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SOMOS CIENCIA

Cirugía robótica para cáncer de próstata

Cirugía moderna para el cáncer de mama

Cirugía para la enfermedad de Parkinson

Errores más comunes en hernías laparoscópicas • Cirugía laparoscópica para cáncer de colon y recto: estado actual en Puerto Rico Oncología musculoesquelética Suplemento HIV- Treaters • Fibrilación atrial secundario a mixoma grande en un hombre de 68 años

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Indication

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Important Safety Information Contraindication • Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated due to the potential for increased risk of tumor lysis syndrome (TLS).

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Important Safety Information (continued) Tumor Lysis Syndrome • Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden treated with VENCLEXTA. • VENCLEXTA poses a risk for TLS in the initial 5-week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at each dose increase. • Patients should be assessed for TLS risk, including evaluation of tumor burden and comorbidities, and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricemics. Reduced renal function (CrCl <80 mL/min) further increases the risk. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. • Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp inhibitors may increase the risk of TLS at initiation and during the ramp-up phase, and may require dose adjustment due to increases in VENCLEXTA exposure. Neutropenia • Grade 3 or 4 neutropenia developed in 64% (124/194) of patients treated with VENCLEXTA in combination with rituximab and in 63% (216/344) of patients treated with VENCLEXTA monotherapy. Febrile neutropenia occurred in 4% of patients treated with VENCLEXTA in combination with rituximab and in 6% of patients treated with VENCLEXTA monotherapy. Monitor complete blood counts throughout treatment. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Immunization • Do not administer live attenuated vaccines prior to, during, or after treatment with VENCLEXTA until B-cell recovery. Advise patients that vaccinations may be less effective. Embryo-Fetal Toxicity • VENCLEXTA may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Adverse Reactions • In combination with rituximab, serious adverse reactions were reported in 46% of patients, with the most frequent (≥5%) being pneumonia (9%). The most common adverse reactions (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), cough (22%), and nausea (21%).

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V.5.2018. National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 2, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. 2. VENCLEXTA Prescribing Information. 3. AbbVie’s Venetoclax receives breakthrough therapy designation from FDA in combination with rituximab for the treatment of patients with relapsed/ refractory chronic lymphocytic leukemia [press release]. North Chicago, IL: AbbVie Inc. https:// news.abbvie.com/news/abbvies-venetoclax-receives-breakthrough-therapy-designation-fromfda-in-combination-with-rituximab-for-treatment-patients-with-relapsedrefractory-chroniclymphocytic-leukemia.htm. Accessed March 21, 2018.

FDA BREAKTHROUGH THERAPY DESIGNATION3

• As monotherapy, serious adverse reactions were reported in 52% of patients, with the most frequent (≥5%) being pneumonia (9%), febrile neutropenia (5%), and sepsis (5%). The most common adverse reactions (≥20%) of any grade were neutropenia (50%), diarrhea (43%), nausea (42%), upper respiratory tract infection (36%), anemia (33%), fatigue (32%), thrombocytopenia (29%), musculoskeletal pain (29%), edema (22%), and cough (22%). Drug Interactions • For patients who have completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the dose by at least 75% when used concomitantly with strong CYP3A inhibitors. Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor. • Avoid concomitant use of moderate CYP3A inhibitors or P-gp inhibitors. If an inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor patients more closely for signs of VENCLEXTA toxicities. Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor. • Patients should avoid grapefruit products, Seville oranges, and starfruit during treatment as they contain inhibitors of CYP3A. • Avoid concomitant use of strong or moderate CYP3A inducers. • Avoid concomitant use of narrow therapeutic index P-gp substrates. If these substrates must be used, they should be taken at least 6 hours before VENCLEXTA. • Monitor international normalized ratio (INR) closely in patients receiving warfarin. Lactation • Advise nursing women to discontinue breastfeeding during treatment with VENCLEXTA. Females and Males of Reproductive Potential • Advise females of reproductive potential to use effective contraception during treatment with VENCLEXTA and for at least 30 days after the last dose. • Based on findings in animals, male fertility may be compromised by treatment with VENCLEXTA.

Please see Brief Summary of full Prescribing Information on the following pages.

La importancia de un análisis de “cash flow”, realizar una buena radiografía financiera, analizar estrategias financieras y seleccionar una firma de asesores con buenos credenciales, es de suma importancia. Pero, más aún, es importante realizar un análisis de los contratos que respaldan lo anterior escrito.

urante el transcurso de nuestras vidas tendremos que firmar muchos contratos. Como por ejemplo, el contrato de arrendamiento de un apartamento, el préstamo de un auto, un contrato de empleo y hasta la hipoteca de nuestro primer hogar. Sin embargo, durante la planificación financiera tenemos que evaluar y firmar muchos contratos de productos financieros que, en los momentos más cruciales, podrían ayudarnos o perjudicarnos si no prestamos atención a “las letras pequeñas”. Cuando concretamos un contrato, estos incluyen los costos de manejo y en ocasiones, costos internos administrativos de los productos que, en múltiples ocasiones, se incrementan gradualmente y provocan una erosión en nuestras ganancias. Los contratos también pueden incluir posibles cláusulas de penalidad a la hora de retiro prematuro y endosos muy costosos, que benefician más a las compañías que a los mismos individuos, que son quienes más lo necesitan. Es por esto que en el momento más crucial, necesitamos que nuestros contratos estén a nuestro favor y no, en nuestra contra.

Por tal razón, las hojas de trabajo sobre lo pactos escritos son interesantes y requieren pensamiento. Sin embargo, realizar un buen análisis de un contrato, entender su lenguaje, términos y condiciones así como entender las estrategias financieras que trae consigo, será la diferencia entre el éxito y las sorpresas que puedan surgir a la hora de tomar una decisión de futuro. Basado en una experiencia de 16 años y con un amplio peritaje en análisis de contratos, exhortamos a exigir a los profesionales de servicios financieros que le presenten todas las opciones existentes, siempre con un enfoque educativo encaminado a trabajar en las metas trazadas a corto, mediano y largo plazo. En Trust MD, nuestros clientes reciben de manera gratuita un análisis profundo financiero el cual incluye una radiografía financiera y análisis de “cash flow”. De esta manera nos asegurarnos que se cumplan todos los objetivos. Para más información, puede llamarnos al 787-507-2237 ó 7875 07-2236. También puede escribirnos un correo electrónico a info@trustmdcorp.com.

www.trustmdcorp.com

CONTENIDO 37

Cirugía Laparoscópica para cáncer de colon y recto: Estado actual en Puerto Rico

Errores más comunes en hernias laparoscópicas

Retos para la prevención del VIH en Puerto Rico por medio de PrEP

Cirugía robótica para cáncer de próstata

VIH y el paciente mayor de edad

Cirugía moderna para el cáncer de mama

Nuevas terapias antiretrovirales: El futuro de la condición del VIH

Oncología musculoesquelética

Cirugía para la enfermedad de Parkinson

Suplemento HIV- Treaters

Fibrilación atrial secundario a Mixoma grande en un hombre de 68 años

Agenda médica

Convenciones

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 Alejandra González ,Mayra Acevedo, Susana María Rico REALIZADORA AUDIOVIZUAL Alejandra Montenegro Arango PROGRAMADORES WEB Diego Esteban Gutiérrez, Frank Arley Carvajal Rincón ARTISTAS GRÁFICOS Marcela Castro Villamarín, Pablo Bermúdez Robayo 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

PRINCIPAL OFICIAL EJECUTIVA

Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521

Síguenos en www.medicinaysaludpublica.com, www.facebook.com/revistamsp, en Twitter @revistamsp, en LinkedIn como Revista Puertorriqueña de Medicina y Salud Pública. Las normas editoriales de la Revista Puertorriqueña de Medicina y Salud Pública para la publicación de artículos originales y cartas al editor pueden ser accesadas en la página web: www.medicinaysaludpublica.com, y solicitadas a través de msp@editorialmundo.com. Medicina y Salud Pública es una publicación de la REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA. Medicina y Salud Pública tiene como política corregir y aclarar cualquier información incorrecta que pueda ser publicada en su revista. Medicina y Salud Pública no asume responsabilidad alguna por los anuncios, artículos y otros servicios anunciados en nuestra publicación.

Revista Puertorriqueña de Medicina y Salúd Pública

BOLÍVAR ARBOLEDA-OSORIO, MD FACS FICS Presidente, Sociedad Puertorriqueña de Senología, Pasado Presidente, capítulo de PR del American College of Surgeons Director, HIMA-San Pablo Breast Institute/Oncológico, Caguas Profesor Asociado de Cirugía, Universidad Central Del Caribe barboledamd@gmail.com - Oficina 787-961-4211

Robots y tecnología: la nueva realidad en el quirófano

on gran placer que ponemos ante vuestra consideración esta primera Edición Quirúrgica de la Revista Medicina y Salud Pública (MSP). ¡Las dificultades que todos encontramos luego del paso del Huracán María atrasó nuestra fecha inicial de publicación, pero el tesón de nuestra estirpe se irguió sobre los problemas y hemos salido adelante! Durante los pasados años hemos estrechado alianzas con la plantilla editorial de esta revista y ahora vemos los frutos de tan selecta colaboración. Escoger solo algunos temas para esta edición no ha sido fácil, en vista de la gran gama que compagina la labor quirúrgica. Sin embargo, esto también implica que gozamos de múltiples recursos en nuestro país para contribuir al conocimiento de nuestros colegas La rápida proliferación de avances tecnológicos se ve plasmada en los artículos que nuestros autores colaboradores redactado para su disfrute. Exploraremos los campos de la ortopedia oncológica, cirugía laparoscópica general y del colon, neurocirugía para el Parkinson, cirugía robótica de la próstata y cirugía avanzada para el cáncer de la mama. Es que la tecnología ha cambiado no solo la fisonomía de las salas de operaciones sino, también, los requerimientos que se espera de los cirujanos, a los que la digitalización les ha ofrecido capacidades impensables hace unos años. «La robótica

se está empezando a utilizar, así como las técnicas de realidad aumentada. Se está trabajando en algo similar a las gafas de Google, que integran un mapa cuando estás caminando por la calle, y que en un futuro inmediato estarán a disposición de los médicos, permitiendo integrar estudios de resonancia o TAC con lo que está viendo el cirujano en el momento de la operación». Estados Unidos y Alemania están a la cabeza en la implantación de la cirugía mínimamente invasiva, posible gracias a las técnicas de navegación. Esta cirugía conlleva una recuperación menos dolorosa y más rápida para el paciente, lo que se traduce en menor tiempo de hospitalización, menor uso de analgésicos y menor necesidad de transfusiones. «La inversión tecnológica es una inversión eficiente y por ello es importante que los gestores de los hospitales públicos y de las compañías de seguros sean conscientes de la necesidad de asumir el costo». Una af irmación que, parecía imposible, la robotización ha llegado a la cirugía para quedarse y sus posibilidades no han hecho más que empezar. Espero que esta sea la primera de muchas otras colaboraciones entre Medicina y Salud Publica y los especialistas quirúrgicos de Puerto Rico. De tener alguna sugerencia para futuras ediciones siéntanse en la libertad de comunicarse conmigo.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Errores más comunes en hernias laparoscópicas Por: Juan Carlos López de Victoria, MD Board Certified General Surgeon Advanced Laparoscopy Minimally Invasive Bariatric and General Surgeon

Resumen: Cualquier procedimiento conlleva un riesgo de error y complicaciones. La reparación de hernias por laparoscopia no está exenta de estos riesgos, aunque muchos de estos pueden ser evitados con un buen conocimiento anatómico y observando los principios básicos de las reparaciones libres de tensión. Abstract: Any surgical procedure carries an inherent risk of error and complications. Laparoscopic hernia repair carries these risks but there are ways of preventing these pitfalls. A good anatomical understanding and applying the basic hernia repair principle of tension free repair, these errors can be avoided.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Palabras Clave: Hernia inguinal, hernia incisional, hernia umbilical, triángulo del dolor, triángulo de la muerte, malla

Keywords: Inguinal hernia, incisional hernia, umbilical hernia, triangle of pain, triangle of doom, mesh

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Una hernia es un defecto o espacio en la fascia, tejido que da soporte y sostiene a los músculos en su lugar. Estas hernias suelen aparecer como abultamiento en distintos lugares de la pared abdominal. Los lugares más frecuentes son en la ingle (inguinal), el ombligo (umbilical) y en cicatrices de operaciones previas (incisional). El uso de laparoscopia -para reparar estas hernias- ha tenido un gran auge y aceptación en la comunidad quirúrgica debido a buenos resultados y una recuperación más pronta de los pacientes. Como en toda operación, uno de los errores primordiales es la selección inadecuada del paciente y el tipo de procedimiento a realizarse. No todos los procedimientos pueden ser realizados por laparoscopia ya que este procedimiento requiere del uso de anestesia general. Si el paciente, por alguna razón médica preexistente, no tolera la anestesia general, entonces no es un candidato para laparoscopia. Pacientes con coagulopatía, fallo hepático descompensando o pacientes con defectos extremadamente grandes, tampoco son candidatos para laparoscopia.

más importantes de recurrencia de hernia es fumar. Se recomienda dejar de fumar al menos 4 semanas antes de la operación. Fumar aumenta cuatro veces más el riesgo de recurrencia de hernia. Pruebas de nicotina el día de la operación puede indicar si el paciente continúa fumando o no.

