonces, este modo de tratamiento ha cambiado la vida de miles de personas. En 1989 se realizó el primer trasplante exitoso de un donante vivo, el cual consiste en extraer parte del lóbulo izquierdo del hígado de un donante vivo para ser implantado en el recipiente13. En 2014 se realizaron 6.729 trasplantes de hígado, de los cuales 6.449 (95.8%) fueron de donantes cadavéricos y unos 280 (4.2%) de donantes vivos14. La lista de espera por un hígado es de aproximadamente 15.000 personas.

El proceso de selección de un candidato a trasplante es uno muy exhaustivo y riguroso, el cual conlleva un camino largo para recorrer. Durante este proceso se evalúan múltiples aspectos sobre el paciente, incluyendo su enfermedad de hígado, comorbilidades, el aspecto social y su estado psicológico. Este

proceso está regulado en Estados Unidos por la “United Network for Organ Sharing” (UNOS), una organización independiente y sin fines de lucro, comprometida con salvar vidas, la cual unifica y apoya los esfuerzos de trasplante y donación. Al existir un número mayor de pacientes en necesidad de trasplante que el número de donantes disponible, UNOS creó unas reglas que sirven de estándares para asegurar que el proceso de selección de candidatos para trasplante sea uno justo y adecuado.

La prioridad asignada a los candidatos a trasplante es de acuerdo con la severidad de su enfermedad hepática, utilizando como principal determinante la escala conocida como “Model for End-Stage Liver Disease” (MELD), la cual asigna una puntuación que varía desde 6 hasta 40 puntos.

Esta puntuación estima el riesgo de mortalidad dentro de los próximos 90 días si no se realiza un trasplante de hígado16 . Una puntuación elevada le adjudica una mayor prioridad al paciente en espera a ser trasplantado. Esta puntuación se calcula utilizando el “International Normalized Ratio” (INR), la bilirrubina total en suero y la creatinina en suero.

Actualmente se debe evaluar para paciente de hígado todo aquel paciente con cirrosis con una puntuación de 15 puntos o más en la escala MELD, y todo paciente que haya desarrollado complicaciones como ascit is, encefa lopat ía Revista Puertorriqueña de Medicina y Salúd Pública

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“Se comenzó a evaluar pacientes pediátricos para lograr el primer trasplante en el año 2016. También se espera realizar trasplantes de hígado y riñón simultáneos” hepática o hemorragia por várices.

Comenzando el 11 de enero de 2016, la escala MELD fue actualizada para incluir el nivel de sodio en la sangre como un factor adicional, según establecido en el 2014 por la Red de Trasplante y Procuraduría de Órganos (OPTN, por sus siglas en inglés) y UNOS17.

Existen contraindicaciones para el trasplante de hígado tales como: enfermedad cardiopulmonar que no pueda ser corregida y que conlleve un riesgo prohibitivo para la cirugía, síndrome de inmunodef iciencia 114

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adquirida, malignidad fuera del hígado que no cumpla con criterios de cura, cáncer hepatocelular con metástasis, colangiocarcinoma intrehepático, hemangiosarcoma, anormalidades anatómicas que prevengan el trasplante, sepsis descontrolada, fallo hepático agudo con presión intracraneal sostenida mayor de 50mmHg, carencia de apoyo social e incapacidad de adherirse a un seguimiento médico adecuado1.

Anteriormente el trasplante de hígado no se realizaba en Puerto Rico por lo que el acceso a este tratamiento era uno limitado para nuestra población. En septiembre de 1999, la División de Gastroenterología y Enfermedades del Hígado de la Escuela de Medicina de la Universidad de Puerto Rico, en afiliación con “LifeLink HealthCare Institute” en Tampa, Florida y en colaboración el Fondo Catastrófico del Gobierno del Estado Libre Asociado de Puerto Rico, creó la Clínica de Evaluación para Trasplante de Hígado18. De esta forma se proveyó un mejor acceso

a la evaluación de trasplante sin necesidad de viajar a Estados Unidos. En el periodo de 1993 a 2003 se evaluaron 193 pacientes de los cuales 63 completaron el proceso, 33 fueron enlistados y 21 fueron trasplantados18.

A pesar de este esfuerzo, el acceso seguía siendo uno limitado ya que la cirugía de trasplante de hígado se realizaba en Estados Unidos.

El Centro de Trasplante de Hígado en Auxilio Mutuo fue fundado en el mes de enero de 2012. El mismo cuenta con tres cirujanos especialistas en trasplante de órganos y tres gastroenterólogos, dos de ellos con subespecialidad en trasplante de hígado. El primer trasplante de hígado en Puerto Rico se realizó exitosamente el 25 de febrero de 2012. En 2012, 2013 y 2014 se realizaron 21, 27 y 44 trasplantes respectivamente, mientras que en el 2015, las cifras hasta el 22 de septiembre eran de 37 trasplantes de hígado. La causa principal de trasplante en Puerto Rico es cirrosis secundaria al virus

MSP ARTÍCULO ORIGINAL

“Se comenzó a evaluar pacientes pediátricos para lograr el primer trasplante en el año 2016. También se espera realizar trasplantes de hígado y riñón simultáneos” de hepatitis C (HCV, por sus siglas en inglés) con un total de 34 casos, seguido por 22 casos de cáncer hepatocelular (11 casos asociados a HCV). La esteatohepatitis no relacionada al consumo de alcohol junto a causas criptogénicas (etiología desconocida) ocupan la tercera posición con 14 trasplantes cada uno. De forma interesante, la etiologías autoinmunes como hepatitis autoinmune y colangitis biliar primaria han sido la causa de trasplante de 11 y 8 pacientes, respectivamente. Por último, la cirrosis secundaria al consumo de alcohol fue responsable de 8 trasplantes.

Se comenzó a evaluar pacientes pediátricos para lograr el primer trasplante en el año 2016. También se espera realizar trasplantes de hígado y riñón de manera simultánea.

Conclusión El acceso a un centro de trasplante de hígado en nuestra isla es sin duda alguna un gran avance en la medicina puertorriqueña. Este adelanto en el área de la gastroenterología ha logrado disminuir la paridad que existía en el pasado al momento de considerar un trasplante de hígado como tratamiento definitivo a la enfermedad de hígado avanzada. La concienciación de la disponibilidad y acceso a la opción de un trasplante en nuestra sociedad y comunidad médica es de vital importancia para poder proveer una atención temprana y continuar ofreciendo un tratamiento de excelencia.

Referencias

10. Departamento de Salud del Gobierno de Puerto Rico. Puerto Rico community health assessment: secondary data profile. (2012, septiembre 28). Extraido de: http://wwwsaludgovpr/EstadisticasRegistros-y-Publicaciones/Publicacienes/EvaluacionO/o20de%20 1a%20Saludo/o20de%201a%20Cemunidad°/o20Puerterriqueo/ oC3%B1a0/o20Perfi10/o20de0/o20Datoso/o2OSecundaries0/ o20(Ingl%C3%A9s).pdf 11. AASLD Practice Guidelines. (2015, diciembre 17). Extraido de: http://www.aasld.erg/publications/practice-guidelines-0 12. Starzl TE, Iwatsuki S, Van thiel DH, et al. Evolution of liver transplantation. Hepatology. 1982;2(5): 14-36.

13. Strong RW, Lynch SV, Ong TN, et a1. Successful liver transplantation from a living-donor to her son. N EnglJ Med. 1990;322:1505-1507.

14. Transplants by donor type-2014. (2015, dicembre 11). https:// www.unos.org/data/transplant-trends/#transplants_by_denor_ type+ergan+Liver 15. Waiting list candidates by organ type- All States. (2015, diciembre 11). Extraído de: https://www.unos.erg/data/transplant— trends/#waitlists_by_ergan 16. Viesner R, Edwards E, Freeman R, et a1. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96.

17. Upcoming MELD sodium policy implementation. (2015, noviembre 16). Extraído de: https: / /www.transplantpre.org/ news/li/upcoming-meld-serum-sodium-pelicy-implementation/ 18. Torres EA, Guzman A, Vazquez M, et a1. Improving access to liver transplantation: the University of Puerto Rico Experience. PR Health Sci J. 2004;23(3):183-188.

1. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M; Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar; 59 (3): 1144-1165.

2. Scaglione S1, Kliethermes S, Cao G, Shoham D, Durazo R, Luke A, Volk ML. The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol. 2015 Sep; 49 (8): 690-696.

3. Transplants by organ type-2014. (2015, diciembre 1 1). Extraído de: https:/ /www.un0s.org/about/annual-report/ 4. Alqahtani SA, and Larson AM, Adult liver transplantation in the USA. Curr Opin Gastroenterol. May 201 1; 27(3): 240-247.

5. Pérez CM, Suarez E, Torres EA, Roman K,Colon V. Seroprevalence of hepatitis C virus and associated risk behaviors: A populationbased study in San Juan, PR. IntJ Epidemiol. 2005; 34:593-599.

6. Pérez CM, Marrero E, Melendez M, et al. Seroepidemiology of Viral hepatitis, HIV, and herpes simplex type 2 in the household population aged 21-64 years in Puerto Rico. BMC Infec Dis. 2010; 10:76.

7. Denniston MM, Jiles RB, Drobeniuc J, et a1. Chronic hepatitis C Virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014 Mar 4; 160(5):293-300.

8. Carlo VL, Torres EA, Magne P, et a1. Hispanics with chronic hepatitis C have more fibrosis and cirrhosis. Gastroenterology.

2003; 124:A384.

9. Ghany MG, Kleiner DE, Alter H, et al. Progression of Fibrosis in Chronic Hepatitis C. Gastroenterology. 2003; 124:97-104.

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INDICATION SYMTUZA™ is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

IMPORTANT SAFETY INFORMATION BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA™. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA™. If appropriate, anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

• Do not coadminister SYMTUZA™ and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, cisapride, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), lovastatin, lurasidone, oral midazolam, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

WARNINGS AND PRECAUTIONS

• Severe Acute Exacerbation of Hepatitis B in Patients Coinfected With HIV-1 and HBV: Patients with HIV-1 should be tested for the presence of chronic HBV before initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA™.

Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA™ should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

Start With the Protective Barrier of Darunavir treatment-emergent darunavir, primary PI or TAF mutations across clinical trial populations1*†‡§

• Only 1 patient receiving SYMTUZA™ was found to have M184I/V 2¶

IMPORTANT SAFETY INFORMATION (cont) • Hepatotoxicity: Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA™. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

Appropriate laboratory testing should be conducted prior to initiating and during therapy with SYMTUZA™. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA™.

• Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA™, severe skin reactions may occur. StevensJohnson syndrome was reported with darunavir coadministered with cobicistat in clinical trials at a rate of 0.1%. During darunavir postmarketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA™ immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages. *AMBER was a Phase 3, randomized, double-blind, active-controlled, international, multicenter, noninferiority study assessing the efficacy and safety of once-daily SYMTUZA™ (DRV 800 mg/ COBI 150 mg/FTC 200 mg/TAF 10 mg) vs DRV/COBI + FTC/TDF in treatment-naïve adults (N=725). Primary endpoint was the proportion of patients with VL <50 copies/mL at 48 weeks (noninferiority margin 10% by FDA Snapshot).1,2 EMERALD was a Phase 3, randomized, open-label, international, multicenter, noninferiority study of switching to SYMTUZA™ (DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg) vs continuing on bPI + FTC/TDF therapy in treatment-experienced adults who had been on therapy for ≥6 months with no history of virologic failure on darunavir-based regimens, and who were virologically suppressed prior to and at screening (N=1141). Primary endpoint was the proportion of patients with virologic rebound at Week 48 (noninferiority margin 4%), and a key secondary endpoint was the proportion of subjects who have VL <50 copies/mL at 48 weeks.1,3

†

‡

In the AMBER trial, of 362 treatment-naïve patients taking SYMTUZA™, 8 met the criteria for virologic failure and 7 patients experiencing virologic failure were analyzed for resistance.1,2

In the EMERALD trial, of 763 virologically suppressed patients taking SYMTUZA™, 6 met the criteria for virologic failure and 1 patient experiencing virologic failure was analyzed for resistance.1,3

§

This patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%).2

¶

bPI=boosted protease inhibitor; COBI=cobicistat; DRV=darunavir; FTC=emtricitabine; PI=protease inhibitor; TAF=tenofovir alafenamide; TDF=tenofovir disoproxil fumarate; VL=viral load.

Formulated for Improved Tolerability SYMTUZA™ demonstrated a favorable tolerability profile vs control arm in treatment-naïve patients1

of treatment-naïve subjects discontinued due to adverse events in the SYMTUZA™ arm vs 4% in the control arm1

• The most common adverse reactions occurring in ≥2% of treatmentnaïve patients were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence1 • This is not a complete list of adverse reactions. Please refer to the full Prescribing Information for more information

IMPORTANT SAFETY INFORMATION (cont) • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant

use of SYMTUZA™ and other drugs may result in known or potentially significant drug interactions, some of which may lead to the loss of therapeutic effect of SYMTUZA™ and possible development of resistance or possible clinically significant adverse reactions from greater exposures of concomitant drugs.

Consult the full Prescribing Information for potential drug interactions prior to and during SYMTUZA™ therapy, review concomitant medications during SYMTUZA™ therapy, and monitor for the adverse reactions associated with concomitant medications.

• Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, had been reported in patients treated with combination antiretroviral therapy.

• New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi

syndrome, has been reported with the use of tenofovir prodrugs. SYMTUZA™ is not recommended in patients with creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-infl ammatory drugs are at increased risk of developing renal-related adverse reactions.

In all patients, monitor serum creatinine, creatinine clearance, urine glucose, and urine protein prior to or when initiating SYMTUZA™ and during therapy. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA™ in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

• Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating SYMTUZA™.

• Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA™, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals. Discontinue SYMTUZA™ in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING, on the following pages.

91% Virologic Response Achieved in Treatment-Naïve Patients 1

% of Patients Achieving Virologic Response (VL <50 copies/mL)

100

Control=DRV/c + FTC/TDF.

‡

Included subjects who had ≥50 copies/mL in the Week 48 window (days 295-378); subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. CD4+=cluster of differentiation 4; DRV/c=darunavir/cobicistat; FTC/TDF=emtricitabine/tenofovir disoproxil fumarate; MH=Mantel-Haenszel; VL=viral load.

60

91

%

40

of patients treated with SYMTUZA™ had

20

at Week 48 (<50 copies/mL)*

undetectable VLs (n=362)

(n=363)

SYMTUZA™

Control†

• 4% virologic failure rate in the SYMTUZA™ arm vs 3% in the control arm1‡ 100

91

91% 88% • 4% of patients in the SYMTUZA™ arm had no 80 virologic data vs 8% in the control arm1

% of Patients Achieving Virologic Response (VL <50 copies/mL)

%

IMPORTANT SAFETY INFORMATION (cont) 60 have been • Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus andofhyperglycemia patients treated reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

40

with SYMTUZA™ had

• Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral undetectable VLs therapy. (<50 copies/mL) • Hemophilia: Increased bleeding in hemophiliacs has been reported in patients receiving protease inhibitors.

20 at Week 48 ADVERSE REACTIONS [95% CI (2.7%, -1.6 to 7.1)]* (n=362) (n=363)

• The most common clinical adverse reactions (all grades) occurring 0in at least 2% of treatment-naïve patients were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. This is not a completeSYMTUZA™ list of all adverse drug reactions reported with the use of Control SYMTUZA™. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

DRUG INTERACTIONS

• Consult the full Prescribing Information for SYMTUZA™ for information on significant drug interactions, including clinical comments.

USE IN SPECIFIC POPULATIONS • Pregnancy: SYMTUZA™ is not recommended for use during pregnancy because of substantially lower exposures of darunavir and

cobicistat during pregnancy.

SYMTUZA™ should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA™.

• Renal Impairment: SYMTUZA™ is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute).

• Hepatic Impairment: SYMTUZA™ is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).

• Consult the full Prescribing Information for SYMTUZA™ for additional information on the Uses in Specific Populations.

Please see accompanying Brief Summary, including Boxed WARNING, for SYMTUZA™.

References: 1. SYMTUZA™ [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 2. Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve HIV-1 patients. AIDS. 2018;32:1431-1442. 3. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3 randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34.

Distributed by: Janssen Therapeutics, Division of Janssen Products, LP, Titusville, NJ 08560 © Janssen Therapeutics, Division of Janssen Products, LP 2018 07/18 cp-60915v1

cp-62076v2

B:11.75”

T:11.5”

S:10.3667”

†

88%

80

0

*Based on stratum adjusted MH test where stratification factors are HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and CD4+ cell count (<200 or ≥200 cells/µL).

91%

SYMTUZA™

(darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert.

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions].

INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

DOSAGE AND ADMINISTRATION Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions].

Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions].

Recommended Dosage SYMTUZA is a four-drug fixed dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations].

Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations].

Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy [see Use in Specific Populations and Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA. DOSAGE FORMS AND STRENGTHS Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with “8121” on one side and “JG” on the other side.

CONTRAINDICATIONS SYMTUZA is contraindicated with the following co-administered drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions].

• Alpha 1-adrenoreceptor antagonist: alfuzosin • Antianginal: ranolazine • Antiarrhythmic: dronedarone • Anticonvulsants: carbamazepine, phenobarbital, phenytoin • Anti-gout: colchicine, in patients with renal and/or hepatic impairment • Antimycobacterial: rifampin • Antipsychotics: lurasidone, pimozide • Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine • GI motility agent: cisapride • Herbal product: St. John’s wort (Hypericum perforatum) • Hepatitis C direct acting antiviral: elbasvir/grazoprevir • HMG-CoA reductase inhibitors: lovastatin, simvastatin • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension • Sedatives/hypnotics: orally administered midazolam, triazolam

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets WARNINGS AND PRECAUTIONS Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA. Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions]. Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications and Drug Interactions]: • Loss of therapeutic effect of SYMTUZA and possible development of resistance.

• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications and Drug Interactions].

When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and GuillainBarré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of SYMTUZA, there were no cases of proximal renal tubulopathy (PRT), including Fanconi syndrome, reported in the SYMTUZA group through Week 48. SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation.

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued.

A causal relationship between PI therapy and these episodes has not been established.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe acute exacerbations of hepatitis B [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Severe skin reactions [see Warnings and Precautions]

• Immune reconstitution syndrome [see Warnings and Precautions] • New onset or worsening renal impairment [see Warnings and Precautions] • Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).

The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively.

An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX and F/TDF are presented in Table 3.

Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA PREZCOBIX+FTC/TDF (N=362) (N=363) All At least All At least Grades Grade 2 Grades Grade 2 Diarrhea 9% 2% 11% 2% Rasha 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% 4% <1% Flatulence 2% <1% 1% a Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC and TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a boosted protease inhibitor with FTC and TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%.

Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir).

Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, StevensJohnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive system and Breast disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Laboratory Abnormalities

In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/ TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg per gram (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg per gram (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48.

Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with DRV/COBI + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

EMERALD In EMERALD, boosted Protease Inhibitor (bPI) and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with PREZCOBIX + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a darunavir-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders Redistribution of body fat Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions].

DRUG INTERACTIONS Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drugdrug interactions with other antiretroviral medications is not provided.

Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events (see Table 4).

Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4).

Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4).

Table 2: Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter SYMTUZA Grade Limit N=362 Creatinine Grade 2 >1.3 to 1.8 x ULN 4% Grade 4 ≥3.5x ULN <1% Triglycerides Grade 2 301-500 mg/dL 7% Grade 3 501-1,000 mg/dL 1% Grade 4 > 1,000 mg/dL <1%% Total Cholesterol Grade 2 240-<300 mg/dL 17% Grade 3 >= 300 mg/dL 2% Low-Density Lipoprotein Cholesterol Grade 2 160-189 mg/dL 9% Grade 3 ≥ 190 mg/dL 5% Elevated Glucose Levels Grade 2 126-250 mg/dL 6% Grade 3 251-500 mg/dL <1%

PREZCOBIX+ FTC/TDF N=363 14% 0 4% 1% <1% 4% 1%

4% 1%

6% 0

ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)a SYMTUZA PREZCOBIX+FTC/TDF N=356 N=355 Baseline Week 48 Baseline Week 48 Meanb mg/dL Change mg/dL Change N=304c N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 199 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to 4.1 0.2 4.0 0.1 HDL ratio a Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent postbaseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). b The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. c One subject did not have a Week 48 result for LDL cholesterol (n=303).

The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively.

Renal Laboratory Tests In the AMBER trial, which had 670 adults with no prior antiretroviral treatment history with a median baseline eGFR of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF), mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group from baseline to Week 48. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/ dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg per gram (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg per gram (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions].

Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs.

Table 4: Significant Drug Interactions: Concomitant Drug Class: Drug Name, Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.

Antianginal: ranolazine. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions.

Antiarrhythmics: dronedarone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antiarrhythmics, e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine. Clinical monitoring is recommended upon co-administration with antiarrhythmics. digoxin. When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.

Antibacterials: clarithromycin, erythromycin, telithromycin. Consider alternative antibiotics with concomitant use of SYMTUZA. Anticancer agents: dasatinib, nilotinib. A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. vinblastine, vincristine. For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

Anticoagulants: Direct Oral Anticoagulants (DOACs). apixaban. Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with SYMTUZA depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. rivaroxaban. Coadministration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. betrixaban, dabigatran, edoxaban. No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with SYMTUZA. warfarin. Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response.

Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam. Clinical monitoring of anticonvulsants is recommended.

Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, sertraline.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline.

Other antidepressants: trazodone. When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

Antifungals: itraconazole, ketoconazole, posaconazole. Monitor for increased darunavir or cobicistat adverse reactions. Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole.

Monitor for increased itraconazole or ketoconazole adverse reactions. voriconazole. Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.

Anti-gout: colchicine. Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or lifethreatening reactions. For patients without renal or hepatic impairment: • Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) ×1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.

• Prophylaxis of gout flares – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

• Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimalarial: artemether/lumefantrine. Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.

Antimycobacterials: rifampin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin. Co-administration of SYMTUZA with rifabutin is not recommended.

If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. rifapentine. Co-administration with rifapentine is not recommended.

Antipsychotics: lurasidone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antipsychotics, e.g., perphenazine, risperidone, thioridazine. A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with SYMTUZA. quetiapine. Initiation of SYMTUZA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking SYMTUZA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. β-Blockers: e.g., carvedilol, metoprolol, timolol. Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized

by CYP2D6.

Calcium channel blockers: e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil. Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone methylprednisolone, mometasone, triamcinolone. Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids.

Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

Endothelin receptor antagonists: bosentan. Initiation of bosentan in patients taking SYMTUZA: In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Initiation of SYMTUZA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of SYMTUZA. After at least 10 days following the initiation of SYMTUZA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose.

Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI motility agent: cisapride. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir.

Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. simeprevir. Co-administration with simeprevir is not recommended.

Herbal product: St. John’s wort (Hypericum perforatum). Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

HMG-CoA reductase inhibitors: lovastatin, simvastatin. Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

other HMG-CoA reductase inhibitors, e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin. For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety.

Dosage recommendations with atorvastatin or rosuvastatin are as follows: • atorvastatin dosage should not exceed 20 mg/day • rosuvastatin dosage should not exceed 20 mg/day Hormonal contraceptives: Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are coadministered with SYMTUZA. drosperinone/ethinylestradiol. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. other progestin/estrogen, contraceptives. No data are available to make recommendations on co-administration with oral or other hormonal contraceptives.

Immunosuppressants: cyclosporine, sirolimus, tacrolimus. These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use.

Immunosuppressant/neoplastic: everolimus. Co-administration of everolimus and SYMTUZA is not recommended.

Inhaled beta agonist: salmeterol. Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone.

Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol. A dose decrease may be needed for tramadol with concomitant use.

Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone. Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose.

Initiation of SYMTUZA in patients taking buprenorphine, buprenorphine/ naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.

Phosphodiesterase PDE-5 inhibitors: e.g., avanafil, sildenafil, tadalafil, vardenafil. Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.

Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with SYMTUZA: • Initiation of tadalafil in patients taking SYMTUZA: In patients receiving SYMTUZA for at least one week, start tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

• Initiation of SYMTUZA in patients taking tadalafil: Avoid use of tadalafil during the initiation of SYMTUZA. Stop tadalafil at least 24 hours prior to starting SYMTUZA. After at least one week following the initiation of SYMTUZA, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

• Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose.

Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitorassociated adverse reactions.

Platelet aggregation inhibitor: ticagrelor. Co-administration of SYMTUZA and ticagrelor is not recommended.

Sedatives/hypnotics: orally administered midazolam, triazolam.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem.

With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. parenterally administered midazolam. Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.

This table is not all inclusive

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary There are insufficient human data on the use of SYMTUZA in pregnant individuals from the APR to inform on a potential drug-associated risk of birth defects and miscarriage. Available data from the APR show no difference in rate of overall birth defects for darunavir and emtricitabine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates pregnant individuals and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively) at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA (see Data). No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose.

Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see Data) and [see Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA. Data Human Data Darunavir/Cobicistat: Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum.

Six pregnant individuals completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see Clinical Pharmacology (12.3) in Full Prescribing Information].

One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period.

There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

Darunavir: Based on prospective reports to the APR of 679 live births following exposure to darunavir-containing regimens during pregnancy (including 425 exposed in the first trimester and 254 exposed in the second/ third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with first trimester exposure to darunavir containing-regimens and 2.4% (95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavircontaining regimens.

Cobicistat: Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.

Emtricitabine: Based on prospective reports to the APR of 3749 exposures to emtricitabine-containing regimens during pregnancy (including 2614 exposed in the first trimester and 1135 exposed in the second/third trimester), there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to emtricitabine-containing regimens and 2.1% (95% CI: 1.4% to 3.1%) with the second/third trimester exposure to emtricitabine-containing regimens.

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA™ (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Tenofovir alafenamide: Insufficient numbers of pregnancies with exposure to tenofovir alafenamide have been reported to the APR to estimate the rate of birth defects.

Animal Data Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA. Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7-20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA. Emtricitabine: Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. Tenofovir Alafenamide (TAF): TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF. Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States not to breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are present in the milk of lactating rats. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data).

Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving SYMTUZA. Data Animal Data Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 66% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat: During the pre/postnatal developmental toxicology study, at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.

Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use The safety and effectiveness of SYMTUZA in pediatric patients less than 18 years of age have not been established. Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

Juvenile Animal Toxicity Data Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on postnatal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

Geriatric Use Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Renal Impairment SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with SYMTUZA [see Warnings and Precautions].

Hepatic Impairment No dosage adjustment of SYMTUZA is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment.

SYMTUZA has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Product of Canada Manufactured by: Patheon Inc, 2100 Syntex Ct Mississauga ON L5N 7K9, Canada Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 © 2018 Janssen Pharmaceutical Companies cp-62058v1

2019

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

Puerto Rico

Título

Lugar

Coordinador o Contacto

26 de enero de 2019

San Juan Capestrano Annual Convention

San Juan Marriott Resort & Stellaris Casino

AMEC

787-289-8989 amec@amec-pr.com

CONVENCIÓN

27 de enero de 2019

Women’s Health Conference 2019

Puerto Rico Convention Center San Juan, PR

SDMS Group

787-731-3325 jdiaz@sdmsgroup.com

CONFERENCIA

7 de febrero de 2019

Post Ash Conference 2019

Popular Center San Juan

AMEC

787-289-8989 amec@amec-pr.com

CONFERENCIA

7 al 10 de febrero de 2019

Digestive Diseases of the Caribbean 2019

Sheraton Convention Center San Juan, PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com

CONVENCIÓN

14 al 17 de febrero de 2019

Convención Anual Sociedad Puertorriqueña de Pediatría

Sheraton Convention Center San Juan, PR

SDMS Group

787-731-3325 info@sdmsgroup.com

CONVENCIÓN

22 al 24 de febrero de 2019

Simposio anual- Asociación de Acupuntura de PR

Centro de Banquete Los Chavales San Juan, PR

Asociación de Acupuntura de PR

787-759-8325 www.aacupuntura.org

SIMPOSIO

23 de febrero de 2019

6to Simposio Cardiovascular- Hospital Episcopal San Lucas

Complejo Ferial Juan H. Cintrón Ponce, PR

Hospital San Lucas-Ponce

787-844-2080

SIMPOSIO

1 de marzo de 2019

1er Congreso de Salud Mental de PR

San Juan Marriot Hotel San Juan, PR

Pedro Del Valle

787-562-1516 pldvalle@hotmail.com

CONGRESO

2 de marzo de 2019

Simposio Ortopédico de Columna-SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT)

787-723-6751 asis.spot@gmail.co

7 al 9 de marzo 2019

Convención Anual Academia Médica del Sur

Ponce Hilton Hotel Ponce, PR

Acadeia Médica del Sur academiamedicadel sur@gmail.com

787-843-0610

CONVENCIÓN

8 al 10 de marzo de 2019

Convención anual-American College of Physicians

Hotel la Concha San Juan, PR

RIVS Marketing

787-548-0047 info@rivsmarketing.co

CONVENCIÓN

9 de Marzo de 2019

Be Brave Rheumatic Updates and Research Trend

Fraternidad AFDA El Condado, Calle Cervantes #2 San Juan, PR

Fundación Bechara & Asociación de Reumatólogos de PR

787-512-2223 www.fundacionbechara.org

CONFERENCIAS

5 al 6 de abril Pulmonary and Critical Care Congress de 2019 2019-Sociedad Puertorriqueña de Neumología

Ponce Hilton Hotel Ponce, PR

Business Planners

Merna morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

6 de abril de 2019

Sheraton Convention Center Hotel San Juan, PR

AMEC

787-289-8989 amecpr@gmail.com

CONGRESO

6 al 7 de abril Convención Anual Academia de Patología de 2019 y Medicina de Laboratorio de PR

Sheraton Convention Center San Juan, PR

Serra & Serra Group

787-640-5776 patologospr@serrayserra.com

CONVENCIÓN

6 de abril de Convención anual Asociación de Psiquiatras de Bayamón 2019

Hotel la Concha San Juan, PR

AMEC

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CONVENCIÓN

25 al 27 abril Convención Anual Academia de Médicos de Familia de PR de 2019

Sheraton Convention Center Hotel San Juan, PR

SDMS

787-731-3325 info@sdmsgroup.com

CONVENCIÓN

27 de abril 2019

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología

787-723-6751 asis.spot@gmail.com

SIMPOSIO

26 al 27 de Simposio Internacional sobre Latinos y abril de 2019 Enfermedad de Alzheimer

San Juan, PR

Universidad de Puerto 787-250-1312 Rico (RCM) División de Educación mghcme.org/alzheimers Continua

3 al 5 de

Meliá Coco Beach Resort

Educational

Congress 2019 Neurology & Pregnancy-Academia Puertorriqueña de Neurología

Simposio Ortopédico de Medicina Deportiva-SPOT

2da Cumbre Asociaciones Psiquiátricas de

787-646-0780

Comentarios

SIMPOSIO

SIMPOSIO

6 al 7 de abril Convención Anual Academia de Patología de 2019 y Medicina de Laboratorio de PR

Sheraton Convention Center San Juan, PR

Serra & Serra Group

787-640-5776 patologospr@serrayserra.com

CONVENCIÓN

6 de abril de Convención anual Asociación de Psiquiatras de Bayamón 2019

Hotel la Concha San Juan, PR

AMEC

787-289-8989 amecpr@gmail.com

CONVENCIÓN

25 al 27 abril Convención Anual Academia de Médicos de Familia de PR de 2019

Sheraton Convention Center Hotel San Juan, PR

SDMS

787-731-3325 info@sdmsgroup.com

CONVENCIÓN

27 de abril 2019

El San Juan Hotel San Juan, PR

Sociedad 787-723-6751 Puertorriqueña de asis.spot@gmail.com Ortopedia y Coordinador o Contacto Traumatología

26 al 27 de Simposio Internacional sobre Latinos y abril de 2019 Enfermedad de Alzheimer

San Juan, PR

Universidad de Puerto 787-250-1312 Rico (RCM) División de Educación mghcme.org/alzheimers Continua

SIMPOSIO

3 al 5 de mayo de 2019

2da Cumbre Asociaciones Psiquiátricas de Puerto Rico

Meliá Coco Beach Resort Río Grande, PR

Educational partners

787-646-0780 vperez@epcpr.com

CONVENCIÓN

3 al 5 de mayo de 2019

14th Annual Meeting of Infectious Diseases- Sociedad de Enfermedades Infecciosas de Puerto Rico

Embassy Suites Dorado del Mar Dorado, PR

SEINPR

Enid Rivera 804-774-6326 enidrm27@gmail.com

CONVENCIÓN

4 al 5 de mayo de 2019

Convención Anual Sociedad Radiológica (SOCRAD)

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group

787-640-5776 info@socrad.com

CONVENCIÓN

17 al 19 de mayo de 2019

Convención Anual Asociación de Reumatólogos de PR

Wyndham Rio Mar Rio Grande, PR

Serra & Serra Group

787-640-5776 reumalogospr@serrayserra.com

CONVENCIÓN

24 al 27 de mayo de 2019

SPED Annual Convention

Meliá Coco Beach Resort Río Grande, PR

Educational partners

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CONVENCIÓN

21 al 23 de junio 2019

Convención anual Asociación Puertorriqueña de Medicina Física y Rehabiitación

Meliá Coco Beach Resort Río Grande, PR

Serra & Serra Group

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CONVENCIÓN

21 al 23 de junio de 2019

Convención anual Sociedad Puertorriqueña de Cardiología Intervencional

Lugar por confirmar

Sociedad Puertorriqueña de Cardiología Intervencional

Enid Rivera 804-774-6326 enidrm27@gmail.com

CONVENCIÓN

22 de junio de 2019

Simposio Ortopédico de Trauma- SPOT

El San Juan Hotel San Juan, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología

787-723-6751 asis.spot@gmail.com

SIMPOSIO

12 al 14 Julio de 2019

Convención Anual Sociedad Puertorriqueña de Cardiología

Sheraton Convention Center Hotel San Juan, PR

Sociedad Puertorriqueña de Cardiología

787-620-2228 socprcardio@gmail.com

CONVENCIÓN

1 al 4 de agosto de 2019

Convención Caribe Gyn 2019

Ponce Hilton Hotel Ponce , PR

Caribe Gyn

Germaine Quiñones 787-608-1477 caribegyn2015@gmail.com

CONVENCIÓN

16 al 18 de agosto de 2019

8th Respiratory Congress- Coalición de Asma y otras Condiciones Respiratorias Crónicas de PR

Sheraton Convention Center Hotel San Juan, PR

IC Planners

787-504-3655 ivettecolon@icplannerspr.com

CONGRESO

24 de agosto de 2019

Asociación de Gastroenterología y Hepatología Pediátrica de PR

Lugar por confirmar

IC PLANNERS

Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

SIMPOSIO

Wyndham Rio Mar Rio Grande, PR

Sociedad Puertorriqueña de Ortopedia y Traumatología (SPOT)

787-723-6751 asis.spot@gmail.com

CONVENCIÓN

Fecha

Simposio Ortopédico de Medicina Deportiva-SPOT

Título

30 de Agosto Convención Anual Sociedad al 2 de Puertorriqueña de Ortopedia y septiembre Traumatología (SPOT) de 2019

Lugar

SIMPOSIO

Comentarios

11 al 14 de octubre de 2019

Convención anual de la Sociedad de Médicos Graduados de la Escuela de Medicina RCM

San Juan Marriot Resort San Juan, PR

Sociedad de Médicos Graduados de la Escuela de Medicina RCM

787-758-2525 ext. 2038

CONVENCIÓN

26 de Octubre de 2019

Asociación de Médicos Alergistas de PR

Embassy Suites Hotel San Juan, PR

IC PLANNERS

Ivette Colón 787-504-3655 ivettecolon@icplannerspr.com

CONVENCIÓN

25 al 27 de octubre de 2019 8 al 10 de noviembre 2019

Convención anual- Puerto Rico HIV Treaters Association

Embassy Suites Dorado de Mar Dorado, PR

Educational Partners

(787) 646-0780 vperez@epcpr.com

CONVENCIÓN

Convención Anual Asociación Médica de Pediatras Región Este (AMPRE)

Lugar por confirmar

Business Planners

Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

22 al 24 de noviembre 2019

Convención Sociedad Puertorriqueña de Neumología

Wyndham Rio Mar Rio Grande, PR

Business Planners

Merna Morales 787-706-0442 bplanner21@gmail.com

CONVENCIÓN

12 al 15 de diciembre 2019

SPED AACE Congress

Caribe Hilton Hotel San Juan, PR

Educational partners

787-646-0780 vperez@epcpr.com

CONNGRESO

2019

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha

128

Título

Internacional

Lugar

Coordinador o Contacto

15 al 19 de enero de 2019 Caribeean Dermatology Symposium

Westin Grand Cayman, Cayman Islands

Jospeph Fowler

www.globalacademycme.com SIMPOSIO

8 al 10 de febrero de 2019

56 th Clinical Conference in Pediatric Anesthesiology

Disneyland Hotel Anaheim CA,USA

Pediatric Anesthesiology Foundation

www.pediatric-anesthesiology-foundation.com

CONFERENCIA

15 al 16 de febrero de 2019

Congreso en Oncología, Radioterapia e investigación INCART

Catalonia Hotel Santo Domingo, RD

Lacort Medical

www.lacortmedical.com

CONGRESO

22 al 25 de febrero de 2019

2018 American Academy of Alergy, Asthma & Inmunology

Moscone Convention Center South San Francisco CA, USA

American Academy of Alergy, Asthma & Inmunology

anualmeeting.aaaai.org

CONVENCIÓN

16 al 18 de marzo de 2019

American College of Cardiology 2019 Annual Meeting

New Orleans, USA

ACC

(847)-996-5822 acc@experient-inc.com

CONVENCIÓN

16 al 19 de marzo de 2019

2019 Society of Gynecologic Oncology Anual Meeting

Hawaii Convention Center Honolulu, Hawai

Society of Gynecologic Oncology

www.sgo.org

CONVENCIÓN

23 al 26 de marzo de 2019

ENDO 2019-Endocrine Society Annual Meeting

New Orleans, USA

Endocrine Society

www.endocrine.org

CONVENCIÓN

23 al 28 de marzo de 2019

Society of Interventional Radiology 2019 Meeting

Austin Convention Center Austin, Texas USA

Society of Interventional Radiology

www.sirmeeting.org

CONVENCIÓN

20 al 22 de marzo de 2019

Congreso internacional de cáncer en la mujer

San José, Costa Rica

Colegio Médicos Cirujanos de Costa Rica

22102200/22102202

CONGRESO

3 al 6 de abril de 2019

17th World Congress of Endoscopy Surgery

Baltimore Convention Center Baltimore, MD USA

Sages Education & Research Foundation

www.sages2019.org

CONGRESO

6 al 9 de abril de 2019

27th European Congress of Psychiatry-EPA 2019

Varsovia, Polonia

European Phsychiatry epa-congress.org Association

CONGRESO

11 al 13 de abril de 2019

American College of Physicians- Internal Medicine Annual Meeting 2019

Pennsylvania Convention Center Philadelphia, PA USA

American College of Physicians (ACP)

anualmeeting.acponline.org

CONVENCIÓN

11 al 13 de abril de 2019

Annual Regional Anesthesiology and Acute Pain Medicine Meeting 2019

Caesar’s Palace Las Vegas, Nevada USA

American Society of Regional Anesthesia and Pain Medicine (ASRA)

www.asra.com

CONVENCIÓN

12 al 13 de XIX Simposio Internacional de Alergia y abril de 2019 Neumología

Hotel Almirante Cartagena Colombia

Clínica Respiratoria y de Alergias

57-304-6511777

SIMPOSIO

28 th Annual Scientific & Clinical 24 al 28 de abril de 2019 Congress-American College of Endocrinology

Los Angeles Convention Center & JW Marriot Los Angeles, CA USA

American College of Endocrinology

www.aace.com

CONGRESO

25 al 26 de Congreso Internacional de Cirugía abril de 2019 Oculoplástica

Lima, Perú

Sociedad peruana de oftalmología

51-1-4402698

CONGRESO

27 al 30 de Pan -American Congress of Rheumatology abril de 2019 2019

Quito, Ecuador

PANTAR

www.congreso-pantar.com

CONGRESO

2 al 5 de mayo de 2019

Punta Cana, RD

Sociedad Dominicana de Obstetricia y www.sdog.org.do Ginecología

International Convention Center Hard Rock Hotel Punta Cana, RD

Sociedad Interamericana de Cardiología

XXIV Congreso Sociedad Dominicana de Obstetricia y Ginecología “Mujer-Famiia -Salud”

de Medicina y Salúd Pública 15 al 18Revista de Puertorriqueña Congreso Interamericano de Cardiología mayo de 2019 2019