“PACIENTES CON COAGULOPATÍA, FALLO HEPÁTICO DESCOMPENSANDO O PACIENTES CON DEFECTOS EXTREMADAMENTE GRANDES, TAMPOCO SON CANDIDATOS PARA LAPAROSCOPIA”

centímetros. La reparación de la hernia debe ser libre de tensión. Para lograr esto, es necesario el uso de malla como refuerzo a la reparación de la hernia. Existen diversos tamaños, formas y materiales de este recurso, disponibles para la selección al momento del procedimiento. Para efecto de este artículo discutiremos por separado las hernias inguinales de las insicionales/umbilicales, ya que su abordaje es distinto. La reparación de hernias inguinales por laparoscopia ha tomado un gran auge en los últimos años debido al resultado comparable al acercamiento abierto y a que el dolor postoperatorio es menor. También se ha demostrado una recuperación más rápida en cuanto al funcionamiento social del paciente. No obstante, es una de las técnicas con una de las curvas de aprendizaje más alta. Es importante tener un buen dominio de la técnica, pero más importante aún, es entender la anatomía de esta área. Hay dos áreas en específico que ameritan atención especial al momento de la disección y la colocación de la malla: el triángulo del dolor y el triángulo de la muerte.

Una vez decidida la operación, preoperativamente se deben tomar medidas preventivas contra trombos y coágulos. Esto se logra con medicamentos anticoagulantes o el uso de medias de compresión ant iemból icas. También, es Una vez seleccionado el paciente, recomendado el uso de antibióticos El triángulo del dolor se define hay que asegurarse que esté profilácticos antes de comenzar la por sus bordes entre el tracto medicamente optimizado. Esto operación para disminuir eventos de iliopúbico, los vasos gonadales y incluye que no tenga un foco de infecciones. la ref lexión del peritoneo. Si al infección (respiratoria, piel, orina) momento de la disección se realiza y que sus comorbilidades estén Se ha demostrado exhaustivamente un corte, se utiliza una fuente de médicamente controladas (presión, que uno de los errores más comunes calor como electrocauterio o se diabetes, asma). Pacientes con es no utilizar malla para la operación aplica un remache para fijar la obesidad mórbida deben bajar de laparoscópica o abierta de hernias malla en esta área, el paciente peso en casos electivos. También, se inguinales, hernias incisionales y sufrirá un dolor severo. Este dolor ha demostrado que una de las causas hernias umbilicales mayores de dos puede variar desde una molestia 10

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

“Los errores en la cirugía laparoscópica siempre estarán presentes pero pueden ser reducidos manteniendo atención a la anatomía y la técnica adecuada. Es sumamente importante seleccionar bien los pacientes y el tipo de abordaje a realizarse” crónica hasta un dolor intenso agudo que requiera preoperación de inmediato. Es importante mantener la disección a un mínimo cerca de esta área. El triángulo de la muerte tiene por bordes los vasos gonadales, el conducto deferente y el borde peritoneal. Dentro de este se encuentra la arteria y la vena iliaca. Cualquier error en esta área puede ser fatal. La mejor manera de identificar el triángulo de la muerte es siguiendo los vasos epigástricos inferiores que se encuentran en la pared abdominal anterior. Es imperativo mantenerse lejos de esta área. Las hernias insicionales ocurren luego de una operación abdominal en hasta un 30 por ciento de los pacientes. La reparación por laparoscopia es una técnica que se utiliza cada vez más en estos casos. Esto debido a la disminución en infección de heridas, hematomas, tiempo de hospitalización y menor dolor. Sin embargo, al aumentar el número de casos, también aumenta el número de errores que llevan a complicaciones durante este procedimiento. El error número uno es el no utilizar malla. El no utilizar malla en la reparación de hernias incisionales resulta en hasta un 63 por ciento de recurrencia dentro de los 10 años a diferencia de un 23 por ciento con el uso de malla. Esto se debe al principio básico de la reparación de hernias que establece que la reparación debe ser libre de

tensión. Otro error común es el no reaproximar el defecto luego de utilizar incisiones relajantes. La pared abdominal es un órgano dinámico y para que este funcione bien requiere que los músculos estén cerca de su posición original. Para esto, hay que cerrar el defecto y reforzarlo con una malla. La posición de los trocares es también vital para poder reparar una hernia por laparoscopia. Entendiendo que las mayorías de hernias están en la parte ventral del abdomen, se deben colocar los trocares lo más lateralmente posibles para poder fijar la malla luego. Otro error que se comete a menudo es no dejar suficiente superposición de la malla. La mayoría de los expertos recomiendan por lo menos 5 centímetros de los bordes de la hernia para que haya suficiente cubierta de la malla. La malla debe estar completamente plana, ya que cualquier doblez aumenta la incidencia de recurrencias y herniamiento de este material. Un error frecuente es el uso de fuentes de calor cerca del intestino para la disección de adherencias. Esto puede causar enterotomías al momento o tardías, produciendo derrames de contenidos entéricos con posibles consecuencias nefastas. Se recomienda el uso de tijeras para esta disección y aceptación del exudado sanguíneo a consecuencia de esto. Dejar el saco herniario

aumenta la incidencia de seromas luego de la operación, por eso es aconsejable removerlo. La formación de seroma también puede ser evitada con el uso de fajas inmediatamente luego de la operación. Los errores en la cirugía laparoscópica en la reparación de hernias siempre estarán presentes. Sin embargo, pueden ser reducidos manteniendo atención a la anatomía y la técnica adecuada. E s su ma mente i mpor t a nte seleccionar bien los pacientes y el tipo de abordaje a realizarse. Más importante aún es recordar el primer principio de la hernialogía laparoscópica: si no puedes hacer el caso por laparoscopia de manera segura, no titubees en convertirlo en un procedimiento abierto. Referencias:

1.Current Surgical Therapy 12th edition, John L Cameron 2.Phillips E, Arregui M, Carrol J, et al. Incidence of complications following laparoscopic hernioplasty Surg Endosc 1995; 9:16-21 3. Payne J, Complications of laparoscopic inguinal herniorrhaphy Semin Laparosc Surg 1997;4(3):166-181 4. LeBlanc KA Laparoscopic incisional and ventral hernia repair: Complications- how to avoid them Hernia 2004 Dec;8(4):323-31

Revista Puertorriqueña de Medicina y Salúd Pública

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

Cirugía robótica

para cáncer de próstata Por: Ronald Cadillo, MD Especialista en Urología y Oncología Robótica

Resumen: La prostatectomía radical asistida por robot (PRAR) se ha convertido en el tratamiento quirúrgico de elección para el cáncer de próstata localizado. Esta preferencia está relacionada a la menor morbilidad relacionada a la disminución del sangrado, dolor postoperatorio y a similares resultados oncológicos cuando se compara con la prostactectomía radical abierta (PRA). PRAR se ha desarrollado continuamente con el fin de mejorar los resultados funcionales relacionados a continencia urinaria y potencia sexual. Este desarrollo ha sido posible por nuevos conceptos técnicos y tecnológicos. Estos avances han permitido que la morbilidad continúe mejorando y que el uso de la PRAR se aplique a casos más complejos. Este artículo tiene como objetivo brindar una idea global de la cirugía robótica para cáncer de próstata. Abstract: Robotic assisted radical prostatectomy (RARP) is the most popular surgical treatment used for localized prostate cancer. This preference is related to a less morbidity: decreased blood loss, less post-operative pain and similar oncological outcomes when compare to open radical prostatectomy. RARP has been continually modified looking to improve the most worrisome functional outcomes such as urinary incontinence and erectile dysfunction. This evolution was based in the development of new technology and surgical techniques. All these efforts have made possible that the morbidity has continue improving which has made possible the use of RARP for more complex cases. The main objective of this article is to give a global vision about robotic surgery and prostate cancer. 18

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Palabras clave: CaP= Cancer de prostata, PRAR=Prostatectomía radical asistida por robot, Braquiterapia, Crioterapia, TUMT= Termoablación transuretral por microondas, Prolieve, Linfadenectomía extendida, Oligometástasis. Keywords: CaP= Prostate cancer, RARP: Robotic assisted radical prostatectomy, Brachytherapy, Cryotherapy, TUMT: Transurethral microwave thermotherapy, Prolieve, eLND: Extended lymph node dissection, Oligometastasis.

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"La PRAR es una de las operaciones técnicamente más demandantes debido a la cantidad de pasos con que cuenta la cirugía y a las expectativas oncológicas y funcionales (continencia urinaria y potencia)"

El cáncer de próstata (CaP) representa el 30% de todos los nuevos casos diagnosticados de cáncer en Estados Unidos. Es la segunda causa de muerte más frecuente relacionada a cáncer en hombres. En el 2015, alrededor de 220,800 hombres fueron diagnosticados de CaP(1). La creación del PSA (antigeno prostático específico) como instrumento de cernimiento, incrementó el diagnóstico de pacientes con cáncer localizado de próstata. Cerca del 80% de los pacientes recientemente diagnosticados tendrán CaP localizado(2). En 1998, D’Amico et al. propusieron la estratificación de los pacientes con cáncer de próstata en tres grupos: bajo, intermedio y alto riesgo de acuerdo al PSA inicial, estadio clínico (TNM) y la clasificación de Gleason de la biopsia(3). Dependiendo del grupo de riesgo, del historial del paciente y estudios radiológicos, el CaP localizado cuenta con los siguientes tratamientos: observación, braquiterapia, crioterapia, radiación externa y cirugía. El tratamiento quirúrgico del CaP incluye diferentes abordajes: abierto, laparoscópico y robótico. En 1992, Schuessler et al.(4), reportaron su inicial experiencia con el abordaje laparoscópico. Sin embargo, la limitada movilidad de los instrumentos y el prolongado tiempo operatorio, hizo que esta cirugía no ganase tanta popularidad. A pesar de que este procedimiento no ganó aceptación general, todavía es realizado en ciertos centros. En 2000, Menon et al.(5) realizaron la primera prostatectomía radical asistida por robot (PRAR) usando el sistema Da Vinci (Intuitive CA, Sunnyvale). Dicho sistema cuenta con muchas características que superaban las limitaciones encontradas con la laparoscopia: imagen tridimensional, instrumentos articulados con seis grados de movimiento, cancelación del tremor, movimiento a escala (1:5) y magnificación de 10 veces. Aunque la prostatectomía radical abierta (PRA) está estandarizada y bien establecida como técnica quirúrgica para pacientes con CaP, el abordaje robótico se ha convertido en el método más común. En Estados Unidos, más del 80% de las prostatectomías radicales 20

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son realizadas usando cirugía robótica(6). La PRAR es una de las operaciones técnicamente más demandantes debido a la cantidad de pasos con que cuenta la cirugía y a las expectativas oncológicas y funcionales (continencia urinaria y potencia). Los resultados, desde el punto de vista oncológico y funcional, son similares a la cirugía abierta con las ventajas de menor sangrado, menor estancia hospitalaria, menor requerimiento de medicinas para el dolor y convalecencia más corta (7)(8)(9)(10). Existen diferentes publicaciones intentando definir la curva de aprendizaje de este procedimiento. Los avances básicos están relacionados a 50 casos. Sin embargo, los resultados quirúrgicos óptimos (continencia, potencia, y márgenes positivos) fueron alcanzados alrededor de los 300 casos; lo que nos demuestra de la complejidad en términos del control del cáncer, anastomosis vesicouretral y disección de las bandeletas neurovasculares(11)(12). Esto acentúa más el hecho de que la PRAR es una cirugía reconstructiva tanto como oncológica(12). Las ventajas en visión y movilidad que ofrece el robot brindan esta posibilidad(13)(14)(15). Debido a la complejidad de la PRAP, se recomienda empezar por pacientes de bajo riesgo antes de progresar a casos de alto riesgo. En cirugía robótica, la ausencia de la sensación táctil hace necesario que los detalles anatómicos sean apreciados muy bien. La experiencia brinda un conocimiento más amplio de la anatomía y planos quirúrgicos que permiten el abordaje de casos más complejos tales como: cáncer de próstata de alto riesgo, prostatomegalia, lóbulos medios de próstata, cirugías prostáticas previas (resección transuretral, vaporización laser, TUNA, Prolive, etc), cirugías intrabdominales y pélvicas previas, problemas de coagulación y obesidad mórbida. Estos últimos casos usualmente se abordan en centros de referencia con alto volumen. Si bien es cierto, la complejidad en estos casos es alta, existen diferentes publicaciones que demuestran buenos resultados(16)(17). Un candidato típico es un paciente con cáncer localizado de próstata (T1/ T2) sin evidencia de metástasis. Existen múltiples