Comentarios

CONGRESO

809-685-0331 siac2019@bcocongresos.com CONGRESO

20 al 22 de marzo de 2019

Congreso internacional de cáncer en la mujer

San José, Costa Rica

Colegio Médicos Cirujanos de Costa Rica

22102200/22102202

CONGRESO

3 al 6 de abril de 2019

17th World Congress of Endoscopy Surgery

Baltimore Convention Center Baltimore, MD USA

Sages Education & Research Foundation

www.sages2019.org

CONGRESO

Varsovia, Polonia

European Phsychiatry epa-congress.org Association

CONGRESO

2019 6 al 9 de

Agenda Médica

27th European Congress of Psychiawww.medicinaysaludpublica.com abril de try-EPA 2019 2019

11 al 13 de abril de 2019

American College of Physicians- Internal Medicine Annual Meeting 2019

Pennsylvania Convention Center Philadelphia, PA USA

American College of Physicians (ACP)

anualmeeting.acponline.org

CONVENCIÓN

11 al 13 de abril de 2019

Annual Regional Anesthesiology and Acute Pain Medicine Meeting 2019

Caesar’s Palace Las Vegas, Nevada USA

American Society of Regional Anesthesia and Pain Medicine (ASRA)

www.asra.com

CONVENCIÓN

12 al 13 de XIX Simposio Internacional de Alergia y abril de 2019 Neumología

Hotel Almirante Cartagena Colombia

Clínica Respiratoria y de Alergias

57-304-6511777

SIMPOSIO

28 th Annual Scientific & Clinical 24 al 28 de abril de 2019 Congress-American College of Endocrinology

Los Angeles Convention Center & JW Marriot Los Angeles, CA USA

American College of Endocrinology

www.aace.com

CONGRESO

25 al 26 de Congreso Fecha Título Internacional de Cirugía abril de 2019 Oculoplástica

Lugar Lima, Perú

Sociedad peruana o Contacto Coordinador 51-1-4402698 de oftalmología

27 al 30 de Pan -American Congress of Rheumatology abril de 2019 2019

Quito, Ecuador

PANTAR

2 al 5 de mayo de 2019

XXIV Congreso Sociedad Dominicana de Obstetricia y Ginecología “Mujer-Famiia -Salud”

Punta Cana, RD

Sociedad Dominicana de Obstetricia y www.sdog.org.do Ginecología

15 al 18 de mayo de 2019

Congreso Interamericano de Cardiología 2019

International Convention Center Hard Rock Hotel Punta Cana, RD

Sociedad Interamericana de Cardiología

809-685-0331 siac2019@bcocongresos.com CONGRESO

18 al 22 de mayo de 2019

2019 American Psychiatric Association Annual Meeting

San Francisco, CA USA

American Psychiatric Association

www.psychiatry.org

CONVENCIÓN

18 al 21 de junio de 2019

XVII Congreso de la Sociedad Cubana de Ginecología y Obstetricia

XVII Congreso de la Sociedad Cubana de Ginecología y Obstetricia

Sociedad Cubana de Ginecología y Obstetricia

www.ginecobstcuba.com

CONGRESO

20 al 28 de julio de 2019

2019 AMHE Medical Convention

Habana, Cuba

AMHE-Marie Bruno

(202)-681-3506 www.amhe.org

CONVENCIÓN

1 al 3 de agosto de 2019

Congreso Sociedad Latinoamericana de Cardiología Intervencionista (SOLACI)

Frei Caneca Convention Center Sao Paulo, Brazil

SOLACI

www.solacicongress.org

CONGRESO

7 al 10 de agosto de 2019

15 Encuentro Latinoamericano de Cirujanos de Cadera y Rodilla ELCCR

Cento de convenciones Las Americas Cartagena Colombia

ELCCR

direccion@elccr.org

CONGRESO

19 al 21 de septiembre de 2019

6to Simposio Internacional de Pie y Tobillo

Cartagena Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología

secretaria@sccot.org.com

SIMPOSIO

25 al 30 de octubre de 2019

American College of Gastroenterology 2019 Annual meeting

San Antonio, TX USA

American College of Gastroenterology

https://gi.org

CONVENCIÓN

8 al 3 de noviembre de 2019

American College of Rheumatology 2019 Annual Meeting

Atlanta, GA USA

American College of Rheumatology

www.rheumatology.org

CONVENCIÓN

24 al 26 de noviembre de 2019

Congreso Internacional de Medicina Deportiva

Cartagena Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología

secretaria@sccot.org.com

CONGRESO

21 de noviembre de 2019

1er Curso Nacional de Ortopedia para Médicos Generales

Bucaramanga Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología

secretaria@sccot.org.com

curso

22 al 24 de noviembre de 2019

14 Encuentro Nacional de Residentes de Ortopedia y Traumatología

Bucaramanga Colombia

Sociedad Colombiana de Cirugía Ortopédica y Traumatología

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Revista Puertorriqueña de Medicina y Salúd Pública

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Southern Pathology

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acreditado por el CAP como el mejor laboratorio en Puerto Rico

ras 30 años como líderes en la industria de laboratorios patológicos, Southern Pathology, logró obtener la acreditación del Colegio Americano de Patólogos (CAP, por sus siglas en inglés), convirtiéndose en el primer y único laboratorio del sector privado en Puerto Rico en alcanzar esta certificación.

Tomó alrededor de cuatro años de arduo trabajo para cumplir con las exigencias rigurosas del CAP. Por esa razón, para el patólogo Dr. Adalberto Mendoza, fundador de Southern Pathology, esto representa un log ro extraord inar io.L a acreditación obtenida los posiciona en el país como los únicos en cumplir con los estándares de calidad más elevados que requiere un laboratorio de patología anatómica y molecular para su funcionamiento.

"El CAP es la organización más grande a nivel mundial que agrupa patólogos certificados por el “board” de la especialidad y cuentan con miles de ellos dentro y fuera de Estados Unidos. Esta organización vela por la salud de la ciudadanía en pruebas de laboratorios y enfatiza la calidad en los servicios. Para obtener la

acreditación tienen que mirar las cualificaciones del personal, ya que deben cumplir con los requisitos y el examen de la especialidad siendo uno de los más importantes el director de laboratorios. Mientras velan por el aspecto de seguridad, entre otros aspectos, se somete el laboratorio a inspección y a la visita del programa de proeficiencia. Es decir, el sistema de calidad externa en el que el laboratorio debe recibir una evaluación sobresaliente. Si se aprueba todo lo anterior, se equivale a tener un laboratorio de la más alta calidad que existe en el mundo occidental. Con esta acreditación estamos al nivel más alto de los Estados Unidos", promovió Mendoza, quien fue el primer presidente del Colegio de Médicos de Puerto Rico.

Ante esto, el servicio de Southern Pathology -que se ubica en el pueblo de Ponce y en la Avenida Américo Miranda en San Juan- garantiza a los pacientes, hospitales, centros de salud y médicos en oficinas privadas la más alta calidad en el sistema de salud y disminuye dramáticamente los errores. También a nivel laboral, les abre una brecha de competencia

profesional a cada uno de los empleados.

"No existe un laboratorio de patología privado con esta acreditación hasta ahora. En el proceso se necesitaron cuatro años de preparación en los que se montó un equipo de trabajo y se buscó una persona experta en cumplimiento que lideró el proyecto pero todos los integrantes participaron y nos permitieron obtener notas sobresalientes. Sin duda, esto elevará la calidad de los laboratorios en Puerto Rico, y estimulará a que otros laboratorios se interesen en esta acreditación", enfatizó Mendoza, quien labora junto a otros seis patólogos especializados.

En detalle, Southern Pathology tuvo que modificar las políticas y procedimientos ya establecidos y otros elementos que cada departamento exige según la reglamentación del CAP. María Plaza, directora de cumplimiento, quien lideró el proyecto, dijo sentirse contenta al ver realizada la acreditación que dura cuatro años, y asegura que buscarán continuar revalidando la misma.

"Salimos con un 99.3% de

cumplimiento y menos de 0.71% (en deficiencia) en los hallazgos, cuando estamos hablando de sobre mil estándares, que tienes que cumplir.

Ese porcentaje fue bien positivo y es un reflejo del trabajo que hacemos todos. También, tuvimos áreas con cero deficiencias como el laboratorio molecular y citología que lograron un 100%. La acreditación es por dos años y, estamos muy contentos porque fue un trabajo en conjunto", destacó Plaza.

Para mantenerse acreditados, de ahora en adelante, los inspectores visitarán sorpresivamente las instalaciones para corroborar que en efecto mantienen el nivel de

al personal, evaluaron todos los manuales y estaban impresionados.

Es un orgullo para nosotros, ya que fue un reto para la organización y para el personal porque el trabajo no para y está en un proceso de crecimiento continuo”. La presidenta añadió que “No es un proceso de solo manejar la acreditación sino al mismo tiempo recibir empleados nuevos -porque estamos abriendo plazas-, adiestrarlos, traer instrumentos nuevos, implantar metodología, entre otros. Este proceso como tal es uno adicional a los que se está trabajando como laboratorio. Pero nosotros siempre nos hemos guiado por el Colegio de

"La acreditación requiere que un patólogo tenga ciertas cualificaciones para demostrar competencia de ese profesional y experiencia. Mi labor en el proceso es cumplir con los requisitos académicos del CAP y que ese director se haya involucrado suficiente con el proceso de los laboratorios para asegurarse de que los asuntos que están bajo su responsabilidad no han sido delegados como la seguridad ocupacional o asegurarse que el laboratorio tenga la cantidad necesaria de personas para atender las pruebas que recibimos diariamente. Con esto se busca que los resultados salgan en el menor tiempo posible. Las pruebas, en más

Sra. Melanie Mendoza, presidenta de Southern Pathology

Dr. Adalberto Mendoza, Patólogo y Fundador de Southern Pathology

Lcda. María Plaza, Directora de Cumplimiento de Southern Pathology

calidad. Southern Pathology además mantiene los estándares que exige el Departamento de Salud y otras organizaciones de la industria, por lo que, en cierto modo, no fue difícil lograr sumarse a los 8 mil laboratorios acreditados por CAP que hay en Estados Unidos y 437 a nivel internacional.

Por su parte, Melanie Mendoza, actual presidenta del laboratorio e hija de su fundador, destacó que "fue muy gratificante escucharlos (los miembros del comité examinador del CAP) expresarse de la manera en que hablaron sobre nuestras políticas y procedimientos. Ellos tuvieron la oportunidad de entrevistar

Patólogos Americanos, o sea, que teníamos una buena base".

Sin embargo, se presentan, quizás, más retos ya que las guías del colegio cambian anualmente, pero esto no representaría algo negativo, todo lo contrario "así podemos mantener un laboratorio de calidad", agregó.

de un 85% de los casos, las hacemos en dos días laborables", aseguró Miller, también exdirectora del Instituto de Ciencias Forenses.

Southern Pathology realiza un sinnúmero de pruebas, entre ellas biopsias, efusiones, e inmunohistoquímicas. Dentro del conjunto de los varios hospitales que trabajan con el laboratorio se encuentran el Hospital San Lucas, Hospital Pila, Mayagüez Medical Center y Metropolitano de San Germán. Además, este laboratorio es el único a nivel mundial que cuenta con la acreditación del Medical Tourism Association obtenida en el año 2016.

Nivel de calidad recae en director de laboratorio El director de laboratorio juega una posición fundamental para hacer que el laboratorio funcione en los niveles óptimos de calidad. En este caso, la doctora María Conte Miller tiene a su cargo el velar las mejores condiciones de prácticas de patología.

FOR THE TREATMENT OF SCHIZOPHRENIA IN ADULTS

Tanara

INVEGA TRINZA® patient

Tanara is a real patient living with schizophrenia.

Individual experience may vary.

Help Patients Progress Through Their Treatment Journey To the Longest Dosing Interval Available 2

Learn more at invegatrinzahcp.com INDICATIONS INVEGA TRINZA® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate) for at least four months.

INVEGA SUSTENNA® (paliperidone palmitate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

See full Prescribing Information for complete Boxed Warning Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

INVEGA SUSTENNA® and INVEGA TRINZA® are not approved for use in patients with dementia-related psychosis.

References: 1. INVEGA SUSTENNA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2018. 2. INVEGA TRINZA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; July 2018.

Please refer to Brief Summary of Safety and Prescribing Information on adjacent pages.

IMPORTANT SAFETY INFORMATION (cont’d) Contraindications: INVEGA TRINZA® and INVEGA SUSTENNA® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementiarelated psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA®, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval.

Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

T:11.5”

B:11.75”

S:10.3667”

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses.

Elderly female patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension and Syncope: INVEGA TRINZA® and INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA TRINZA® and INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA TRINZA® and INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/ neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA TRINZA® and INVEGA SUSTENNA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® and INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/ mm3) and follow their WBC until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA TRINZA® and INVEGA SUSTENNA® elevate prolactin levels, and the elevation persists during chronic administration.

Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® and INVEGA SUSTENNA®. INVEGA TRINZA® and INVEGA SUSTENNA® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA TRINZA® and INVEGA SUSTENNA® do not adversely affect them.

Seizures: INVEGA TRINZA® and INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA TRINZA® or INVEGA SUSTENNA® kits. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA TRINZA® or INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

Pregnancy/Nursing: INVEGA TRINZA® and INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA® or INVEGA SUSTENNA®.

Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA TRINZA® or INVEGA SUSTENNA® during pregnancy. INVEGA TRINZA® and INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® or INVEGA SUSTENNA® and any potential adverse effect on the breastfed infant from INVEGA TRINZA® or INVEGA SUSTENNA® or the mother’s underlying condition.

Commonly Observed Adverse Reactions for INVEGA TRINZA®: The most common adverse reactions (incidence ≥5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism.

Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. cp-64206v1 Please see Brief Summary of Prescribing information on following pages. Before prescribing INVEGA TRINZA® please refer to the full Prescribing Information including Boxed WARNING. Please see full Prescribing Information, including Boxed WARNING for INVEGA SUSTENNA®, available at InvegaSustennahcp.com.

© Janssen Pharmaceuticals, Inc. 2018. 09/18 cp-52087v2

INVEGA TRINZA®

(paliperidone palmitate) extended-release injectable suspension, for intramuscular use Brief Summary BEFORE PRESCRIBING INVEGA TRINZA®, PLEASE SEE FULL PRESCRIBING INFORMATION, INCLUDING BOXED WARNING. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA® is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions].

INDICATIONS AND USAGE INVEGA TRINZA® (paliperidone palmitate), a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® (1-month paliperidone palmitate extendedrelease injectable suspension) for at least four months [see Dosage and Administration (2.2) and Clinical Studies (14) in Full Prescribing Information].

CONTRAINDICATIONS INVEGA TRINZA® is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drugtreated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA TRINZA® is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions].

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, or INVEGA TRINZA® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions].

Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. Consideration should be given to the long-acting

INVEGA TRINZA® (paliperidone palmitate) nature of INVEGA TRINZA®. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

QT Prolongation Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a doubleblind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixeddose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product.

In the Thorough QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (Cmax ss=113 ng/mL) was approximately 2-fold the exposure with the maximum recommended 819 mg dose of INVEGA TRINZA® administered in the deltoid muscle (predicted median Cmax ss=56 ng/mL). In this same study, a 4 mg dose of the immediaterelease oral formulation of paliperidone, for which Cmax ss=35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.

In the four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett’s QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

In the long-term maintenance trial of INVEGA TRINZA® in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA® in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.

Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, INVEGA TRINZA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs.

In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA TRINZA®, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA®. However, some patients may require treatment with INVEGA TRINZA® despite the presence of the syndrome.

Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA TRINZA®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Data from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 1.

Table 2. Change in Fasting Lipids from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia

Table 1. Change in Fasting Glucose from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia

Serum Glucose Change from baseline

Serum Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) a

Double-Blind Phase Open-Label (relative to Phase double-blind baseline) (relative to open-label baseline) Paliperidone Placebo INVEGA TRINZA® Palmitatea Mean change from baseline (mg/dL) n=397 n=120 n=138 1.2 -1.6 -1.2 Proportion of Patients with Shifts n=397 n=128 n=148 2.3% 2.3% 4.1% (9/397)

(3/128)

(6/148)

During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information].

Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Data from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 2.

Cholesterol Change from baseline LDL Change from baseline HDL Change from baseline Triglycerides Change from baseline

Double-Blind Phase Open-Label (relative to Phase double-blind baseline) (relative to open-label baseline) Paliperidone Placebo INVEGA TRINZA® Palmitatea Mean change from baseline (mg/dL) n=400 n=120 n=138 0.5 -0.4 0.9 n=396 n=119 n=138 1.1 -0.4 1.1 n=397 n=119 n=138 -0.2 -0.5 -1.3 n=400 n=120 n=138 0.1 -2.0 5.1 Proportion of Patients with Shifts 2.0% 3.9% 1.4%

Cholesterol Normal to High (<200 mg/dL to (8/400) (5/128) (2/148) ≥240 mg/dL) LDL Normal to High 0.3% 0.8% 0% (<100 mg/dL to (1/396) (1/127) (0/148) ≥160 mg/dL) HDL Normal to Low 8.6% 9.4% 13.5% (34/397) (12/127) (20/148) (≥40 mg/dL to <40 mg/dL) Triglycerides Normal 4.5% 1.6% 8.1% to High (<150 mg/dL to (18/400) (2/128) (12/148) ≥200 mg/dL) a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information].

Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the long-term maintenance trial with INVEGA TRINZA® in subjects with schizophrenia are presented in Table 3.

Table 3. Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from the Long-Term Maintenance Trial with INVEGA TRINZA® in Subjects with Schizophrenia Open-Label Phase (relative to open-label baseline) Paliperidone Palmitatea n=466 1.42

Double-Blind Phase (relative to double-blind baseline) Placebo

INVEGA TRINZA®

n=142 n=157 -1.28 0.94 Weight (kg) Change from baseline 15.2% 0.7% 9.6% Weight Gain ≥ 7% increase from baseline a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information].

Orthostatic Hypotension and Syncope Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope was reported in < 1% (1/506) of subjects treated

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

with the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. In the long-term maintenance trial, orthostatic hypotension was reported as an adverse event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of INVEGA TRINZA® during the open-label phase; there were no cases reported during the double-blind phase in either treatment group.

INVEGA TRINZA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA TRINZA®. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of druginduced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA TRINZA® at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue INVEGA TRINZA® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

Hyperprolactinemia Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration.

Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

In a long-term maintenance trial of INVEGA TRINZA®, elevations of prolactin to above the reference range (>13.13 ng/mL in males and >26.72 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of males in the INVEGA TRINZA® group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the INVEGA TRINZA® group than in the placebo group (32% vs.

15%). During the double-blind phase, 1 female (2.4%) in the INVEGA TRINZA® group experienced an adverse reaction of amenorrhea, while no potentially prolactin-related adverse reactions were noted among females in the placebo group. There were no potentially prolactin-related adverse reactions among males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368) were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks after a single injection of INVEGA TRINZA® at the end of the open-label phase, mean (SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL in females (N=107).

During the open-label phases 27% of females and 42% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse reactions in females. Among males in the open-label phase, no potentially prolactin-related adverse reaction was observed with a rate greater than 3%.

Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA® [see Adverse Reactions].

Antipsychotics, including INVEGA TRINZA®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

Seizures In the long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month paliperidone palmitate extended-release injectable suspension which included four fixeddose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the 1-month injection experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.

Like other antipsychotic drugs, INVEGA TRINZA® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA TRINZA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Priapism Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA TRINZA®, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption of Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA TRINZA® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions] • Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions] • Neuroleptic malignant syndrome [see Warnings and Precautions] • QT prolongation [see Warnings and Precautions] • Tardive dyskinesia [see Warnings and Precautions] • Metabolic changes [see Warnings and Precautions] • Orthostatic hypotension and syncope [see Warnings and Precautions] • Falls [see Warnings and Precautions] • Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions] • Hyperprolactinemia [see Warnings and Precautions] • Potential for cognitive and motor impairment [see Warnings and Precautions] • Seizures [see Warnings and Precautions] • Dysphagia [see Warnings and Precautions] • Priapism [see Warnings and Precautions] • Disruption of body temperature regulation [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

Patient Exposure The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extendedrelease injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA® during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA® and 145 subjects received placebo during the double-blind placebo-controlled phase. The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA® group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA® concomitantly with other oral antipsychotics.

Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA® group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.

Discontinuation of Treatment Due to Adverse Events: The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the doubleblind phase, no INVEGA TRINZA®-treated subject and one placebo-treated subject discontinued due to adverse events.

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA®-Treated Patients: The safety profile of INVEGA TRINZA® was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 4 lists the adverse reactions reported in a longterm maintenance trial in subjects with schizophrenia.

Demographic Differences An examination of population subgroups in the long-term maintenance trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.

Extrapyramidal Symptoms (EPS) Data from the long-term maintenance trial provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 5), and (5) incidence of spontaneous reports of EPS (Table 6).

Table 4. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA®-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia --- Open Label--- ------- Double Blind -------Placebo INVEGA TRINZA® Paliperidone Palmitatea System Organ Class (N=506) (N=145) (N=160) Adverse Reactionb %c %c %c General disorders and administration site conditions Injection site reaction 12 0 3 Infections and infestations Upper respiratory tract 5 4 10 infection Urinary tract infection <1 1 3 Metabolism and nutrition disorders Weight increased 10 3 9 Nervous system disorders Akathisia 5 2 5 Headache 7 4 9 Parkinsonism 5 0 4 Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA® group during the double-blind phase and which occurred at greater incidence than in the placebo group. a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® prior to randomization to either placebo or INVEGA TRINZA® in the subsequent double-blind phase [see Clinical Studies (14) in Full Prescribing Information]. b The following terms were combined: Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling.

Weight increased includes Weight increased, Waist circumference increased.

Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis.

Akathisia includes Akathisia, Restlessness.

Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion. c Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.

Table 5. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication Percentage of Subjects Open-label Double-blind Phase Phase Paliperidone Placebo INVEGA TRINZA® Palmitatea (N=506) (N=145) (N=160) Scale % % % 6 3 6 Parkinsonismb Akathisiac 3 1 4 Dyskinesiad 1 3 3 11 9 11 Use of Anticholinergic Medicationse a

During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information]. b For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at any time (Global score defined as total sum of items score divided by the number of items) c For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at any time d For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at any time e Percent of subjects who received anticholinergic medications to treat EPS Table 6. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Percentage of Subjects Open-label Double-blind Phase Phase Paliperidone Placebo INVEGA TRINZA® Palmitatea (N=506) (N=145) (N=160) EPS Group % % % 10 3 8 Overall percentage of subjects with EPS-related adverse events Parkinsonism 4 0 4 Hyperkinesia 5 2 5 Tremor 2 0 1 Dyskinesia <1 1 1 Dystonia 1 0 1 a During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA® [see Clinical Studies (14) in Full Prescribing Information].

Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism Hyperkinesia group includes: Akathisia, restlessness Dystonia group includes: Blepharospasm, dystonia, muscle spasms After injection of INVEGA TRINZA® in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common. After injection of INVEGA TRINZA® in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness.

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to INVEGA TRINZA®.

Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Pain Assessment and Local Injection Site Reactions Investigator ratings of injection site. Redness and swelling were observed in 2% or less of subjects in the INVEGA TRINZA® and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe). There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to INVEGA TRINZA® injection.

Subject ratings of injection site pain. Subject evaluations of injection pain during the double-blind phase also were similar for placebo and INVEGA TRINZA®.

Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain. Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA TRINZA® The following additional adverse reactions were identified in the long-term maintenance trial. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) occurred at an incidence lower than that of placebo-treated patients.

Cardiac disorders: tachycardia Gastrointestinal disorders: nausea, vomiting Metabolism and nutrition disorders: hyperinsulinemia Psychiatric disorders: anxiety Additional Adverse Reactions Reported in Clinical Trials with the 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month paliperidone palmitate extended-release injectable suspension: Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Ear and labyrinth disorders: vertigo Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache General disorders and administration site conditions: asthenia, fatigue Immune system disorders: hypersensitivity Investigations: electrocardiogram abnormal Metabolism and nutrition disorders: decreased appetite, increased appetite Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope Psychiatric disorders: agitation, nightmare Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction Respiratory, thoracic and mediastinal disorders: cough Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria Vascular disorders: hypertension

Cardiac disorders: bundle branch block left, sinus arrhythmia Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions: edema, edema peripheral Immune system disorders: anaphylactic reaction Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, torticollis, trismus Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders: hypotension, ischemia Postmarketing Experience The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions sections of the package inserts for those products.

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

DRUG INTERACTIONS Drugs Having Clinically Important Interactions with INVEGA TRINZA® Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) in Full Prescribing Information], results from studies with oral paliperidone should be taken into consideration when assessing drugdrug interaction potential. In addition, consider the 3-month dosing interval and long half-life of INVEGA TRINZA® [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Table 7. Clinically Important Drug Interactions with INVEGA TRINZA® Concomitant Drug Name or Drug Class Drugs with Potential for Inducing Orthostatic Hypotension

Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John’s Wort)

Levodopa and Other Dopamine Agonists

Clinical Rationale

Clinical Recommendation

Because INVEGA TRINZA® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA TRINZA® is administered with other therapeutic agents that have this potential [see Warnings and Precautions].

The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions].

Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Avoid using CYP3A4 and/or P-gp inducers with INVEGA TRINZA® during the 3-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.7) in Full Prescribing Information].

Monitor and manage patient as clinically appropriate.

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

Drugs Having No Clinically Important Interactions with INVEGA TRINZA® Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA TRINZA® is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA TRINZA® [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pharmacokinetic interaction between lithium and INVEGA TRINZA® is unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes.

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone.

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data No developmental toxicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension.

There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extendedrelease injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-release injectable suspension based on mg/m2 body surface area.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m2 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone.

Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/ m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL® package insert).

Lactation Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone (see Clinical Considerations).

Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA®, and the clinical significance on the breastfed infant is not known [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA® and any potential adverse effects on the breastfed child from INVEGA TRINZA® or from the mother’s underlying condition.

Clinical Considerations Infants exposed to INVEGA TRINZA® through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with INVEGA TRINZA® may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA TRINZA®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/.

Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA TRINZA® during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA® [see Clinical Pharmacology (12.3) in Full Prescribing Information], and the clinical significance of INVEGA TRINZA® administered before pregnancy or anytime during pregnancy is not known.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA TRINZA®, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective

Pediatric Use Safety and effectiveness of INVEGA TRINZA® in patients less than 18 years of age have not been established. Use of INVEGA TRINZA® is not recommended in pediatric patients because of the potential longer duration of an adverse event compared to shorter-acting products. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.

INVEGA TRINZA® (paliperidone palmitate)

INVEGA TRINZA® (paliperidone palmitate)

Juvenile Animal Studies No juvenile animal studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension.

In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

The long-term effects of INVEGA TRINZA® on growth and sexual maturation have not been fully evaluated in children and adolescents.

symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

Management of Overdosage Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA TRINZA® overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.

Consider the prolonged-release characteristics of INVEGA TRINZA® and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

Geriatric Use Clinical studies of INVEGA TRINZA® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, monitor renal function and adjust dosage [see Dosage and Administration (2.5) in Full Prescribing Information].