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publicaciones de pacientes de bajo e intermedio riesgo con muy buenos resultados. Sin embargo, 20-30% de los pacientes diagnosticados serán de alto riesgo sin evidencia de metástasis(18). PRAP ha mostrado similares resultados oncológicos incluyendo: rango de márgenes quirúrgicos positivos, recurrencia bioquímica, requerimiento de terapia adyuvante y obtención de nódulos linfáticos cuando se compara con la cirugía abierta en pacientes de alto riesgo (9). Se ha observado que la experiencia y alto volumen de casos son necesarios para alcanzar estos resultados en este tipo de pacientes(6)(9)(19). El número de publicaciones de cirugía robótica en este grupo no es tan amplia pero ha demostrado ser segura y factible con buenos resultados oncológicos a mediano plazo, aceptable morbilidad, y excelente resultados quirúrgicos, patológicos y funcionales (continencia urinaria y potencia sexual)(6)(20). E l manten im iento de la continencia es una causa grande de insatisfacción para los pacientes. Después de remover la próstata, el esfínter interno no existe y la continencia depende del esfínter externo. La preservación del cuello de la vejiga y otras modificaciones han mejorado la rapidez de recuperación y el rango de continencia hasta 90-95% reportado en algunas series(21). La preservación de las bandeletas neurovasculares se ha visto que puede inf luir también en este resultado (22). El mantenimiento de la continencia depende de la cirugía y de ciertas características del paciente como son: edad, obesidad, comorbilidades, continencia urinaria preoperatoria y patología del cáncer.(21)(22)(23)

El efecto de la función eréctil es otra consecuencia relacionada a la cirugía. Se han hecho múltiples investigaciones acerca de la causa, prevención y tratamiento de la disfunción eréctil. En 1982, Walsh et al.(24) presentaron los resultados de su investigación acerca de la inervación en las corporas cavernosas responsables de la erección. En esta investigación, él demostraba que el plexo pélvico usualmente era lesionado durante la disección del ápice y la ligadura de los pedículos prostáticos. Briganti et al.(25), dividieron a los pacientes de acuerdo a los grupos de riesgo (bajo, intermedio y alto) y usó esta clasif icación para comparar la recuperación de la función eréctil. Los resultados demostraron que los pacientes de bajo riesgo tenían una mejor posibilidad de recuperar sus erecciones en comparación a los pacientes de alto riesgo. Gandaglia et al.(26), compararon la prostatectomía radical abierta con PRAR en relación a la disección de las bandeletas neurovasculares. Dicho estudio encontró que los pacientes de riesgo bajo e intermedio tenían un mayor beneficio en el grupo de PRAR. Sin embargo, en los pacientes de riesgo alto, no se encontró diferencia entre ambos grupos. Desde ese estudio, se han realizado investigaciones tratando de mejorar estos resultados en pacientes de alto riesgo. Los pacientes de alto riesgo y con biopsias prostáticas con elevado volumen de cáncer tienen un riesgo mayor a tener enfermedad extra prostática e incrementa el riesgo de márgenes positivos durante la disección de las bandeletas neurovasculares llevando a un control inferior del cáncer. El uso preoperatorio del MRI en

pacientes de alto riesgo ha mostrado una sensibilidad alrededor del 80% en detectar extensión extracapsular (27). Estos resultados han llevado a recomendar su uso a fin de poder planear la cirugía y ofrecer expectativas reales a los pacientes (28)(29). Otros planteamientos han sido enfocados en relación a la disección de las bandeletas neurovasculares: intrafascial vs interfascial. Rifaioglu et al. (30) realizaron un estudio comparativo de ambos métodos en cadáveres. Dicho estudio demostró que la disección intrafascial preserva más fibras simpáticas que la interfascial sin incrementar el riesgo de penetración de la cápsula prostática. Estos enfoques están siempre en relación al grupo de riesgo y patología del cáncer. Patel et al. (31) publicaron su investigación acerca de la disección antégrada o retrógrada de las bandeletas neurovasculares. La disección retrograda mostró tener un mejor rango de recuperación de la erección durante el primer año. Sin embargo, al segundo año no existía diferencia.

"LOS RESULTADOS DEMOSTRARON QUE LOS PACIENTES DE BAJO RIESGO TENÍAN UNA MEJOR POSIBILIDAD DE RECUPERAR SUS ERECCIONES EN COMPARACIÓN A LOS PACIENTES DE ALTO RIESGO"

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"Actualmente si el riesgo es de 3 a 5% dependiendo del normograma se está recomendando hacer una linfadenectomía extendida (incluye obturador, iliaca externa e interna)"

La metástasis a los nódulos linfáticos (+NM) está relacionada a un mal pronóstico. Los pacientes de bajo riesgo, en quienes se realiza linfadenectomía, tienen 1% de probabilidad de +NM. No existe un estudio randomizado que demuestre el beneficio directo de la linfadenectomía en pacientes con cáncer de próstata. Sin embargo, el procedimiento tiene sus riesgos: linfedema, linfocele, sangrado y trombosis venosa profunda. Debido a esto, se han desarrollado normogramas a fin de determinar el riesgo de metástasis linfática y así valorar si vale la pena realizar la linfadenectomía. Actualmente, si el riesgo es de 3 a 5 %, dependiendo del normograma

Bibliografia:

se está recomendando hacer una linfadenectomía extendida (incluye obturador, iliaca externa e interna). Algunos estudios han sugerido ventajas diagnósticas y terapéuticas de la linfadenectomía extendida en pacientes de riesgo intermedio a alto (32)(33)(34). Recientemente se están realizando investigaciones en pacientes con oligometástasis, con la intención de ver si existe algún beneficio en el pronóstico y tratamiento de estos pacientes (35). Cabe destacar que todos estos avances en operar pacientes de alto riesgo, alto volumen de cáncer, oligometástasis, disección inter fascia l vs int ra fascia l, linfadenectomía extendida (35), uso de indocianina para mejorar la

1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015. http://www.cancer.org/acs/ groups/content/@editorial/documents/document/acspc-044552. pdf. Accessed May 28, 2015. 2. Cooperberg MR, Broering JM, Kantoff PW, et al. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol. 2007;178(3 pt 2):S14-S19. 3. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–74. 4. Schuessler WW, Schulam PG, Clayman RV, et al. Laparoscopic radical prostatectomy: initial short-term experience. Urology. 1997;50(6):854-857. 5. Menon M, Shrivastava A, Tewari A, et al. Laparoscopic and robot assisted radical prostatectomy: establishment of a structured program and preliminary analysis of outcomes. J Urol. 2002;168(3):945-949.

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disección de las bandeletas y nódulos linfáticos (36) fue promovido posterior al desarrollo de la cirugía robótica. En Puerto Rico, el primer caso se realizó en diciembre del 2007. Desde entonces se viene realizando con regularidad. Tenemos uno de los volúmenes quirúrgicos más grandes en Suramérica, Centroamérica, Caribe y Canadá. Sin duda, esta tecnología -asociada a nuestra experiencia- nos ha permitido su uso en otros tipos de cirugía oncológica y reconstructiva relacionada con urología. Los límites de sus aplicaciones se han estado expandiendo cada día más y solo el tiempo dirá hasta donde llegaremos.

6. Parsons JK, Messer K, Palazzi K ,et al. Diffusion of surgical innovations, patient safety, and minimally invasive radical prostatectomy [Erratum appears in JAMA Surg. 2014;149(9):961]. JAMA Surg. 2014;149(8):845-851. 7. Ficarra V, Novara G, Artibani W, Cestari A, Galfano A, et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol. 2009;55:1037–63. 8. Ficarra V, Novara G, Fracalanza S, D’Elia C, Secco S, et al. A prospective, nonrandomized trial comparing robot-assisted laparoscopic and retropubic radical prostatectomy in one European institution. BJU Int. 2009;104:534–9. 9. Tewari A, Srivasatava A, Menon M. Members of the VIP Team. A prospective comparison of radical retropubic and robotassisted prostatectomy: experience in one institution. BJU Int. 2003;92:205–10. 10. Agarwal PK, Sammon J, Bhandari A, Dabaja A, Diaz M, et al. Safety profile of robotassisted radical prostatectomy: a standardized report of complications in 3317 patients. Eur Urol.

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2011;59:684–98. 11. Lavery HJ, Samadi DB, Albala D, Ahlering T, Tewari A, Costello AJ, Patel VR, et al. The advances learning curve in robotic prostatectomy: a multi-institutional survey. J Robot Surg. 2009 Oct; 3(3):165. 12. Sooriakumaran P1, John M, Wiklund P, Lee D, Nilsson A, Tewari AK, et al. Learning curve for robotic assisted laparoscopic prostatectomy: a multi-intitutional study of 1794 patients. Minerva Urol Nefrol. 2011 Sep;63(3):191-8. 13. Simone G, Papalia R, Ferriero M, Guaglianone S, Gallucci M. Laparoscopic “single knot-single running” suture vesico-urethral anastomosis with posterior musculofascial reconstruction. World J Urol. 2012;30:651–7. 14. Joshi N, de Blok W, van Muilekom E, van der Poel H. Impact of posterior musculofascial reconstruction on early continence after robot-assisted laparoscopic radical prostatectomy: results of a prospective parallel group trial. Eur Urol. 2010;58:84-9. 15. Ficarra V, Gan M, Borghesi M, Zattoni F, Mottrie A. Posterior muscolofascial reconstruction incorporated into urethrovescical anastomosis during robot-assisted radical prostatectomy. J Endourol. 2012;26:1542–5. 16. Canda E, Balbay D. Robotic radical prostatectomy in high-risk prostate cancer current perspectives. Asian J Androl.2015. NovDec;17(6):908-15. 17. Stroup SP, Kane CJ. Robotic-assisted laparoscopic prostatectomy for high-risk prostate cancer: technical considerations and review of the literature. ISRN Urol 2011. 2011 201408. 18. Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol. 2008;26:211–8. 19. Gautum Agarwal, Oscar Valderrama, Adam M. Luchey, and Julio M. Pow-Sang, Robotic-Assisted Laparoscopic Radical Prostatectomy, Cancer Control July 2015;22(3):283-90. 20. Stroup SP, Kane CJ. Robotic-assisted laparoscopic prostatectomy for high-risk prostate cancer: technical considerations and review of the literature. ISRN Urol 2011. 2011 201408. 21. Ficarra V, Novara G, Rosen RC, et al. Systematic review and meta- analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol. 2012;62(3):405-417. 22. Suardi N, Moschini M, Gallina A, et al. Nerve-sparing approach during radical prostatectomy is strongly associated with the rate of postoperative urinary continence recovery. BJU Int. 2013;111(5):717722. 23. Kawachi MH. Counterpoint: robot-assisted laparoscopic prostatectomy: perhaps the surgical gold standard for prostate cancer care. J Natl Compr Canc Netw. 2007;5:689- 92. 24. Walsh PC, Donker PJ. Impotence following radical

prostatectomy: insight into etiology and prevention. J Urol. 1982;128(3):492-497. 25. Briganti A, Gallina A, Suardi N, et al. Predicting erectile function recovery after bilateral nerve sparing radical prostatectomy: a proposal of a novel preoperative risk stratification. J Sex Med. 2010;7(7):2521-2531. 26. Gandaglia G, Suardi N, Gallina A, et al. How to optimize patient selection for robotassisted radical prostatectomy: functional outcome analyses from a tertiary referral center. J Endourol. 2014;28(7):792-800. 27. Park BH, Jeon HG, Choo SH, et al. Role of multiparametric 3.0 tesla magnetic resonance imaging in prostate cancer patients eligible for active surveillance. BJU Int. 2014;113(6):864-70. 28. Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, et al. ESUR prostate MR guidelines 2012. Eur Radiol. 2012;22:746–57. 29. Villeirs GM, De Meerleer GO, De Visschere PJ, Fonteyne VH, Verbaeys AC, et al. Combined magnetic resonance imaging and spectroscopy in the assessment of high grade prostate carcinoma in patients with elevated PSA: a single-institution experience of 356 patients. Eur J Radiol. 2011;77:340–5. 30. Rifaioglu MM, Davarci M, Ozgur T, et al. Histopathologic evaluation of neurovascular bundles and periprostatic tissue in interfascial and intrafascial nervesparing radical prostatectomy technique: a cadaveric anatomic study. Urology. 2013;82(4):94854. 31. Coughlin G, Dangle PP, Palmer KJ, Samevedi S, Patel VR. Athermal early retrograde release of the neurovascular bundle during nerve-sparing robotic-assisted laparoscopic radical prostatectomy. J Robot Surg. 2009 Mar;3(1):13-7. 32. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, et al. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology. 2001;58:843–8. 33. Abdollah F, Schmitges J, Sun M, Tian Z, Briganti A, et al. A critical assessment of the value of lymph node dissection at radical prostatectomy: a population-based study. Prostate. 2011;71:1587– 94. 34. Schiavina R, Manferrari F, Garofalo M, Bertaccini A, Vagnoni V, et al. The extent of pelvic lymph node dissection correlates with the biochemical recurrence rate in patients with intermediate- and high-risk prostate cancer. BJU Int. 2011;108:1262–8. 35. Gakis G, Boorjian SA, Briganti A, Joniau S, Karazanashvili G, et al. The role of radical prostatectomy and lymph node dissection in lymph node-positive prostate cancer: a systematic review of the literature. Eur Urol. 2014 Aug;66(2):191-9. 36. Chennamsetty A, Zhumkhawala A, Tobis SB, Ruel N3, et al. Lymph Node. Fluorescence During Robot-Assisted Radical Prostatectomy With Indocyanine Green: Prospective Dosing Analysis. Clin Genitourin Cancer. 2017 Aug;15(4):529-34.

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NOW APPROVED Approved in 2012 for adults with moderate to severe RA1

INDICATIONS Rheumatoid Arthritis • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Psoriatic Arthritis • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. IMPORTANT SAFETY INFORMATION BOXED WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR 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. If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/ XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

FOR ADULTS WITH

ACTIVE PsA1 Visit XELJANZPsAHCP.com.

The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus–associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. WARNINGS AND PRECAUTIONS SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ/XELJANZ XR in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including BOXED WARNING, on the following pages.

XELJANZ DELIVERED RAPID RELIEF AS EARLY AS WEEK 2 AND POWERFUL EFFICACY AT MONTH 3. RESPONSES WERE SUSTAINED AT MONTH 6 AND OUT TO YEAR 11-4 OPAL Clinical Program Description1-4 All patients in the Oral Psoriatic Arthritis TriaL (OPAL) Clinical Program had active PsA for ≥6 months based on the CASPAR, ≥3 tender/painful joints and ≥3 swollen joints, and active plaque psoriasis. Across all treatment arms, patients were required to receive a stable dose of one csDMARD throughout the studies. In both clinical trials, the primary endpoints were ACR20 response rate and change from baseline in HAQ-DI score at month 3. To control for type I error at the 5% level for primary and certain secondary endpoints, statistical testing was performed for XELJANZ 10 mg BID arm, then XELJANZ 5 mg BID arm vs placebo arm, in a hierarchical sequence. Testing stopped at any point in a ﬁxed sequence wherever statistical signiﬁcance was not reached. The testing hierarchy was ACR20 response rate, change from baseline in HAQ-DI score, PASI75 response rate, change from baseline in LEI score, change from baseline in DSS, change from baseline in SF-36 score, and change from baseline in FACIT-F total score at month 3. For the family of ACR response rates at month 3, the separate hierarchy was ACR20, ACR50, and ACR70. For the ACR20 response rates at each trial visit, the separate hierarchy was month 3, 2, 1, and week 2. Nonresponder imputation was applied to missing data for ACR response rates. Mixed model for repeated measures was used without imputation for missing values for change from baseline in HAQ-DI score, LEI score, DSS, SF-36 score, or FACIT-F total score.

OPAL Beyond (Study PsA-II) in TNFi-IR Patients1-3,a

*P≤0.05 vs placebo

ACR20 response rate (% of patients)†

100 Placebo-controlled period 80

60%

50%*

(n=78)

(n=65)

50%

27%*

(n=33)

(n=35)

24%

A 6-month, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in which 394 adult patients with active PsA who had inadequate response to at least one TNFi received either XELJANZ 5 mg BID, 10 mg BID, or placebo. At month 3, all patients randomized to placebo were advanced to XELJANZ 5 mg BID or 10 mg BID in a blinded manner based on their initial randomization sequence. Across all treatment arms, all patients were required to receive a stable dose of one conventional synthetic disease-modifying antirheumatic drug (csDMARD, also known as a nonbiologic DMARD, which included methotrexate, sulfasalazine, and leﬂunomide). Stable low-dose oral glucocorticoids allowed.

Placebo + csDMARD (N=131) to XELJANZ 5 mg BID + csDMARD (N=66)

All patients on placebo advanced to XELJANZ at month 3.1

(n=31)

13%

OPAL Beyond (Study PsA-II)1-3

XELJANZ 5 mg BID + csDMARD (N=131)

(n=17)

Week 2 1

Month 3 Primary endpoint

All other time points measured were secondary endpoints. n at each time point=number of patients who achieved an ACR20 response.

†

OPAL Broaden (Study PsA-I) in csDMARD-IR (Nonbiologic DMARD-IR), TNFi-Naïve Patients1,3,4,a Study PsA-I was not designed to demonstrate noninferiority or superiority of XELJANZ to Humira® (adalimumab).1 *P≤0.05 vs placebo **P≤0.05 vs placebo, nominalb

ACR20 response rate (% of patients)†

100 Placebo-controlled period

68% 67%

(n=73)

52%**

22%* 22%**

60%

50%*

(n=24)

(n=64)

(n=54)

33%

(n=23)

(n=35)

(n=55)

All patients on placebo advanced to XELJANZ at month 3.1

(n=35)

0 1

Month 3 Primary endpoint

Placebo + csDMARD (N=105) to XELJANZ 5 mg BID + csDMARD (N=52) Humira® 40 mg s.c. q 2 wk + csDMARD (N=106)

(n=6)

Week 2

XELJANZ 5 mg BID + csDMARD (N=107)

All other time points measured were secondary endpoints.

OPAL Broaden (Study PsA-I)1,3,4 A 12-month, randomized, double-blind, double-dummy, active-controlled, placebocontrolled, multicenter, phase 3 trial in which 422 adult patients with active PsA who had inadequate response to at least one csDMARD and were TNFi-naïve received either XELJANZ 5 mg BID, 10 mg BID, Humira® 40 mg s.c. q 2 wk, or placebo. At month 3, all patients randomized to placebo were advanced to XELJANZ 5 mg BID or 10 mg BID in a blinded manner based on their initial randomization sequence. Across all treatment arms, all patients were required to receive a stable dose of one csDMARD (also known as nonbiologic DMARD, which included methotrexate, sulfasalazine, and leﬂunomide). Stable low-dose oral glucocorticoids allowed. Study PsA-I was not designed to demonstrate noninferiority or superiority of XELJANZ to Humira®.

n at each time point=number of patients who achieved an ACR20 response.

†

a b

Nonresponder imputation was applied to missing sign/symptom data.1,2,4 Nominal P values not adjusted for multiplicity.3 ACR20 response is defined as an improvement of 20% or more from baseline in the number of tender/painful and swollen joints and in at least 3 of the following domains: Patient’s Global Assessment of arthritis, Physician’s Global Assessment of arthritis, Patient’s Assessment of Arthritis Pain, disability as measured by the HAQ-DI, or hsCRP level.2,4 ACR=American College of Rheumatology; BID=twice daily; CASPAR=Classification Criteria for Psoriatic Arthritis; csDMARD=conventional synthetic disease-modifying antirheumatic drug; DMARD=disease-modifying antirheumatic drug; DSS=Dactylitis Severity Score; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI=Health Assessment Questionnaire-Disability Index; hsCRP=high-sensitivity C-reactive protein; IR=inadequate responder; LEI=Leeds Enthesitis Index; PASI=psoriasis area and severity index; PsA=psoriatic arthritis; q 2 wk=every 2 weeks; RA=rheumatoid arthritis; s.c.=subcutaneously; SF-36=Medical Outcomes Study 36-Item Short-Form Health Survey; TNFi=tumor necrosis factor inhibitor. The recommended dose of XELJANZ is 5 mg twice daily or XELJANZ XR 11mg once daily used in combination with nonbiologic DMARDs. The efficacy of XELJANZ/XELJANZ XR as a monotherapy has not been studied in psoriatic arthritis.1 XELJANZ XR 11 mg administered once daily is pharmacokinetically equivalent to XELJANZ 5 mg administered twice daily. The recommended dose in patients with moderate to severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily.1 Humira is a registered trademark of AbbVie Inc.

IMPORTANT SAFETY INFORMATION (cont’d) Tuberculosis Evaluate and test patients for latent or active infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Consider anti-TB therapy prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was observed in clinical studies with XELJANZ. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea. MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. In the 7 controlled rheumatoid arthritis clinical studies, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. In Phase 2B controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus–associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine. Other malignancies were observed in clinical studies and the post-marketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). LABORATORY ABNORMALITIES Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at 1 month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/ XELJANZ XR treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/ XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Anemia Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/ XELJANZ XR should be interrupted until this diagnosis has been excluded. Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ/ XELJANZ XR therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia. VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. A varicella virus naïve patient experienced dissemination of the vaccine strain of varicella zoster virus 16 days after vaccination with live attenuated virus vaccine which was 2 days after 5 mg twice daily treatment with tofacitinib. The patient recovered after discontinuation of tofacitinib and treatment with antiviral medication. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy. GENERAL Specific to XELJANZ XR Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation. HEPATIC and RENAL IMPAIRMENT Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. The recommended dose in patients with moderate hepatic impairment or with moderate or severe renal impairment is XELJANZ 5 mg once daily. ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%). USE IN PREGNANCY There are no adequate and well-controlled studies in pregnant women and the estimated background risks of major birth defects and miscarriage for the indicated population is unknown. Based on animal studies, tofacitinib has the potential to affect a developing fetus. Women of reproductive potential should be advised to use effective contraception.

Please see additional Important Safety Information on the previous pages, and brief summary of full Prescribing Information, including BOXED WARNING, on the following pages. References: 1. XELJANZ/XELJANZ XR [prescribing information]. New York, NY: Pfizer Inc; December 2017. 2. Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377(16):1525-1536. 3. Data on file. Pfizer Inc, New York, NY. 4. Mease P, Hall S, FitzGerald O, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537-1550. PP-XEL-USA-2979-01 All rights reserved. © 2018 Pfizer Inc. Printed in USA/January 2018 Humira is a registered trademark of AbbVie Inc.

XELJANZ® (tofacitinib)/XELJANZ® XR (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ/XELJANZ XR 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. If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. The risks and beneﬁts of treatment with XELJANZ/XELJANZ XR should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. INDICATIONS AND USAGE Rheumatoid Arthritis • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. Psoriatic Arthritis • XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and beneﬁts of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/ XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/ XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Tuberculosis Patients should be evaluated and tested for latent or active

infection prior to and per applicable guidelines during administration of XELJANZ/XELJANZ XR. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR 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 who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea. Malignancy and Lymphoproliferative Disorders Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine. Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. Laboratory Abnormalities Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter. Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/ XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/ mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Anemia Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded. Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy. Manage patients according to clinical guidelines [e.g., National

Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Vaccinations Avoid use of live vaccines concurrently with XELJANZ/ XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy. General Specific to XELJANZ XR As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation. ADVERSE REACTIONS Clinical Trial 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 predict the rates observed in a broader patient population in clinical practice. Rheumatoid Arthritis The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. The most common serious adverse reactions were serious infections. The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients. Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days). Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days). Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients

who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% conﬁdence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% conﬁdence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (some fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspeciﬁed (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema

Laboratory Abnormalities Lymphopenia In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure. Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Neutropenia In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections. In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials. Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes. In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups. In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy. Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm. • Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm. • Mean LDL/HDL ratios were essentially unchanged in XELJANZtreated patients. In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy. In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials. Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Clinical Experience in Methotrexate-Naïve Patients Study VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies I-V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA). Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF-inhibitor (TNFi). Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNFi. This clinical trial included a 3-month placebo controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline. The safety proﬁle observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety proﬁle observed in rheumatoid arthritis patients.

Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0-3 months) and at Least 1% Greater Than That Observed in Rheumatoid Arthritis Patients on Placebo XELJANZ 5 mg Twice Daily

XELJANZ 10 mg Twice Daily*

Placebo

N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Diarrhea

4.0

2.9

2.3

Nasopharyngitis

3.8

2.8

Upper respiratory tract infection

4.5

3.8

3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

Preferred Term

N reﬂects randomized and treated patients from the seven clinical trials *The recommended dose of XELJANZ is 5 mg twice daily.

DRUG INTERACTIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib). Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., ﬂuconazole). Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin). Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ/XELJANZ XR with potent immunosuppressants has not been studied in rheumatoid arthritis and psoriatic arthritis. Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended. USE IN SPECIFIC POPULATIONS All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib). Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/ XELJANZ XR during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972. Risk Summary There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use in pregnant women. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. The background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively. Based on animal studies, XELJANZ/XELJANZ XR has the potential to affect a developing fetus. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg once daily, respectively. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg twice daily. Data Human Data In the tofacitinib clinical development programs, birth defects and miscarriages were reported. Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/ day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, ﬁbula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/ day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats). Lactation Risk Summary It is not known whether tofacitinib is excreted in human milk. Additionally, there are no data to assess the effects of the drug on the breastfed child. However, tofacitinib is excreted in rat milk at concentrations higher than in maternal serum. Women should not breastfeed while treated with XELJANZ/XELJANZ XR. A decision should be made whether to discontinue breastfeeding or to discontinue XELJANZ/XELJANZ XR. Data Human Data There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use during breastfeeding. Animal Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured. Females and Males of Reproductive Potential Contraception Females Embryofetal toxicity including malformations occurred in embryofetal development studies in rats and rabbits. Females of reproductive potential should be advised to use effective contraception during treatment with XELJANZ/XELJANZ XR and for at least 4 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with XELJANZ/XELJANZ XR. Infertility Females Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential. Pediatric Use The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established. Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. Use in Diabetics As there is higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes. Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions, therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate hepatic impairment. XELJANZ/ XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology. Renal Impairment XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ/XELJANZ XR was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockcroft-Gault equation) less than 40 mL/ min (or in patients with active psoriatic arthritis with creatinine clearance values less than 50 mL/min). No dose adjustment is required in patients with mild renal impairment. OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ/XELJANZ XR. Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours. There is no specific antidote for overdose with XELJANZ/XELJANZ XR. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment. This brief summary is based on XELJANZ®/XELJANZ® XR (tofacitinib) Prescribing Information LAB-0445-12.0 Issued: December 2017

December 2017

ESFORZÁNDONOS PARA VENCER EL CÁNCER. JUNTOS.