Renal Impairment Use of INVEGA TRINZA® is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Use of INVEGA TRINZA® in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) is based on the previous dose of the 1-month paliperidone palmitate extended-release injectable suspension that the patient was stabilized on prior to initiation of INVEGA TRINZA® [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Hepatic Impairment INVEGA TRINZA® has not been studied in patients with hepatic impairment.

Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Patients with Parkinson’s Disease or Lewy Body Dementia Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA TRINZA®. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

DRUG ABUSE AND DEPENDENCE Controlled Substance INVEGA TRINZA® (paliperidone) is not a controlled substance.

Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

OVERDOSAGE Human Experience No cases of overdose were reported in premarketing studies with paliperidone palmitate injection. Because INVEGA TRINZA® is to be administered by health care professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and

INVEGA TRINZA® (paliperidone palmitate) Extended-Release Injectable Suspension Product of Ireland Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 © 2015 Janssen Pharmaceutical Companies cp-64092v1

www.medicinaysaludpublica.com Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Periodistas: Mayra Acevedo, Susana María Rico, Jean Vélez, César Fuquen, LauraMojica, Rosmery Cernadas

Enfoque integral para la población: reto del Ministerio de Salud de República Dominicana

Dr. Rafael Sánchez Cárdenas, ministro de Salud de República Dominicana la presidencia de COMISCA Revista Puertorriqueña de Medicina y Salúd Pública

145

Revista

El ministro de Salud de Belice, Ing. Pablo Saúl Marín recibe de manos del Dr. Rafael Sánchez Cárdenas, ministro de Salud de República Dominicana la presidencia de COMISCA en la reunión del Consejo de Ministros de Salud de Centroamérica y República Dominicana

E

l doctor Rafael Sánchez Cárdenas, el nuevo Ministro de Salud Pública y Asistencia Social de República Dominicana, inicia su función con el propósito de implementar proyectos de salud que trabajen en la promoción de salud desde un punto de vista holístico.

El Ministro llega en la fase concluyente del plan decenal anterior, por ello también inicia con el nuevo plan que se establecerá partiendo de los principales temas de políticas públicas.

Entre ellos, uno de los temas que más preocupa al Ministro son los altos índices que se registran por la mortalidad maternoinfantil, comparado con la región latinoamericana.

Con el fin de atender los temas de prioridad el doctor Sánchez, mencionó en entrevista con Medicina y Salud Pública (MSP) que, se esforzará por trabajar en “la reorganización del ministerio, para realizar un monitoreo frente al servicio y labor que se realiza desde el servicio nacional de salud y las clínicas privadas a través de la creación mecanismos de evaluación”.

También habló de la promoción y prevención de enfermedades a través de la educación, lo cual, como lo afirma el Ministro, ayuda a la reducción de la presencia de enfermedades como el Zika, dengue y chikungunya. En este punto también mencionó que “las poblaciones más afectadas son las que presentan un nivel de pobreza mayor debido a la inequidad que existe en el modelo”.

Sin embargo, afirmó que durante el mandato del presidente Medina se han implementado programas para estas poblaciones con bajos 146

Revista Puertorriqueña de Medicina y Salúd Pública

recursos. Iniciando con la población infantil, a la cual se le están cubriendo las necesidades básicas de alimentación, solucionando problemáticas como el bajo rendimiento escolar y el hambre en los niños. De este modo, pretenden educar ciudadanos con mejores condiciones para hacer la prevención y recibir las campañas de salud con un nivel de conciencia más elevada.

Fortalezas en el sistema de salud Durante la entrevista con MSP el doctor Sánchez, destaca el enfoque que se le está dando al sistema de salud, ya que este no solo implica la curación del cuerpo físico, “es un campo psicosocial que no dependen únicamente de la biología, hay elementos psicológicos que inciden en daños mentales y físicos que condicionan la salud” afirmó.

Hablando sobre la necesidad de un sistema de salud integral, dijo que “nunca en la historia nacional el nivel de inversión pública había sido tan grande”. Haciendo referencia a la inversión en recursos humanos, prevención, modificación de las infraestructuras y en la comunicación y promoción de la salud.

Asimismo, mencionó el nuevo plan que se está llevando a cabo para permitir que las personas con bajos recursos económicos puedan acceder a los tratamientos que necesitan, ya que a través de la compra conjunta de medicamentos con países de la región se espera que los costos de los mismos bajen significativamente con el fin de hacerlos asequibles.

Revista

Humanismo y profundidad intelectual El doctor Rafael Sánchez busca en la sabiduría del hombre más allá de la medicina demostrando amplios conocimientos sobre la filosofía, las artes, la literatura y la cultura hispanoamericana.

Dr. Rafael Sánchez Cárdenas, ministro de Salud de República Dominicana la presidencia de COMISCA

¿Qué lee doctor, qué acostumbra leer?

Filosofía. ¿Qué está leyendo actualmente?

Estoy leyendo un libro de un amigo y compañero que escribió sobre el sistema ético moral, principios, valores e indicadores. Yo creo que es una clasificación, una taxonomía que no existe en la filosofía. Habían elementos muy sueltos, pero este señor, en un pequeño libro que escribió y que ya se tradujo al alemán, el estudió en la Universidad de Konstanz en Alemania, me parece un aporte muy interesante. ¿Cuál es su autor preferido dominicano?

Juan Bosch ¿Y de las obras de Juan Bosch?

De Don Juan muchas, pero la Composición Social Dominicana para mí es un documento que fue muy revelador, porque puede constatar la conexión entre lo descrito en el libro y la realidad social que vivíamos. Quizás, eso me motivó a intervenir en la política y a meterme en todo eso. ¿Que tipo de género literario prefiere y tiene en su biblioteca?

La poesía me gusta siempre. Yo tuve etapas en ese sentido. Yo tuve una etapa de poesía, de Neruda, Machado, Hernández, Becker, o sea, tuve todas las etapas.

Buesa también, en mi colegio la biblioteca fue donada por el Padre Justo, franciscano ya anciano que fundó y dirigió el colegio. Entonces, en esa donación estaban todos los clásicos españoles y entonces, yo en el recreo solía en un rinconcito que había, me iba a leer esos clásicos.

Ya en bachillerato, sí empiezo a leer otras cosas, un poco de filosofía. Fui seguidor de la teología en liberación y todo ese tipo de cosas, las fui leyendo y entonces tuve esa etapa religiosa de trabajo en las comunidades juveniles en la iglesia y trabajé bastante tiempo en ese sentido. ¿Usted fue militante, seguidor activo de la teología de la liberación?

Sí, un admirador. Un admirador “flybe to”, bueno y en aquellos años uno de los libros que más me gustó, no parte de teología, pero fue escrito por un cura, que es La Pedagogía del Oprimido, escrito por el brasileño Paulo Freire. ¿Ha leído el Retrato del Colonizado de Albert Memmi?

Lo he leído, lo he leído. ¿Usted me lo dice por boricua? Yo me he leído La Guaracha del Macho Camacho de Luis Rafael Sánchez.

De hecho, el tema de la enajenación en La guaracha del Macho Camacho es uno que se presenta de una manera muy compleja. ¿Y qué más ha leído de Puerto Rico? ¿Ha leído a Juan Antonio Corretjer?

Juan Antonio, Abelardo Díaz Alfaro y además el Jíbaro insigne también ha escrito muchas cosas bonitas. ¿El Jíbaro insigne se refiere a Don Rafael?

A Don Rafael, claro que sí. ¿Pero ya ese en el género musical?

El género sí, pero vaya a ver qué género. Se puede decir, que a la música puertorriqueña le he dado seguimiento. La bomba me encantaba.

Revista Puertorriqueña de Medicina y Salúd Pública

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NOW APPROVED�

For the first time in over a decade, a new oral treatment option for the management of moderate to severe pain associated with endometriosis.

• Available in 2 oral dosages (150 mg QD and 200 mg BID)1

Dysmenorrhea (150 mg or 200 mg)

Nonmenstrual Pelvic Pain (150 mg or 200 mg)

The first and only oral GnRH antagonist specifically developed for women with moderate to severe endometriosis pain1

Dyspareunia* (200 mg only)

*Statistical significance for dyspareunia was not achieved with the 150-mg dose of ORILISSA.1

INDICATION1

ORILISSA™ (elagolix) is indicated for the management of moderate to severe pain associated with endometriosis.

IMPORTANT SAFETY INFORMATION1

CONTRAINDICATIONS • ORILISSA is contraindicated in women who are pregnant (exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss), in women with known osteoporosis or severe hepatic impairment (due to risk of bone loss), or with concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).

WARNINGS AND PRECAUTIONS Bone Loss • ORILISSA causes a dose-dependent decrease in bone mineral density (BMD), which is greater with increasing duration of use and may not be completely reversible after stopping treatment.

• The impact of ORILISSA-associated decreases in BMD on longterm bone health and future fracture risk is unknown. Consider assessment of BMD in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis.

• Limit the duration of use to reduce the extent of bone loss.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy • Women who take ORILISSA may experience a reduction in the amount, intensity, or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders • Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials.

• ORILISSA users had a higher incidence of depression and mood changes compared to placebo and ORILISSA users with a history of suicidality or depression had an increased incidence of depression.

Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate.

©2018 AbbVie Inc. North Chicago, IL 60064

400-1939046

• Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORILISSA if such events occur.

Hepatic Transaminase Elevations • In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3 times the upper limit of the reference range occurred with ORILISSA. • Use the lowest effective dose and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice.

• Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.

Reduced Efficacy with Estrogen-Containing Contraceptives • Based on the mechanism of action of ORILISSA, estrogencontaining contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown.

• Advise women to use non-hormonal contraceptives during treatment and for one week after discontinuing ORILISSA. ADVERSE REACTIONS • The most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions, and mood changes.

These are not all the possible side effects of ORILISSA. Safety and effectiveness of ORILISSA in patients less than 18 years of age have not been established.

REFERENCE: 1. Orilissa [package insert]. North Chicago, IL: AbbVie Inc; 2018.

Please see Brief Summary of full Prescribing Information on the following pages of this advertisement.

Learn more about this new treatment option at ORILISSA.com/hcp

Printed in the U.S.A.

July 2018

DO NOT RE-SIZE 400-1939046

ORILISSA™ (elagolix) tablets, for oral use

Dosing Regimen

Maximum Treatment Coexisting Duration Condition

Initiate treatment with 24 months ORILISSA 150 mg once daily

None

Consider initiating treatment 6 months with ORILISSA 200 mg twice daily

Dyspareunia

Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended.

Moderate hepatic impairment (ChildPugh Class B)

6 months

Hepatic Impairment No dosage adjustment of ORILISSA is required in women with mild hepatic impairment (Child-Pugh A).

Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss: • ORILISSA 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of ORILISSA 200 mg twice daily is not recommended for women with moderate hepatic impairment [see Use in Specific Populations].

• ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications and Use in Specific Populations].

Missed Dose Instruct the patient to take a missed dose of ORILISSA on the same day as soon as she remembers and then resume the regular dosing schedule.

• 150 mg once daily: take no more than 1 tablet each day.

• 200 mg twice daily: take no more than 2 tablets each day.

CONTRAINDICATIONS ORILISSA is contraindicated in women: • Who are pregnant [see Use in Specific Populations]. Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss.

• With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions] • With severe hepatic impairment because of the risk of bone loss [see Use in Specific Populations] • With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil) [see Drug Interactions] WARNINGS AND PRECAUTIONS Bone Loss ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions].

The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Women who take ORILISSA may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner [see Adverse Reactions]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials. ORILISSA subjects had a higher incidence of depression and mood changes compared to placebo, and ORILISSA subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history [see Adverse Reactions]. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions]. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORILISSA if such events occur.

Hepatic Transaminase Elevations In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with ORILISSA. Use the lowest effective dose of ORILISSA and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks [see Adverse Reactions].

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 1

Table 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent Adverse Reactions Occurring in at Least 5% of Subjects (either ORILISSA Dose Group) and at a Greater Incidence than with Placebo

Hot Flush or Night Sweats Headache Nausea Insomnia Mood altered, mood swings Amenorrhea Depressed mood, depression, depressive symptoms and/or tearfulness Anxiety Arthralgia

ORILISSA 150 mg Once Daily N=475 % 24 17 11 6 6 4

ORILISSA 200 mg Placebo Twice Daily N=734 N=477 % % 46 9 20 12 16 13 9 3 5 3 7 <1

3

6

2

3 3

5 5

3 3

Less Common Adverse Reactions: In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either ORILISSA dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.

The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.

Bone Loss The effect of ORILISSA on BMD was assessed by dual-energy X-ray absorptiometry (DXA).

In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in ORILISSA-treated subjects compared to an increase in placebo-treated subjects.

In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with ORILISSA 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with ORILISSA 150 mg once daily, 7% with ORILISSA 200 mg twice daily and < 1% with

placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.

In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with ORILISSA 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with ORILISSA 150 mg once daily, 6% with ORILISSA 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.

Table 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6 ORILISSA ORILISSA 150 mg 200 mg Once Daily Twice Daily Placebo EM-1 N

183

180

277

Percent Change from Baseline, %

-0.3

-2.6

0.5

Treatment Difference, % (95% CI)

-0.9 (-1.3, -0.4)

-3.1 (-3.6, -2.6)

EM-2 N

174

183

271

Percent Change from Baseline, %

-0.7

-2.5

0.6

Treatment Difference, % (95% CI)

-1.3 (-1.8, -0.8)

-3.0 (-3.5, -2.6)

To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with ORILISSA 150 mg once daily or ORILISSA 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1).

In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment.

Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with ORILISSA and who had a follow-up DXA 12-months off treatment.