En AbbVie, creamos vínculos con oncólogos, pacientes, pagadores, grupos de apoyo, autoridades de salud y otras compañías farmacéuticas, porque sabemos que adelantar el conocimiento científico sobre esta enfermedad tan impactante no es algo que una persona, ni una compañía, pueden hacer por sí solas. Juntos podemos llevar a cabo investigaciones que amplíen nuestro conocimiento de la enfermedad y sus mecanismos, para desarrollar moléculas nuevas que impacten significativamente el tratamiento del cáncer.

CONOZCA MÁS ACERCA DE LOS VÍNCULOS QUE ESTAMOS CREANDO EN WWW.ABBVIE.COM personas. pasión. posibilidades.

Palabras clave: Mastectomía total con preservación del complejo pezón/areola, cáncer de seno, reconstrucción de seno Metamorfosis, Sandra Reyes

Key Words: Nipple sparing mastectomy, breast cancer, breast reconstruction

MSP ARTÍCULO DE REVISIÓN

Cirugía moderna

para el

cáncer de mama

Por: Bolívar Arboleda Osorio, MD, FACS Presidente de la Sociedad Puertorriqueña de Senología Pasado Presidente del Colegio Americano de Cirujanos capítulo de PR Director del HIMA San Pablo Breast Institute/ Oncológico, Caguas Profesor Asociado de Cirugía de la Universidad Central del Caribe

Coautora: Diana Avilés Castillo, MD Cirugía plástica reconstructiva Board Certified American Association of Plastic Surgery

Resumen: La mastectomía total con preservación del complejo pezón/areola ha adquirido más visibilidad entre las opciones quirúrgicas para el tratamiento del cáncer de mama. Las pacientes óptimas para este procedimiento deben ser escogidas con cuidado, es decir pacientes con tumores pequeños limitados a un cuadrante del seno sin envolvimiento de la piel o el pezón y con poca o ninguna ptosis. Las complicaciones de dicho procedimiento pueden ser ligeramente superiores a otras cirugías conservadoras de mama y la tasa de necrosis del pezón ha ido en disminución gracias al uso de los avances tecnológicos disponibles. En los casos apropiados la tasa de recurrencia local debe ser aceptablemente baja.

Summary: Nipple Sparing Mastectomy (NSM) has become more common among the surgical options for the treatment of early stage breast cancer. Patients for this procedure should be selected with care, mostly patients with smaller tumors limited to one quadrant of the breast, without involvement of the breast skin or nipple and with no or very little ptosis. Complications for this procedure could be slightly more than other breast conserving surgeries but the rate of nipple necrosis has been steadily decreasing when the appropriate technological advances are utilized. The rate of nipple necrosis should be acceptably low.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

Figura 1

l cáncer de mama es una de las afecciones oncológicas más comunes en la mujer (1, 2) . Al descubrirse en etapas tempranas este terrible mal puede tratarse con excelentes resultados(3). La terapia principal de este tumor se basa en la remoción quirúrgica del mismo, acompañada de otras opciones terapéuticas como la hormonoterapia, quimioterapia y la radioterapia en los casos apropiados. Dentro de las alternativas quirúrgicas se han utilizado desde las opciones más antiguas como la mastectomía radical y la radical modificada(4,5), la mastectomía parcial con biopsia de los nódulos centinela(6,7), mastectomía total con reconstrucción inmediata, y, en algunos casos selectos mastectomía total con preservación del complejo pezón/areola (NSM por sus siglas en inglésNipple Sparing Mastectomy) y reconstrucción inmediata (8,9) . Esta última opción ha tomado tracción en el ámbito quirúrgico dedicado a estos tratamientos y en este artículo describiremos la historia, técnica, indicaciones y resultados esperados de la misma. Historia: La mastectomía radical se practicó como el estándar del tratamiento quirúrgico del cáncer de mama desde su incepción al final del siglo XIX por Halstead hasta mediados del siglo XX(4). Luego Patey describe la mastectomía radical modificada, eventualmente demostrando una recurrencia local de 10% a los diez años, comparable con la mastectomía radical 32

Revista Puertorriqueña de Medicina y Salúd Pública

y con menor morbilidad (5, 10). La mastectomía total con preservación del complejo pezón/areola (Nipple Sparing Mastectomy) fue descrita por primera vez por Hinton en el 1984(9). Lagios et al describen en su estudio en 1979, la incidencia de la afección del complejo pezón/areola, similar a la incidencia del envolvimiento de la piel de la mama en cualquier otro lugar, lo cual establece los parámetros potenciales para el éxito de esta operación(11). Técnica oncológica: Se han descrito varias técnicas para realizar esta operación, siendo las más comunes la incisión periareolar con extensión lateral (incisión omega), la incisión a través del pezón-areola con o sin extensiones, y la incisión en el surco infra-mamario con extensión lateral. Nuestra preferida es la incisión omega, seguida por la del surco infra-mamario. Estas incisiones permiten dividir el tejido mamario en su totalidad, acompañadas por la incisión axilar provista para la remoción de los nódulos centinela. Durante el período perioperatorio utilizamos preferentemente la técnica de tecnecio-99m para la detección de los nódulos centinela y tratamos de evitar el inyectar tinte azul en el seno durante la operación para facilitar la disección del tejido mamario. En ocasiones utilizamos la técnica de disección reversa de los ganglios axilares, inyectando el brazo ipsilateral en lugar de la mama, y así evitamos los ganglios que han acumulado tinte azul (12). Más recientemente, se ha promulgado el uso de otras tecnologías para la

MSP ARTÍCULO DE REVISIÓN

"ACTUALMENTE EN PUERTO RICO LA RECONSTRUCCIÓN EN DOS FASES ES LA MÁS COMÚN, AUNQUE EN ESTADOS UNIDOS Y EN EUROPA SE HA VUELTO MÁS POPULAR HACERLO EN UNA FASE"

detección de nódulos centinela tales como verde de indocianina con fluorescencia y emulsión de óxido de hierro, pero estas técnicas todavía no se han establecido como estándar. Una vez realizadas las incisiones hacemos disección utilizando el electrocauterio en el plano inferior a tejido subcutáneo, separándolo del tejido glandular en propiedad. Una vez llegamos al área del complejo pezón/areola nos separamos a un plano más profundo por unos 3-4 milímetros; luego tomamos el tejido retroareolar que hemos dejado atrás y lo removemos con una pinza hasta el nivel subdermal. Ese tejido es separado para análisis patológico como el margen del pezón. Este margen puede ser analizado por el patólogo mediante un corte por congelación para determinar si es recomendable remover el pezón o no. En algunos casos podemos revisar la circulación de los colgajos mamarios utilizando inmuno-f luorescencia con verde indocianina y una cámara especializada para ese propósito(13). La cirugía entonces prosigue en forma convencional en cuanto a disecar la mama de la fascia pectoral y removerla. Luego prosigue la fase reconstructiva. Reconstrucción: Existen varias maneras de reconstruir el seno y el uso de cada una de las técnicas depende de las características de la paciente y el tipo de cáncer. Entre las opciones disponibles, tenemos la reconstrucción a base de implantes o el uso de colgajos de abdomen (TRAM flap) o espalda (Latissimus flap). Actualmente en Puerto Rico y en Estados Unidos, la mayoría de la reconstrucciones mamarias se hacen a base de implantes ya que esta es la forma más sencilla, con menos riesgos y dado a los avances en las técnicas podemos lograr un resultado muy natural(14). La reconstrucción mamaria con implantes se puede hacer de forma inmediata se comienza el mismo día de la mastectomía, o de forma dilatada, luego de que la paciente complete su tratamiento para el cáncer. La reconstrucción mamaria

se puede hacer en una o dos fases dependiendo del tumor, el tamaño del seno, historial de radiación, y la meta de tamaño que queremos lograr. En el caso de la cirugía de preservación del pezón como se mantiene toda la piel podemos hacer la reconstrucción de forma inmediata e incluso la podemos hacer en una sola fase si las características de la paciente son favorables(15). Técnica reconstructiva: Una vez el cirujano general saca todo el tejido mamario y los nódulos apropiados de la axila, el cirujano plástico procede con la reconstrucción mamaria. Actualmente en Puerto Rico la reconstrucción en dos fases es la más común, aunque en Estados Unidos y en Europa se ha vuelto más popular hacerlo en una fase. La reconstrucción en dos fases conlleva poner un expansor de tejido posterior al músculo pectoral y una malla de tejido dermal acelular (ADM- Acellular Dermal Matrix) en la parte inferior al músculo para cubrir por completo el polo inferior del implante(16). Esta malla proviene de un banco de tejido cadavérico humano que ha sido procesado para removerle todas sus propiedades antigénicas y nos provee un andamio para el crecimiento de tejido nuevo en un área que está deficiente de tejido(17). El ADM nos permite llenar el implante más rápido, disminuir el riesgo de contracción capsular y lograr un seno con una apariencia más natural(18 , 19). Una vez ponemos el expansor de tejido, éste se llena poco a poco en la clínica con agua salina hasta llegar al tamaño deseado. Luego procedemos con la segunda cirugía en la cual sacamos el expansor de tejido y ponemos un implante permanente, ya sea de silicona o salina. En la técnica de una sola fase, al momento de la mastectomía, se pone el implante de silicona anterior o posterior al músculo. El uso de la malla ADM es bien importante en estos casos ya que disminuye el riesgo de una mala posición del implante, nos permite poner más volumen y nos da mejor cobertura para que el implante no quede justo debajo de la piel. En la reconstrucción de la mama los implantes mamarios que más se favorecen Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

son los de silicona ya que mantienen mejor la forma, se sienten más natural y tienen menor incidencia de ondulaciones visible a través de la piel. Los implantes de silicona que tenemos hoy día están compuestos por distintos tipos de silicona que varían de acuerdo a su cohesividad. El más reciente que tenemos en el mercado es el llamado “Gummy Bear Implant” que está compuesto por un gel de silicona con alto grado de cohesividad. Por lo tanto, este implante mantiene su forma y si se rompe, no se riega el material. En el caso de que la paciente tenga un seno pequeño a moderado, con poca o ninguna caída y desee mantener su seno

del mismo tamaño o más pequeño podemos hacer la reconstrucción en una fase poniendo un implante permanente y una malla al momento de la mastectomía. El uso de las mallas nos ha permitido, incluso, poner el implante anterior al musculo lo cual disminuye el tiempo operatorio, el dolor postoperatorio y el riesgo de animación del implante debido al movimiento del pectoral. Esta nueva modalidad de poner el implante anterior al músculo requiere el uso de dos mallas, lo cual aumenta significativamente el costo de la cirugía y por lo tanto aún no ha sido bien acogida en Puerto Rico.

Preop foto

Con expansor puesto

3 meses post implante final

Reemplazando el expansor por el implante final

Implante final y reconstrucción contra-lateral

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

"La mastectomía con preservación del complejo pezón/areola debe reservarse para casos donde el tumor sea pequeño en relación al volumen del seno, tumores que no estén directamente relacionados con el pezón y que no tengan envolvimiento directo de la piel de la mama"

Indicaciones: La indicación para este tipo de cirugía debe seguir los mismos cánones que cualquier otro tipo de intervención oncológic. Es decir, no violentar la seguridad de la resección del tumor en aras de la recuperación. Claro está que siendo una técnica relativamente nueva antes de llegar a ser la técnica de elección para este tipo de cirugía. Al presente no existen criterios claros en cuanto a qué paciente debe ofrecerse esta alternativa. Como guía general, la mastectomía con preservación del complejo pezón/areola (NSM) debe reservarse para casos donde el tumor sea pequeño en relación al volumen del seno, tumores que no estén directamente relacionados con el pezón y que no tengan envolvimiento directo de la piel de la mama, y casos de resección profiláctica incluyendo aquellas pacientes BRCA positivas(20). De esta manera, aseguramos preservar el margen quirúrgico adecuado. El uso del MRI de la mama nos ayuda a elegir estos casos, ya que puede definir mejor la extensión del tumor a áreas aledañas al pezón, a pesar de un examen clínico negativo. Otras contraindicaciones a este procedimiento son la enfermedad de Paget del pezón, escleroderma y ptosis severa del seno. En nuestra práctica particular hemos limitado la mastectomía con preservación del complejo pezón/areola (NSM) a pacientes no fumadoras con estadios tempranos (estadio 0, 1, 2-A y algunos 2-B). En adición, el tumor debe estar a 1.0 cm del pezón o más y la enfermedad debe estar limitada a un solo cuadrante del seno. Reconocemos que las indicaciones y selección de la paciente siguen en aumento(21) pero

hemos decidido tomar un derrotero cautelar en lo que se establecen criterios específicos para este procedimiento. El American Society of Breast Surgeons está llevando a cabo un registro de pacientes que han recibido una mastectomía con preservación del complejo pezón/ areola (NSM) y a mayo 15 de 2018 ya se acercaba al dintel de matrícula de 2,000 casos. Probablemente para el próximo año esta data ya esté lista para la publicación La Sociedad Puertorriqueña de Senología también se dispone a preparar una guía general en este aspecto. Resultados esperados: Sin duda alguna, el primer resultado esperado es obtener una tasa de recurrencia similar a los procedimientos establecidos, a saber la mastectomía parcial con escisión de nódulo centinela o la mastectomía radical modificada con reconstrucción. La revisión de literatura de Headon et al y De La Cruz et al demuestra que este nivel de éxito es posible(22, 23). Esta revisión incluyó 73 estudios que representan 12,358 procedimientos en 10,935 pacientes. Las indicaciones incluyeron carcinomas invasivos, carcinoma in situ, y cirugías profilácticas. La media de seguimiento fue de 38.3 meses. El análisis conjunto demostró una tasa de recurrencia local de 2.38%. La tasa de complicaciones generales fue de 22% y la de necrosis del pezón fue de 5.9%. Si miramos las tasas comparando los estudios publicados antes del 2013 y los posteriores a ese año, vemos que la tasa de complicaciones y de necrosis ha ido disminuyendo con el paso del tiempo y al adquirir más experiencia en este procedimiento. (ver figura #2) En los años venideros veremos un aumento en este tipo de procedimientos aquí en Puerto Rico.

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Referencias: 1. https://www.cdc.gov/cancer/breast/statistics/index.htm 2.http://w w w.estadisticas.gobierno.pr/iepr/LinkClick. aspx?fileticket=XNd4xX_dMjg%3D&tabid=186 3 . h t t p s : // w w 5 . k o m e n . o r g / B r e a s t C a n c e r / ChancesForSurvivalBasedOnCancerStage.html 4. Halstead, WS. The results of radical operations for the cure of cancer of the breast. Trans Am Surg Assoc. 1907;25:61–79. 5. Madden JL et al. Modified radical mastectomy. Ann Surg. 1972 May; 175(5):624-34. 6. Veronesi U. Conservative treatment of breast cancer: a trial in progress at the Cancer Institute of Milan. World J Surg. 1977 May; 1(3):324-6. 7. Giuliano AE et al. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994 Sep; 220(3):391-8; discussion 398-401. 8. Gerber B et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study. Ann Surg. 2009 Mar; 249(3):461-8. 9. Hinton CP et al. Subcutaneous mastectomy for primary operable breast cancer. Br J Surg. 1984 Jun; 71(6):469-72. 10. Handley RS et al. Conservative Radical Mastectomy (Patey's Operation) Annals of Surgery: December 1969 - Volume 170 - Issue 6 - ppg 880-882 11. Michael D. Lagios, MD et al. A guide to the frequency of nipple involvement in breast cancer Am Journal of Surg - July 1979Volume 138, Issue 1, Pages 135–142 12. V. Suzanne Klimberg Axillary Reverse Mapping Plastic Surgery Key (search engine) https://plasticsurgerykey. com/axillary-reverse-mapping/ 13. Jones GE et al. Fluorescent intraoperative tissue angiography for the evaluation of the viability of pedicled TRAM flaps. Plast Reconstr Surg 2010; 124(4S):53 36

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14. Colwell AS et al. Breast reconstruction following nipplesparing mastectomy: predictors of complications, reconstruction outcomes, and 5-year trends. Plast Reconstr Surg. 2014;133:496– 506. 15. Colwell AS et al. Retrospective review of 331 consecutive immediate single-stage implant reconstructions with acellular dermal matrix: indications, complications, trends, and costs. Plast Reconstr Surg. 2011;128:1170–1178. 16. Colen,S.R. Immediate two-stage breast reconstruction utilizing a tissue expander and implant. In S. L. Spear (Ed.), Surgery of the Breast: Principles and Art, 1st Ed. Philadelphia: Lippincott-Raven, 1998. 17. Spear SL, Parikh PM, Menon NG. Acellular dermis assisted breast reconstruction. In: Spear SL, ed. Surgery of the Breast: Principles and Art. Philadelphia: Lippincott Williams & Wilkins; 2011: 406-411. 18. Weichman KE et al. The use of acellular dermal matrix in immediate two-stage tissue expander based reconstruction. Plast Reconstr Surg. 2012; 129: 1049-1058 19. Breuing KH, Colwell AS. Inferolateral AlloDerm hammock for implant coverage in breast reconstruction. Ann Plast Surg. 2007;59:250–255 20. Jakub JW, et al. Oncologic Safety of Prophylactic NippleSparing Mastectomy in a Population With BRCA Mutations: A Multi-institutional Study. JAMA Surg. 2018;153(2):123. 21. Niemeyera M et al. Nipple-Sparing Mastectomy - Extended Indications and Limitation Breast Care Journal, v.5(4); 2010 Aug 22. HL Headon, et al. The Oncological Safety of Nipple-Sparing Mastectomy: A Systematic Review of the Literature with a Pooled Analysis of 12,358 Procedures Arch Plast Surg. 2016 Jul; 43(4): 328– 338. 23. De La Cruz L, et al. Overall Survival, Disease-Free Survival, Local Recurrence, and Nipple-Areolar Recurrence in the Setting of Nipple-Sparing Mastectomy: A Meta-Analysis and Systematic Review. Ann Surg Oncol. 2015 Oct;22(10):3241-9. doi: 10.1245/ s10434-015-4739-1. Epub 2015 Aug 5.

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Cirugía laparoscópica para cáncer de colon y recto: estado actual en Puerto Rico Por: Ramón K. Sotomayor Ramírez, MD, FACS Cirugía General y Oncológica, HIMA San Pablo en Caguas

Palabras clave: Laparoscopia, cirugía colorrectal, coloctomía Keywords: Laparoscopy, colorectal surgery, laparoscopic colectomy

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Resumen: La cirugía laparoscópica para cáncer de colon y recto es una alternativa viable en el manejo de cáncer colorrectal. Las ventajas son recuperación rápida, estadía corta, heridas pequeñas, y menores complicaciones. Los resultados en cirugía oncológica laparoscópica deben ser similares a la cirugía abierta. Puede estar contraindicada en tumores extensos, invadiendo otros órganos y en pacientes inestables. Las complicaciones técnicas pueden ser prevenibles y se deben identificar lo más pronto posible.

Abstrac: Laparoscopic surgery for cancer of the colon and the rectum has evolved into a viable alternative. Advantages include faster recovery, shorter hospital stay, smaller incisions and less complications than traditional open surgery. It is technically challenging, and the results of laparoscopic oncologic surgery must equal those of open surgery. It may be contraindicated in extensive tumors, tumors involving other organs or hemodynamically unstable patients. Technical complications are in large part preventable and must be identified as soon as possible.

Ventajas y limitaciones de la cirugía colorrectal laparoscópica: El desarrollo de la cirugía laparoscópica para cáncer de colon y recto ha sido uno de los grandes logros en Puerto Rico en el campo de la cirugía oncológica. Aunque técnicamente es más difícil que la cirugía abierta, ofrece una serie de ventajas para el paciente. Principalmente, heridas más pequeñas, menor dolor postoperatorio, disminución en el uso de narcóticos y una recuperación temprana. Los pacientes se levantan con mayor rapidez, el tiempo que sufre el intestino de íleo posoperatorio es menor, el intestino funciona más rápido y la estadía hospitalaria es menor, lo que justifica la inversión en equipo e instrumentación. Las complicaciones cardiorespiratorias y problemas relacionados a la herida y la pared abdominal son menores.(1,2)

No obstante, la cirugía laparoscópica exige el mismo rigor que la cirugía tradicional abierta en el manejo intraoperatorio de los órganos, con manipulación mínima del tumor, márgenes amplios y linfadenectomías apropiadas para cada lesión. Esto ha hecho que hoy día, la cirugía mínimamente invasiva se pueda ofrecer y utilizar eficazmente en la mayoría de las resecciones electivas para cáncer de colon y recto, bajo el cuidado de cirujanos con dedicación y experiencia. (Fig 1) El desarrollo de la cirugía laparoscópica de colon surge luego de la publicación de un ensayo clínico que compara la cirugía tradicional abierta con cirugía laparoscópica. Este fue el COST trial (Clinical Outcomes Study Trial), publicado en el 2004 en el New England Journal of Medicine y muestra resultados similares en parámetros oncológicos. Entre ellos, la calidad de los márgenes, el número de ganglios linfáticos en los especímenes, la recurrencia local, y sobrevida a 5 años. (3) Al mismo tiempo se desarrollaron instrumentos que facilitaban la cirugía. Estos son: los selladores de vasos por medio de ultrasonido (Harmonic Scalpel Ethicon) y sistemas de energía bipolar avanzados (Ligasure US Surgical), el desarrollo de grapadoras de tejido para uso exclusivo endoscópico y de los protectores de herida que permitieron atender los primeros casos utilizando la técnica asistida con la mano. (4) Reportamos en el 2008 nuestra experiencia con 77 casos utilizando la técnica handassisted, en las cuales se reflejaron las ventajas de la cirugía mínimamente invasiva con complicaciones no mayores a la cirugía abierta. Luego de e esto, se reportó en el Boletín de la Asociación Médica los casos de resecciones segmentales, utilizando solamente la

Figura 1: La imagen muestra las incisiones para una colectomía izquierda, sigmoidectomía o resección anterior baja. Las mismas varían de acuerdo a la discreción del cirujano. 38

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técnica laparoscópica, con resultados aceptables. Se discute en esa publicación las limitaciones y problemas inherentes de la técnica laparoscópica y se advierte sobre potenciales complicaciones. (5,6) En la actualidad se ha validado a través de múltiples publicaciones, la más reciente fue el North American Cancer Treatment Group (NOCTG 147). Este fue un ensayo clínico de quimioterapia en carcinoma de colon estadio III. Utilizaron los datos de cirugía retrospectivamente y compararon grupos de cirugía abierta y cirugía laparoscópica entre 3.397 pacientes. Los casos de laparoscopia tuvieron un mayor contaje de ganglios linfáticos y márgenes de resección similares que cirugía abierta. Se observó que pacientes con obstrucción, perforación y adherencias severas, eran más propensos a convertirlos a cirugía abierta. Un dato importante fue que se observó que en los cinco años que duró el estudio, el número de casos laparoscópicos aumentó, mientras que los casos de cirugía abierta disminuyeron. (7) Indicaciones actuales en cáncer de colon y recto Las indicaciones principales son cánceres en varias etapas, pólipos indeterminados y lesiones que no se han podido remover endoscópicamente. Estas lesiones se deben marcar con tinta para uso endoscópico, ya que en la laparoscopia perdemos la capacidad de palpación, y el tener una marca en el colon facilita localizar la lesión por laparoscopia. Las operaciones más comunes son las resecciones segméntales del colon derecho, transverso y del sigmoide. Debido a que contienen la mayoría de la patología del colon y recto y porque su localización es estrictamente abdominal, las hacen más llevaderas desde el punto de vista técnico. Áreas más críticas y técnicamente más exigentes lo son las resecciones anteriores bajas, la resección abdominoperineal, ambas operaciones para cáncer de recto y la colectomía total abdominal. Para cirugía laparoscópica del colon se requiere preparación mecánica del intestino, profilaxis de antibióticos y de trombosis de venosa profunda y anestesia general. Está reservada para pacientes hemodinámicamente estables, no deben tener coagulopatía y, por lo general, son casos electivos. No obstante, hay situaciones de carácter urgente que se

pueden llevar a cabo por laparoscopia. La colectomía derecha, por lo general, se hace en posición supina, con 3 o 4 trocares y utiliza una herida pequeña para extraer el espécimen y completar la anastomosis intestinal, aunque en algunos casos la anastomosis se puede hacer intracorpórea. Se puede completar en una o dos horas, al igual que la resección del colon transverso. (Fig 2)

Figura 2: La imagen muestra la disección del mesenterio con el instrumento de energía. La disección es de medial a lateral, abordaje vascular para completar la linfadenectomía.