Figure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4 1% 0%

Percent Change (95% CI) from Baseline

Table 1. Recommended Dosage and Duration of Use

Reduced Efficacy with Estrogen-Containing Contraceptives Based on the mechanism of action of ORILISSA, estrogen containing contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown.

Advise women to use non-hormonal contraceptives during treatment with ORILISSA and for one week after discontinuing ORILISSA [see Use in Specific Populations, Drug Interactions].

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: • Bone loss [see Warnings and Precautions] • Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see Warnings and Precautions] • Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and Precautions] • Hepatic transaminase elevations [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ORILISSA was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with ORILISSA (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old.

Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months.

Serious Adverse Events Overall, the most common serious adverse events reported for subjects treated with ORILISSA in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with ORILISSA 150 mg once daily and 0.2% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.

Adverse Reactions Leading to Study Discontinuation In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with ORILISSA 150 mg once daily and 9.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo.

Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.

In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with ORILISSA 150 mg once daily and 3.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to decreased BMD. Common Adverse Reactions: Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either ORILISSA dose group and at a greater frequency than placebo are noted in the following table.

-1% -2% -3% -4% -5% -6%

# of Subjects Placebo 150 mg Once Daily 200 mg Twice Daily

271 79 79 Month 0

271 79 79

79 79

79 79

Month 6 Month 12 On Treatment

Month 6 Off Treatment

Placebo ORILISSA 150 mg Once Daily ORILISSA 200 mg Twice Daily

Figure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4 1% 0%

Percent Change (95% CI) from Baseline

INDICATIONS AND USAGE ORILISSA is indicated for the management of moderate to severe pain associated with endometriosis.

DOSAGE AND ADMINISTRATION Important Dosing Information • Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses.

• Take ORILISSA at approximately the same time each day, with or without food.

• Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives [see Warnings and Precautions].

• Limit the duration of use because of bone loss (Table 1) [see Warnings and Precautions].

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

-1% -2% -3% -4% -5% -6%

# of Subjects 150 mg Once Daily 200 mg Twice Daily

30 51

Month 0

30 51

30 51

Month 6 Month 12 On Treatment

29 48

30 51

Month 6 Month 12 Off Treatment

ORILISSA 150 mg Once Daily ORILISSA 200 mg Twice Daily

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Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies EM-1 and EM-2), ORILISSA was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.

Table 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3 ORILISSA 150mg Once Daily

Table 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2 ORILISSA

Adverse Reactions

150 mg Once Daily (N=475) n (%)

200 mg Twice Daily (N=477) n (%)

Placebo (N=734) n (%)

Completed suicide

1 (0.2)

0

0

Suicidal ideation

1 (0.2)

1 (0.2)

0

A 44-year-old woman received 31 days of ORILISSA 150 mg once daily then completed suicide 2 days after ORILISSA discontinuation. She had no relevant past medical history; life stressors were noted.

Among the 2090 subjects exposed to ORILISSA in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued ORILISSA and two completed the clinical trial treatment periods.

Hepatic Transaminase Elevations In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dosedependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with ORILISSA (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4).

Changes in Lipid Parameters Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during ORILISSA treatment in EM-1 and EM-2.

In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with ORILISSA and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with ORILISSA and placebo, respectively. The highest measured serum triglyceride concentration during treatment with ORILISSA was 982 mg/dL. Table 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies EM-1 and EM-2 ORILISSA 150 mg Once Daily N=475

ORILISSA 200 mg Twice Daily N=477

Placebo N=734

Mean change at Month 6

5

13

-3

Maximum increase during Treatment Period

137

107

122

Mean change at Month 6

2

4

1

Maximum increase during Treatment Period

43

52

45

Mean change at Month 6

<1

11

-3

Maximum increase during Treatment Period

624

484

440

LDL-C (mg/dL)

HDL-C (mg/dL)

Triglycerides (mg/dL)

Lipid increases occurred within 1 to 2 months after the start of ORILISSA and remained stable thereafter over 12 months.

Hypersensitivity Reactions In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of ORILISSA treated-subjects and 6.1% of placebotreated subjects. These events led to study drug discontinuation in 0.4% of ORILISSA-treated subjects and 0.5% of placebo-treated subjects.

Endometrial Effects Endometrial biopsies were performed in subjects in Study EM-1 and its extension at Month 6 and Month 12. These biopsies showed a dosedependent decrease in proliferative and secretory biopsy patterns and an increase in quiescent/minimally stimulated biopsy patterns. There were no abnormal biopsy findings on treatment, such as endometrial hyperplasia or cancer.

Based on transvaginal ultrasound, during the course of a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in a dose-dependent decrease from baseline in mean endometrial thickness.

Effects on menstrual bleeding patterns The effects of ORILISSA on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. ORILISSA led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 2

ORILISSA 200mg Twice Daily

Placebo

Baseline Month 3 Baseline Month 3 Baseline Month 3 Mean bleeding/ spotting days in prior 28 days

5.3

2.8

5.7

0.8

5.4

4.6

Mean Intensity scorea

2.6

2.2

2.5

2.0

2.6

2.4

aIntensity

for subjects who reported at least 1 day of bleeding or spotting during 28 day interval. Scale ranges from 1 to 4, 1 = spotting, 2 = light, 3 = medium, 4 = heavy ORILISSA also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for ORILISSA 150 mg once daily, 13-52% for ORILISSA 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-15% for ORILISSA 150 mg once daily and 46-57% for ORILISSA 200 mg twice daily.

After 6 months of therapy with ORILISSA 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with ORILISSA 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.

After 12 months of therapy with ORILISSA 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with ORILISSA 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.

DRUG INTERACTIONS Potential for ORILISSA to Affect Other Drugs Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with ORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A. Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp).

Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).

Potential for Other Drugs to Affect ORILISSA Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.

Concomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong CYP3A inhibitors to 6 months.

Co-administration of ORILISSA with drugs that induce CYP3A may decrease elagolix plasma concentrations.

The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown. Co-administration of ORILISSA with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of ORILISSA and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated.

Drug Interactions - Examples and Clinical Management Table 7 summarizes the effect of co-administration of ORILISSA on concentrations of concomitant drugs and the effect of concomitant drugs on ORILISSA. Table 7. Established Drug Interactions Based on Drug Interaction Trials

Concomitant Drug Class: Drug Name

Effect on Plasma Exposure of Elagolix or Concomitant Drug

Clinical Recommendations

↑ digoxin

Clinical monitoring is recommended for digoxin when co-administered with ORILISSA.

Antimycobacteria ↑ elagolix rifampin

Concomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and rifampin to 6 months.

Antiarrhythmics digoxin

Benzodiazepines oral midazolam

↓ midazolam

Consider increasing the dose of midazolam and individualize therapy based on the patient’s response.

Statins rosuvastatin

↓ rosuvastatin

Consider increasing the dose of rosuvastatin.

The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease).

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. Use of ORILISSA is contraindicated in pregnant women.

Discontinue ORILISSA if pregnancy occurs during treatment.

The limited human data with the use of ORILISSA in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with ORILISSA, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups (see Data).

When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD).

Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively (see Data).

The background risk for major birth defects and miscarriage in the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies occurred while the women were receiving ORILISSA or within 30 days after stopping ORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily and the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy.

Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical trials, there were no apparent decreases in birth weights associated with ORILISSA in comparison to placebo.

Animal Data Embryofetal development studies were conducted in the rat and rabbit.

Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/ dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).

In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD. No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development.

The rat study is still expected to provide information on potential non-targetrelated effects of elagolix.

In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.

Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.

Lactation Risk Summary There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of ORILISSA in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORILISSA and any potential adverse effects on the breastfed child from ORILISSA. Data There are no adequate animal data on excretion of ORILISSA in milk.

Females and Males of Reproductive Potential Based on the mechanism of action, there is a risk of early pregnancy loss if ORILISSA is administered to a pregnant woman [see Use in Specific Populations].

Pregnancy Testing Exclude pregnancy before initiating treatment with ORILISSA. Perform pregnancy testing if pregnancy is suspected during treatment with ORILISSA [see Warnings and Precautions].

Contraception Advise women to use effective non-hormonal contraception during treatment with ORILISSA and for one week after discontinuing ORILISSA [see Warnings and Precautions and Drug Interactions].

Pediatric Use Safety and effectiveness of ORILISSA in patients less than 18 years of age have not been established.

Renal Impairment No dose adjustment of ORILISSA is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).

Hepatic Impairment No dosage adjustment of ORILISSA is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.

ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications].

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OVERDOSAGE In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.

Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.

In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, because elagolix has low affinity for the GnRH receptor in the rat [see Use in Specific Populations], and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.

03-B671 ORILISSA PB 7.625 x 10.5(2-1/3).indd 3

PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Advise patients on contraceptive options, not to get pregnant while using ORILISSA, to be mindful that menstrual changes could reflect pregnancy and to discontinue ORILISSA if pregnancy occurs [see Contraindications and Warnings and Precautions].

• Inform patients that estrogen containing contraceptives are expected to reduce the efficacy of ORILISSA. • Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D [see Warnings and Precautions].

• Advise patients to seek immediate medical attention for suicidal ideation and behavior. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions].

• Counsel patients on signs and symptoms of liver injury [see Warnings and Precautions].

• Instruct patients who miss a dose of ORILISSA to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule: ° 150 mg once daily: no more than 1 tablet each day should be taken. ° 200 mg twice daily: no more than 2 tablets each day should be taken.

• Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, www.fda.gov/drugdisposal, and not to flush down the toilet.

Manufactured by AbbVie Inc. North Chicago, IL 60064 © 2018 AbbVie Inc. All rights reserved.

Ref: 03-B671 Revised: July, 2018 206-1956816 MASTER

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Revista

Mujer recibe diagnóstico de síndrome Lady Windermere El Síndrome Lady Windermere (LWS, por sus siglas en inglés) se cataloga como inusual y suele presentarse en mujeres de alta jerarquía y que suprimen la tos. Y aunque en Puerto Rico no se han presentado muchos casos, al hospital Damas en Ponce se acercó una mujer -que en algún momento tuvo un alto estatus social, característica que sugería cambios crónicos específicamente en la língula y el lóbulo medio derecho. La paciente fue tratada con levofloxacina oral diariamente durante 14 días y el síntoma desapareció por completo.

Tampoco requirió intervención.

Doctora Ilean Lamboy, residente de medicina interna del Hospital Damas de Ponce

Vázquez Quintana se atribuye como el cirujano con 750 intervenciones de paratiroides

Buscan confirmación de la erradicación de Bilharzia en la isla

Dr. Enrique Vázquez Quintana

Dr. Juan C. Orengo, epidemiólogo. Dra. Vivia S. Green

Con una trayectoria de más de 30 años en cirugía, el doctor Enrique Vázquez Quintana se atribuyó ser el cirujano con más experiencias endocrinas en Puerto Rico con 750 cirugías de paratiroides.

El médico inició su carrera 1962 y decidió retirarse en el 2013, ocupando grandes puestos dentro del Recinto de Ciencias Médicas y en el gobierno de la isla cuando se desempeñó, por un mes, como secretario del Departamento de Salud en 1994.

El epidemiólogo Juan C. Orengo Valverde y la doctora Vivian S. Green lideran un estudio para que la Organización Mundial de la Salud (OMS) elimine la bilharzia como enfermedad endémica de Puerto Rico. Desde la Ponce Health Sciences University realizan las investigaciones que -en un futuro cercano- respalden que el caracol conocido como Biomphalaria glabrata ya no existe en los cuerpos de agua. Sin embargo el último caso fue reportado en el 2005 y aún en grandes revistas de turismo Puerto Rico aparece como país endémico de la enfermedad.

Raro caso de fascitis necrotizante enciende las alertas A sala de emergencias del Centro Médico de Mayagüez ingresó una paciente de edad avanzada con fascitis necrotizante fulminante, enfermedad que está asociada a comorbilidades de diabetes e hipertensión. La condición se produce porque bacterias se van propagando produciendo crépitos de gas que van atacando los tejidos. Para eliminar la fascitis, la mujer recibió intervención quirúrgica para limpiar el área pero no sobrevivió debido al avanzado estado de la enfermedad.

Doctora María Del Mar Félix Morales, residente del Centro Médico de Mayaguez

152

Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Reportan infección H. Pylori en joven de 17 años

Alarmantes los niveles de estrés y agotamiento en residentes médicos en Puerto Rico

Doctor Víctor Ruíz, residente de medicina familiar del Manatí Medical Center

Pilar Vázquez residente de segundo año de medicina familia del Centro Médico Mayaguez

Tras mostrar resistencia a tratamientos para trombocitopenia inmune (PTI), médicos buscaron posible infección por H. pylori en el paciente afectado y trabajaron en su erradicación para comenzar tratamientos regulares de esteroides e inmunoglobulina intravenosa. El caso fue reportado en el Manatí Medical Center y publicado por el doctor Víctor Ruíz García residente de segundo año en medicina familiar de la mencionada institución hospitalaria.

Un estudio realizado por varios residentes de medicina familiar del Centro Médico de Mayagüez reportó que el 56% de los residentes de medicina familiar en Puerto Rico afirmó tener altos niveles de estrés asociados a agotamiento en su lugar de trabajo. Este estudio enciende una alerta a nivel mundial, ya que en Estados Unidos se han reportado suicidios de médicos residentes por estas causas.

Aunque en Puerto Rico no ha ocurrido un incidente similar, este hospital ya está tomando medidas para evitarlo y reducir los niveles de trabajo de los médicos.