Las operaciones del sigmoide y las resecciones anteriores bajas se llevan a cabo en posición de semilitotomía, donde se prepara el abdomen y el área perineal. Son 3 o 4 trocares, pneumoperitoneo con CO2. Se lleva a cabo una disección vascular primaria -de medial a lateral donde se controlan los vasos en sus orígenes con los ganglios linfáticos, se moviliza la flexura esplénica del colon y se trae un conducto vascularizado hacia la reflexión peritoneal donde se hace la anastomosis con una grapadora circular. (Fig 3) Se extrae el espécimen por una herida suprapúbica o periumbilical a través de un protector de herida y se lleva a cabo una sigmoidoscopía flexible intraoperatoria que permite visualizar la conexión o anastomosis e identificar algún problema potencial con la misma. Esto es sumamente útil, ya que los problemas con las conexiones intestinales pueden ser catastróficos si no se diagnostican temprano. (7) En cáncer de recto, la exposición y posicionamiento son similares, pero presenta retos particulares anatómicos. Debido a los confines limitados de la pelvis, la disección del recto para la resección total mesorectal es más difícil. (Fig 4) No obstante, se hace la disección distal a la lesión, se divide el recto con una grapadora endoscópica y se hace la anastomosis con una grapadora Revista Puertorriqueña de Medicina y Salúd Pública

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Figura 3: La imagen muestra el uso de la grapadora circular para la anastomosis entre el colon y el recto.

circular. Hoy día, se recomienda el tratamiento neoadyuvante para lesiones estadio III en adelante, por lo cual muchos pacientes ya han recibido radiación a la pelvis y, en algunos casos, a discreción del cirujano se hacen ileostomías protectivas para minimizar problemas con las anastomosis rectales bajas. La resección abdominoperineal está indicada en cáncer de recto, donde la función del esfínter no se puede preservar. La disección laparoscópica facilita la disección profunda en la pelvis hasta visualizar los músculos levadores y hace la parte perineal más llevadera que en cirugía abierta. La colectomía total abdominal es técnicamente desafiante, ya que requiere trabajar en todos los cuadrantes del abdomen. El procedimiento de Hartman resección del rectosigmoide con colostomía es útil en algunos pacientes con obstrucción. También se ha encontrado que la laparoscopia se puede utilizar para derivaciones paliativas colostomías e ileostomías en casos de obstrucción maligna, lo que permite aliviar de forma efectiva y poco dolorosa la recuperación. Esto ha sido particularmente útil en casos de cáncer de recto avanzado, y cáncer ginecológico y de próstata, invadiendo y obstruyendo el recto. Limitaciones, contraindicaciones y prevención de complicaciones No todo paciente es candidato para cirugía laparoscópica y existen casos que comienzan por vía laparoscópica y se tienen que convertir a cirugía abierta. Las razones pueden ser: sangrado que no se pueda controlar, inhabilidad para progresar en la disección, invasión del tumor a otros órganos como, por ejemplo, la vejiga o adherencias del intestino delgado severas. Existen casos en los que la inflamación y adherencias 40

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son tales que pueden hacer la cirugía muy peligrosa. Aquí se puede optar por terminar algún paso de la operación utilizando la técnica handassisted o utilizar una laparotomía formal abierta. Éstas son decisiones que se consideran, no como un fallo de la operación, sino como medida de seguridad para el paciente. La inestabilidad hemodinámica es otra contraindicación, tal como la ascitis, en la enfermedad hepática, la coagulopatía y la coagulopatía que no se pueda corregir preoperatoriamente. La cirugía laparoscópica de cáncer de colon y recto requiere cirujanos y asistentes entrenados y un equipo especializado dedicado. Requiere óptica de alta definición, la disponibilidad de instrumentos de energía, grapadoras, protectores de herida y endoscopía intraoperatoria. Es crítica la atención al detalle para poder minimizar las complicaciones. La hemostasia debe ser absoluta y la disección vascular debe ser meticulosa para que el paciente pueda tener buena evolución y minimizar las complicaciones. Las complicaciones pueden ser menores tales como: infecciones superficiales de herida, sangrado menor postoperatorio o complicaciones comunes como trombof lebitis, atelectasia e infección urinaria. No obstante, existen complicaciones muy temidas, tanto en cirugía abierta como en laparoscopia que pueden ocurrir. En consecuencia, pueden hacer daño a otros órganos como la vejiga o los uréteres y las filtraciones de la anastomosis. Todas las conexiones intestinales están a riesgo de esta temida complicación y por lo cual se implementan estrategias para disminuir su incidencia. entre las que se incluyen: eliminar la tensión, corroborar la vascularidad del tejido y el uso apropiado de las grapadoras intestinales. (7) La endoscopia intraoperatoria es también una herramienta sumamente útil, particularmente en

Figura 4: Imagen tomada durante resección para carcinoma de sigmoide, muestra un mesenterio amplio para incluir ganglios linfáticos. Observe el uso del protector de herida.

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colorrectal. Ha tenido muy buena acogida en cirugía prostática, ginecología y urología pediátrica. Aunque se han hecho en los hospitales de Puerto Rico resecciones para cáncer colorrectal; particularmente en cáncer de recto, su desarrollo ha estado limitado por el costo de la instrumentación requerida y la necesidad de mayor tiempo operatorio. En la prostatectomía, no existe una alternativa viable laparoscópica, al contrario de la colectomía, donde podemos ofrecer cirugía laparoscópica mínimamente invasiva. No obstante, hay Figura 5: La imagen muestra una vista endoscópica con el colonoscopio flexible de la anastomosis colorectal completa literatura y experiencia que indica que el uso del robot con la grapadora circular tiene utilidad en casos de cirugía de cáncer de colon y recto. Por lo tanto, al día de hoy, el futuro inmediato de anastomosis del colon izquierdo y de recto. Se utiliza esta técnica en nuestros hospitales es incierto. un colonoscopio flexible, se visualiza la anastomosis directamente, se insufla aire y potencialmente se pueden Referencias: identificar problemas al momento y corregirlos antes de 1.Position Statement of theSociety of Colon and Rectal Surgeons and theSociety of Gastrointestinal EndoscopicSurgeons(SAGES) que el paciente salga de la sala.(Fig. 5) Se espera que la progresión del paciente en el periodo onLaparoscopicColectomyfor Curable Cancer, 2004. postoperatorio sea de una mejoría constante. Hay que mantener un alto índice de vigilancia para síntomas 2.GuidelinesforLaparoscopicResection of Curable Colon and sutiles que pueden indicar un problema intraabdominal Rectal Cancer. Practiceguidelines, 2006. Publishedby SAGES. mayor, f iebre postoperatoria, sangrado rectal inesperado, o dolor pélvico pueden indicar la presencia 3.Nelson Heidi, et al. TheClinicalOutcomesStudyGroup- A de un absceso intraabdominal o pélvico. Por lo tanto, comparison of Laproscopic and Open Colectomyfor Colon en el periodo postoperatorio, cualquier paciente que no Cancer. The New EnglandJournal of Medicine 2004:350:250-9 siga el curso normal, se debe estudiar con tomografía computarizada y puede necesitar regresar a la sala de 4.Targarona EM et al. Prospectiverandomized trial comparinglaparoscopiccolectomy and handassistedcolectomy. operaciones para corregir algún problema. Comentario sobre cirugía transanal (TAMIS) La cirugía transanal mínimamente invasiva (TAMIS, por sus siglas en ingles), es una alternativa para resecciones a través de un oficio natural. Se utiliza un aditamento que permite la insuflación de CO2 a través del recto y se pasan instrumentos de laparoscopia a través de trocares. Utilizando una técnica meticulosa, se llevan a cabo resecciones de pólipos o lesiones superficiales del recto. Requiere un equipo especializado; es difícil de aprender por las limitaciones de operar en un espacio limitado, pero tiene ventajas en poder remover lesiones sin entrar al abdomen y la pelvis. Se espera que en el futuro sus indicaciones y uso aumenten. Comentario sobre cirugía robótica La cirugía robótica es una variante de la cirugía laparoscópica y es una alternativa viable en cirugía

Applicability, immediateclinicaloutcome, inflamatory response and cost. SurgicalEndoscopy 2002. 16:234-239 5.Sotomayor, Ramon et al. Experiencewith Hand AssistedLaparoscopicSurgery of the Colon. Boletín Asociación Médica de Puerto Rico. 2008; 100(1):13-19. 6.Sotomayor, Ramón K. et al. AnInside Look at LaparoscopicColectomy. Boletín Asociación Médica de Puerto Rico 2010. 102(2);24-32.

7.Sticca, Robert et al. Current Use and SurgicalEfficacy of LaparoscopicColectomy in Colon Caner. Journal of the American College of Surgeons. 2013.(17)2:56-60. 8.Soo Kim, et al. RiskFactorsfor Anastomosis LeakageafterLaparoscopicintracorporeal anastomosis. Journal of the American College of Surgeons, 2009; 209(6) :694-701.

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TALTZ IS IS NOW NOW APPROVED APPROVED TALTZ FOR PSORIATIC PSORIATIC ARTHRITIS ARTHRITIS FOR TALTZPROVIDED PROVIDEDSIGNIFICANT SIGNIFICANT TALTZ

IMPROVEMENT IN IN JOINT JOINT SYMPTOMS SYMPTOMS IMPROVEMENT IN BIOLOGIC-NAIVE PATIENTS WITH PSORIATIC ARTHRITIS 1,2

IN BIOLOGIC-NAIVE PATIENTS WITH PSORIATIC ARTHRITIS1,2 SPIRIT-P1 (BIOLOGIC-NAIVE): ACR RESPONSE RATES AT WEEK 24, NRI SPIRIT-P1 (BIOLOGIC-NAIVE): ACR RESPONSE RATES AT WEEK 24, NRI

58 58

ACR20 %% ACR20 vs 30% vs 30%

40 40

ACR50 %% ACR50 vs 15% vs 15%

23 23

ACR70 %% ACR70 vs 6% vs 6%

Taltz 80 mg every 4 weeks (n=107) Placebo (n=106) Taltz 80 mg every 4 weeks (n=107) Placebo (n=106) P≤.001 vs placebo at week 24 for ACR 20/50/70. P≤.001 vs placebo at week 24 for ACR 20/50/70. Primary endpoint=ACR20 response at week 24. Primary endpoint=ACR20 response at week 24. Nonresponder imputation (NRI) of intent-to-treat population through week 24. Nonresponder imputation (NRI) of intent-to-treat population through 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. 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.

SPIRIT-P2(TNFi-experienced) (TNFi-experienced)(Taltz (Taltz8080mg mgevery every4 4weeks weeksn=122; n=122;placebo placebon=118), n=118),53% 53%ofofpatients patientsreceiving receivingTaltz Taltzachieved achievedACR20 ACR20atatweek week2424vsvs20% 20%forfor InInSPIRIT-P2 placebo. Additionally, 35% and 22% of patients receiving Taltz achieved ACR50 and ACR70, respectively, at week 24 vs 5% and 0% for placebo. placebo. Additionally, 35% and 22% of patients receiving Taltz achieved ACR50 and ACR70, respectively, at week 24 vs 5% and 0% for placebo. ACR20/50/70=American College of Rheumatology 20%/50%/70% response rate. ACR20/50/70=American College of Rheumatology 20%/50%/70% response rate.

SPIRIT-P1AND AND-P2 -P2TRIAL TRIALDESIGN DESIGN SPIRIT-P1

SPIRIT-P1(N=417) (N=417)and andSPIRIT-P2 SPIRIT-P2(N=363) (N=363)were werephase phase3,3,randomized, randomized,double-blind, double-blind,placebo-controlled placebo-controlledtrials trialstotoevaluate evaluatethe theeffi effi cacyand andsafety safetyofof SPIRIT-P1 cacy Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor 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 (TNFi)-experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary effi cacy necrosis factor (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 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 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 armofofadalimumab adalimumab4040mg mgevery every2 2weeks weekswas wasincluded. included.Patients Patientsininallallstudy studyarms armswere wereallowed allowedtotocontinue continuetaking takingstable stablebackground backgroundmedications medications arm during the trial. Inadequate responders (as defi ned by blinded criteria of <20% improvement in tender and in swollen joint counts) at week received during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 1616received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders theplacebo placeboand andadalimumab adalimumabarms armswere werere-randomized re-randomizedtotoTaltz Taltz8080mg mgevery every2 2oror4 4weeks. weeks.Nonresponder Nonresponderimputation imputation(NRI) (NRI)methods methodswere wereused usedforfor ininthe 1,3,4 categorical effi cacy analyses during the double-blind treatment period. 1,3,4 categorical efficacy analyses during the double-blind treatment period.