Estudian posibilidades de inmunoterapias para endometriosis

Board Certified Specialists | Medical Oncology Cancer Treatment Planning | Hematology and Blood Disorders

HEMATÓLOGOS | ONCÓLOGOS

Miguel Oyola investigador de la Ponce Health Science University

Miguel Oyola, estudiante de P.S de la Ponce Health Science University, investiga datos sobre las células B y T para – a través de una nueva forma de inmunoterapia- atacar las lesiones de la endometriosis. Esto se realiza en dos mecanismos totalmente distintos, en los que se extraen las moléculas y se entrena el sistema inmune para atacar las células de la enfermedad. Con ello, buscará cuál es la que mejor respuesta tendría para el tratamiento, resultando en beneficios para los pacientes.

Dr. Rolando Jiménez Acevedo Dra. Karen Santiago Ríos Dra. Maryknoll De La Paz López Dra. Ilean Padua Octaviani Dra. Maryangely Moreno Campa

Guayama La Fuente Town Center #219 787-866-8808 787-864-7035 Yauco Calle Prolongación 25 de Julio 787-992-7209 787-992-7208 Mayagüez Medical Emporium II Suite A-15 (primer piso) 787-831-6429 787-833-7840 caribbeancancercareservices@gmail.com

Ponce Edificio Parra #1 787-284-4830 787-284-4833 787-284-4814 San Germán Medical Plaza #212-213 787-264-5842 787-264-7010 787-264-5700

Revista Puertorriqueña de Medicina y Salúd Pública

www.caribbeancancercarepr.com

153

Revista

154

Triclosán, sustancia nociva para las neuronas

Insulina comprimida, alternativa para acabar con las inyecciones en diabéticos

Triclosán.

Insulina comprimida, alternativa para acabar con las inyecciones en diabéticos Noticias.

El triclosán, una sustancia utilizada en elementos de aseo personal, en realidad produce efectos negativos sobre las neuronas. Esta fue la conclusión obtenida por una investigación en la que se revela que es un agente tóxico para el sistema nervioso, ya que altera el funcionamiento de las neuronas encargadas de la memoria y el sentido espacial, luego de analizar el comportamiento de modelos animales expuestos a dosis directas de esta sustancia, semejantes a los seres humanos que utilizan cotidianamente productos con triclosán.

Investigadores han desarrollado una cápsula -del tamaño de un arándano- que evitaría a los pacientes con diabetes, aplicarse su dosis de insulina a través de una inyección. La innovadora técnica fue desarrollada por el Instituto Tecnológico de Massachusetts (MIT).

De acuerdo con la información, dentro de la píldora hay una aguja diminuta y biodegradable que inyecta la insulina directamente en el organismo -específicamente en el estómago-, ya que su punta está elaborada con insulina liofilizada y comprimida

Crean unidad comprensiva de epilepsia para pacientes puertorriqueños

Continúan estudios sobre enfermedad de Alzhéimer precoz en Colombia

De izquierda a derecha: Javier Chapa, neurólogo; doctor Pita; José Arias Morales Epileptólogos.

Dr. Francisco Lopera Restrepo.

Durante el mes de febrero, Manatí Medical Center inauguró esta nueva unidad enfocada en mejorar la atención de los pacientes de epilepsia, una condición que padecen cerca de 80.000 personas en la isla. La apertura del centro responde a la necesidad de la población de recibir tratamiento médico oportuno y adecuado, ya que actualmente la enfermedad ha sido apartada de los planes médicos que, además, continúan ofreciendo medicamentos obsoletos.

Investigadores adelantan un estudio que busca determinar si, una extraña anomalía genética originaria de ese país y conocida como la ‘mutación paisa’, puede prevenirse con la administración de fármacos que eliminan la placa amiloide antes de que los pacientes pierdan sus habilidades cognitivas y entren a la fase de demencia, fenómeno que ocurre cerca de los 40 años de edad.

Revista Puertorriqueña de Medicina y Salúd Pública

Convenciones 2018 - febrero 2019 Convención anual de la Sociedad de Médicos Graduados de la Escuela de Medicina de la Universidad de Puerto Rico

Revista

35 ta Conferencia de Epilepsia del Caribe

Clase Graduanda del 1968 de la Escuela de Medicina del Recinto de Ciencias Médicas (RCM).

Dra. Miriam Ríos, Neuróloga junto con Michael Rosado, Presidente de la Sociedad Puertorriqueña de Epilepsia.

La Sociedad de Médicos Graduados de la Escuela de Medicina de la Universidad de Puerto Rico celebró su convención anual número 59, la cual contó con un emotivo homenaje a la clase graduanda del 1968.

Esta actividad contó con la asistencia de más de 100 egresados, quienes se unieron con el fin de aprovechar las ofertas académicas y educativas, participar de los eventos de confraternización y fomentar el respaldo a los alumnos y al Recinto de Ciencias Médicas (RCM).

La Sociedad Puertorriqueña de Epilepsia celebró en San Juan su 35 ta Conferencia anual, la cual contó con la asistencia de un centenar de médicos y profesionales de la salud. Entre las conferencias impartidas se destacaron los temas de genética, enfermedades cerebrovasculares y su relación con la epilepsia, síndromes epilépticos más comunes en niños y monitoreo de las manifestaciones de las convulsiones en pacientes.

Convención anual Asociación de Médicos Pediatras de la Región Oeste (AMPRO)

Convención anual de la Academia de Neurología de Puerto Rico

Dra. Sylvia Arce Cardona. Presidenta de la Asociación de Médicos Pediatras de la Región Oeste (AMPRO).

Dr. David Blas, Presidente entrante Academia Puertorriqueña de Neurología.

Temas como la obesidad e hipertensión, manejo del dolor, autismo, emergencias endocrinológicas, entre otros, fueron el foco de atención en la convención anual de la Asociación de Médicos Pediatras de la Región Oeste (AMPRO). Esta actividad contó con la dirección de su actual Presidenta, la Dra. Sylvia Arce Cardona, quien tiene como uno de sus objetivos principales, el aumentar la participación de AMPRO en más actividades de labor comunitaria.

Con la finalidad de mantener al día a todos los Neurólogos de nuestro país sobre los adelantos en el tratamiento de condiciones como la esclerosis múltiple, epilepsia, esclerosis lateral amiotrófica y la migraña crónica, la Academia de Neurología de Puerro Rico celebró su convención anual desde San Juan. Esta actividad contó con la asistencia de más de 200 profesionales, quienes se nutrieron con la información ofrecida tanto por sus conferenciantes, como por médicos residentes que presentaron durante este foro sus investigaciones más recientes. El anfitrión de esta actividad fue su actual Presidente, Dr. David Blas Boria.

Revista Puertorriqueña de Medicina y Salúd Pública

155

Revista

Convenciones 2018 - febrero 2019

Convención anual de la Sociedad de Nefrología de Puerto Rico

Convención anual Asociación de Hematología y Oncología Médica de Puerto Rico

Dr. José Luis Cangiano, Presidente de la Sociedad de Nefrología de Puerto Rico.

Dr. Sixto Pérez, presidente de la AHOMPR.

Con la asistencia de un nutrido grupo de especialistas, la Sociedad de Nefrología de Puerto Rico celebró su tradicional convención anual denominada Avances en Enfermedad Renal. La actividad contó con un grupo de científicos y clínicos con una amplia gama de experiencia en el campo de la nefrología y la hipertensión. En la foto el Dr. José Luis Cangiano, Presidente de la entidad.

a Asociación de Hematología y Oncología Médica de Puerto Rico celebró su convención anual en Río Grande, con una de las más sólidas asistencias que hayan reportado en la actividad. La AHOMPR ofreció conferencias sobre manejo del dolor, inmunoterapia y quimioterapia, manejo de metástasis en pacientes con cáncer de seno, sarcoma óseo, entre otros. En la foto, Dr. Sixto Pérez, Presidente de la Asociación de Hematología y Oncología Médica de Puerto Rico

3 er Simposio de Electrofisiología de la American College of Cardiology

Convención anual Puerto Rico Urological Association

Dr. Juan Carlos Sotomonte, Presidente de la American Collage of Cardiology.

Con la finalidad de educar a la comunidad médica sobre los últimos tratamientos disponibles para enfermedades cardiovasculares, la American College of Cardiology, capítulo de Puerto Rico, celebró su tercer simposio de electrofisiología. El evento contó con la participación de cerca de 200 profesionales de la salud y abarcó a través de cuatro secciones durante el día, los temas de electrofisiología clínica, terapia basada en dispositivos y arritmias cardíacas.

Dr. Ricardo Sánchez, urólogo oncólogo.

La Puerto Rico Urological Association celebró su convención anual número 68 en San Juan. Entre los temas destacados durante la convención, se mencionó el manejo de piedras en el tracto urinario, uroradiología y cáncer urotelial. Esta actividad contó con el Dr. Ricardo Sánchez, Presidente de la organización, como anfitrión.

Sociedad Radiológica de PR Annual Breast Imaging Summit Con la presencia de 250 profesionales de la salud, entre los que se destacaban tecnólogos, radiólogos y mamografistas, se llevó a cabo el Annual Breast Imaging Summit de la Sociedad Radiológica de Puerto Rico. El evento tuvo lugar en San Juan y se presentaron 13 conferencias durante todo el día, impartidas en su mayoría por diversos especialistas puertorriqueños. Varios de los temas discutidos fueron la seguridad y proceso al realizar biopsias, inspección física de pacientes con cáncer de seno, el rol de la sonografía en el diagnóstico de carcinoma ductal in situ (DCIS), entre otros Dra. Mayra Maldonado, radióloga especialista en seno.

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Convenciones 2018 - febrero 2019

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Convención Anual HIV Treaters Medical Association of Puerto Rico

Digestive Diseases of the Caribbean 2019

Maribel Acevedo, presidenta HIVMTD.

Dra. Esther Torres, gastroenteróloga.

Con la asistencia de más de un centenar de médicos y especialistas, la HIV Treaters Medical Association of Puerto Rico celebró su convención número 18 en Dorado. Las conferencias estuvieron relacionadas a temas como prevención de diabetes, manejo y prevención del virus del chikungunya, dengue y zika. Igualmente, se destacaron los avances y logros alcanzados en el tratamiento para el VIH, los mitos y realidades en la comunidad LGBTT, avances en medicamentos, entre otros.

Con una participación alta y variada de especialistas en patología y endoscopía, se llevó a cabo el Digestive Diseases of the Caribbean 2019, de la Asociación Puertorriqueña de Gastroenterología. Este evento reunió una gama de conferenciantes internacionales, quienes llevaron a cabo conferencias sobre manejo de la condición de crhons, carcinoma hepatocelular, identificación y manejo del cáncer coloretal hereditario, cáncer de páncreas, entre otros.

Convención anual de la Sociedad Puertorriqueña de Pediatría

Convención anual Hospital San Juan Capestrano

Dra. Vanessa Santini.

Licenciada Marta Rivera Plaza, Oficial de Operaciones del Hospital San Juan Capestrano.

La Sociedad Puertorriqueña de Pediatría llevó a cabo su convenión anual número 66, la cual contó con una sostenida participación de especialistas en pediatría. Las conferencias se basaron en temas como ADHD, esclerosis múltiple en pacientes pediátricos, manejo y diagnóstico de fibrosis, hidradenitis supurativa, entre otros. Este evento contó con la Dra.Vanessa Santini como anfitriona.

Con la participación de médicos que ejercen su práctica tanto a nivel local, como fuera del país, el Hospital San Juan Capestrano celebró su convención anual en San Juan, con el propósito de reunir, conectar, recargar y educar a los pacientes y familiares que son parte de esta institución. Entre los temas abordados durante la actividad, se encuentran los desórdenes mentales bajo depresión, diagnósticos y tratamientos para el alzheimer, sustancias que afectan la salud de los pacientes, entre otros.

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Johnny Rullán,

hijo ilustre de la medicina puertorriqueña

Dr. Johnny Rullán.

Para Puerto Rico, el Dr. Johnny Rullán es un médico y un hombre digno de todos los honores, no solamente por sus contribuciones a la epidemiología del Caribe y la isla, sino también por su dedicación y entrega a la población general, características irrefutables y fuertemente evidenciadas durante su ejercicio profesional, incluyendo su etapa como Secretario de Salud. No en vano, al Dr. Rullán se le conoce como la primera autoridad y fuente de consulta cuando se trata de indagar acerca de la gestión de la salud en la isla, los problemas de salud pública que atraviesan los puertorriqueños y la certificación de nuevos logros.

Su nombre se lo ha forjado a pulso. Como él mismo lo ha reconocido en varias oportunidades, tomó la decisión de inscribirse en la carrera de medicina en la Universidad de Puerto Rico, ante la reticencia de varias personas y cuando era una opción profesional disputada por un elevado número de jóvenes. Su excelente desempeño lo llevó a Estados Unidos y a Londres en sus primeros años como médico cuando apenas iniciaba la epidemia del VIH / Sida y los conocimientos sobre el tema eran escasos. Como epidemiólogo pudo formarse en el 158

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Epidemic Intelligence Service (EIS), un programa sobre epidemiología intervencional que fortaleció sus habilidades médicas y que ha puesto al servicio de la comunidad, tanto en su práctica privada como en el ejercicio público cuando fue servidor del estado.

Pero, sin duda, su mayor logro fue la apertura de las clínicas especiales para VIH en Puerto Rico en 1990, en las que se han atendido gratuitamente a más de 35.000 pacientes desde que están a disposición de la población. También, es valioso destacar que el Dr. Rullán actualizó los Registros de Cáncer siendo Secretario de Salud, datos que a día de hoy son utilizados en diversas investigaciones que se adelantan en la isla.

En la actualidad, el Dr. Rullán está concentrado en la recuperación total de una recaída de mieloma múltiple, cáncer que ha tratado con trasplantes de médula ósea en más de una oportunidad. Y si bien, hoy en día se encuentra alejado de los escenarios públicos, todavía ejerce la medicina como consultor de su compañía y recibe el cariño y apoyo de su comunidad y una nación que lo reconoce como uno de sus hombres más excelsos.