IMPORTANTSAFETY SAFETYINFORMATION INFORMATION IMPORTANT CONTRAINDICATIONS CONTRAINDICATIONS

Taltzisiscontraindicated contraindicatedininpatients patientswith witha aprevious previousserious serioushypersensitivity hypersensitivityreaction, reaction,such suchasasanaphylaxis, anaphylaxis,totoixekizumab ixekizumaborortotoany anyofofthe theexcipients. excipients. Taltz

WARNINGSAND ANDPRECAUTIONS PRECAUTIONS WARNINGS

Infections Infections Taltzmay mayincrease increasethe therisk riskofofinfection. infection.InInclinical clinicaltrials trialsofofpatients patientswith withplaque plaquepsoriasis, psoriasis,the theTaltz Taltzgroup grouphad hada ahigher higherrate rateofofinfections infectionsthan thanthe theplacebo placebo Taltz 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 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, 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. discontinue Taltz until the infection resolves. Pre-TreatmentEvaluation Evaluationfor forTuberculosis Tuberculosis Pre-Treatment Evaluate patients for tuberculosis (TB) infectionprior priortotoinitiating initiatingtreatment treatmentwith withTaltz. Taltz.Do Donot notadminister administertotopatients patientswith withactive activeTBTBinfection. infection.Initiate Initiatetreatment treatment Evaluate patients for tuberculosis (TB) infection of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after 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 Hypersensitivity Serioushypersensitivity hypersensitivityreactions, reactions,including includingangioedema angioedemaand andurticaria urticaria(each (each≤0.1%), ≤0.1%),occurred occurredininthe theTaltz Taltzgroup groupininclinical clinicaltrials. trials.Anaphylaxis, Anaphylaxis,including including Serious cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz cases leading to hospitalization, has been reported in post-marketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediatelyand andinitiate initiateappropriate appropriatetherapy. therapy. immediately

Taltz is indicated for adults with active psoriatic arthritis. Taltz is also indicated for adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

80 mg/mL

TALTZ CAN PROVIDE A CHANCE OF

COMPLETELY CLEAR SKIN

IN PATIENTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS1 UNCOVER-2: WEEK 12 EFFICACY, NRI

PASI 75

PASI 90

vs 2%

Taltz 80 mg every 2 weeks (n=351)

vs 1%

PASI 100 vs 1%

sPGA 0,1 vs 2%

Placebo (n=168)

Co-primary endpoints=PASI 75 and sPGA 0,1 at week 12.

In UNCOVER-1 (Taltz 80 mg every 2 weeks n=433; placebo n=431) and UNCOVER-3 (Taltz 80 mg every 2 weeks n=385; placebo n=193), Taltz patients achieved similar results: 89% and 87% of Taltz patients achieved PASI 75 vs 4% and 7% for placebo. Additionally, 71% and 68% of Taltz patients achieved PASI 90 vs 1% and 3% for placebo, and 35% and 38% achieved PASI 100 vs 0% and 0% for placebo. Also, 82% and 81% of Taltz patients achieved sPGA 0,1 vs 3% and 7% for placebo.

UNCOVER-1, -2, AND -3 TRIAL DESIGN The Taltz plaque psoriasis clinical program included 3 randomized, double-blind, placebo-controlled trials to evaluate the efficacy and safety of Taltz. All patients were ≥18 years of age and had plaque psoriasis with a body surface area involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score ≥3, and a Psoriasis Area Severity Index (PASI) score ≥12, and were candidates for phototherapy or systemic therapy. Participants were randomized to receive placebo or Taltz 80 mg every 2 weeks following a 160 mg starting dose. In UNCOVER-2 and -3, an additional arm of US-approved etanercept (50 mg twice weekly) was included. Co-primary efficacy endpoints were proportion of patients with an sPGA 0,1 and at least a 2-point improvement from baseline and proportion of patients achieving PASI 75 (at least a 75% reduction in the PASI composite score) at week 12. Nonresponder imputation (NRI) methods were used for categorical efficacy analyses.1

Learn about The Taltz Clear Access Program at taltzsavings.com 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 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; 2017. 2. 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 III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79-87. 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, doubleblind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30. 4. 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. Taltz® is a registered trademark of Eli Lilly and Company. PP-IX-US-1693 12/2017 ©LILLY USA, LLC, 2017. 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

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)

Taltz 80 mg Q2W (N=1167) (n%) 196 (17)

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.

IX HCP BS 01DEC2017

MSP ARTÍCULO DE REVISIÓN

Oncología

musculoesquelética Por: Juan J. Bibiloni, MD Ortopeda oncológico en el Hospital Oncológico de Puerto Rico Catedrático del Recinto de Ciencias Médicas de la Universidad de Puerto Rico

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

Resumen: La oncología musculoesquelética es un campo dentro de la medicina que se dedica a diagnosticar y tratar lesiones benignas y malignas del sistema musculoesquelético. La mayoría de las lesiones en huesos, y las masas en las partes blandas, son de naturaleza benigna, pero es importante hacer una evaluación clínica completa y los estudios de imágenes que sean necesarios para descartar una malignidad. Abstrac: Musculoskeletal oncology is the field within medicine which deals with the diagnosis and treatment of benign and malignant lesions of the musculoskeletal system. Most of these bone and soft tissue lesions are benign in nature but we most do a thorough clinical evaluation and request the best imaging studies which will let us reach a correct diagnosis.

a oncología ortopédica es solo uno de los términos con los que se ha denominado a una de las subespecialidades dentro de la ortopedia. Ésta se dedica al diagnóstico y manejo quirúrgico de aquellas lesiones benignas y malignas que ocurren en el sistema musculoesquelético. Antes de su nombre actual, se le conocía como especialidad en tumores óseos. En los pasados 15 años, es más común referirse a esta subespecialidad como oncología musculoesquelética. Tendemos a relacionar el término “ortopedia” con el manejo de condiciones óseas, aunque esta especialidad también incluye los otros componentes del sistema músculo esquelético como tendones, músculos, coyunturas, ligamentos, etcétera. Se debe tener en cuenta que cuando a la oncología musculoesquelética incluimos aquellas lesiones que ocurren en cualquiera de estos tejidos y se localizan mayormente en las extremidades o la columna. Si nos remontamos al pasado encontramos que el documento egipcio médico más conocido, “El papiro de Ebers”, describe crecimientos cancerosos en los huesos desde alrededor del año 1500 antes de Cristo. Además de esto, Hipócrates reconoció varias formas de cáncer, las que atribuía a lo que denominó la “Bilis negra” y comenzó a adjudicar el término “karkinos” o cangrejo a estos crecimientos anormales e indurados. Clarissimus Galeno en 192 AD usó términos como

Palabras Clave: Oncología musculoesquelética, tumores benignos y malignos de huesos y de partes blandas Keywords: Musculoskeletal oncology, Benign and malignant bone and soft tissue tumor

“karkinos” y “karkinoma” y llamó “sarcomas” a aquellos que surgían en las partes blandas. No fue hasta el siglo 17 que el anatomista Vesalio derrotó la teoría de la “Bilis negra” y postuló que el cáncer es un crecimiento anormal de un tejido en un sitio específico que podía regarse a otros órganos por los linfáticos o la sangre. En la literatura canónica, se reporta el trasplante exitoso de una extremidad de un moro negro que había muerto esa mañana, a un cristiano blanco a quien se le había amputado una extremidad por un proceso canceroso en la tarde del mismo día. Esto se conoce como el “milagro de la pierna negra”. Según este relato, el procedimiento fue llevado a cabo por los hermanos gemelos Cosmas y Damián en el siglo 5to AC. Estos hermanos eran médicos y luego fueron canonizados. No fue hasta finales del siglo 19 y comienzos del 20, cuando se desarrollaron la radiología y luego, al Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

“LA MALIGNIDAD ÓSEA MÁS COMÚN ES LA METÁSTASIS DE UN ADENOCARCINOMA, AQUELLOS TUMORES MALIGNOS QUE SE ORIGINAN EN ÓRGANOS GLANDULARES COMO SENO O PRÓSTATA” combinarse con la naciente patología, se comenzó a comprender mejor el comportamiento de estas entidades. Varios patólogos de renombre durante el transcurso del siglo 20 pusieron orden al caos existente hasta ese momento, con descripciones y correlaciones clínicas cada vez más precisas. Entre ellos quizás los más reconocidos en el campo de las lesiones óseas fueron los doctores Jaffe, Lichtenstein y Ewing. solo por nombrar tres.

Tumores del sistema músculo esquelético: Tumores Óseos Benignos No conocemos la incidencia de los tumores óseos benignos, aunque sí sabemos que son muy abundantes. La mayor parte de estos son hallazgos incidentales en radiografías que se les ordenan a los pacientes con otro propósito. Por ejemplo, es común ver un condroma en el húmero proximal en un paciente que se le ha hecho una radiografía de tórax de rutina. Con algunas excepciones, estas lesiones no requieren tratamiento alguno. Con una evaluación adecuada por un radiólogo u ortopeda es suficiente. La mayoría de los tumores óseos benignos se manejan de esta misma manera. Tumores Óseos Malignos Se consideran tumores óseos malignos a todas aquellas lesiones cancerosas que están localizadas en

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uno o más huesos. Claro está, hay que diferenciar entre las metástasis a huesos, que son aquellas neoplasias que surgen en otros órganos y luego viajan y se establecen en los huesos, y las metástasis que surgen del mismo tejido óseo. Si tomamos en consideración todas las malignidades que ocurren en los huesos hay que concluir que la malignidad ósea más común es la metástasis de un adenocarcinoma, aquellos tumores malignos que se originan en órganos glandulares como seno o próstata. Le seguiría, en un rezagado segundo lugar, el mieloma múltiple y muy distante -en la cola- estarían los tumores primarios de hueso como el osteosarcoma o el condrosarcoma. El manejo de las metástasis a huesos por adenocarcinomas es con frecuencia con propósitos paliativos y no curativos. Lo más importante es reconocer aquellas lesiones metastásicas a hueso que puedan provocar una fractura patológica. Esto con el propósito de estabilizarlas quirúrgicamente antes de que estas se fracturen. De esa manera, se les evita a los pacientes de cáncer pasar por el trauma, tanto físico como emocional, de tener una fractura patológica. Tanto el mieloma múltiple como los tumores óseos primarios, son tratados con protocolos específicos que combinan varios tratamientos de quimioterapia y radioterapia, con resultados variados que dependen en gran medida de su grado patológico y su estadío. El estadío depende de si el tumor está localizado en uno o varios sitios. Tumores Benignos de Partes Blandas La mayor parte de las masas de partes blandas en las extremidades son benignas. Entre estas destacan los lipomas y quistes sinoviales. Todas estas masas, independientemente de su tamaño, deben ser evaluadas por un especialista cualificado. Desgraciadamente muchas de ellas requieren una resonancia magnética o por lo menos un

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sonograma hecho e interpretado por un sonografista experimentado. Cualquiera de estos estudios bien interpretados puede dar una idea certera de la naturaleza de la masa. En términos generales, si no parece una lesión benigna, se debe obtener una biopsia para llegar a un diagnostico patológico definitivo y planificar un tratamiento adecuado. Son incontables los casos de tumores de partes blandas malignas que se han resecado de forma marginal o intralesional por que el cirujano asumió desde un principio que era una lesión benigna y no ordenó los estudios de imágenes adecuados. El llevar a cabo una resección inadecuada compromete la viabilidad de la extremidad y con frecuencia la vida del paciente. Tumores malignos o sarcomas de partes blandas

Estos sarcomas provienen principalmente del tejido conectivo y se estima que son menos de un 1% de los casos nuevos de cáncer al año. Los principios importantes que rigen el comportamiento de estas neoplasias cuando se presentan para nuestra atención son:

• Tamaño • Profundidad dentro del tejido en la extremidad • Grado histológico

El grado histológico está relacionado con el comportamiento del tumor, para saber si éste puede ser agresivo. No podemos inf luir en el lugar en donde surgen ni en su grado histológico, pero si en su tamaño. El tamaño está directamente relacionado al tiempo que transcurre desde que el paciente percibe el

crecimiento anormal hasta que llega a la atención de un especialista. Esto puede ser determinado por varios factores, desde fenómenos sicológicos reconocidos del mismo paciente como la negación, hasta contratiempos administrativos de los que padece nuestro sistema de salud que retrasa, sin ninguna justificación médica, la evaluación adecuada de estas condiciones. Después de que estos pacientes logran acceso a un especialista, generalmente se implementa un proceso de manejo que cuenta con cierta agilidad; con frecuencia el problema es que logre llegar a nuestra atención. No podemos asumir que todas las masas de partes blandas son lipomas o quistes sinoviales. Es nuestro deber insistir en obtener los estudios de imágenes adecuadas para intervenir de forma temprana a estos pacientes. Estoy seguro que de esta manera podríamos curar la mayoría de estas condiciones. Contamos con una buena calidad de médicos en el país. Creo que lo importante es identificar a aquellos pacientes en los que sospechemos una lesión que requiera atención en su sistema musculoesquelético e inmediatamente referirlos a un especialista en este campo. Estoy seguro de que esta situación se repite en otras ramas de la medicina, pero en estos casos el factor tiempo hace la diferencia. Bibliografía

1.Paget J. Lectures in Surgical Pathology. 2Vol. London, 1853 2.Mankin H. The History of Musculoskeletal Tumors 3.Bryan CP: The Papyrus Ebers, 1930 4.Beale L: The Microscope in its Application to Clinical Madicine. 5.London John Churchil, 1858 6.Vesalius, A: De Humani Corporis Fabrici. Base:. 1543

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See what your patients arenâ&#x20AC;&#x2122;t saying about their migraine. Patients living with migraine not only have to suffer from the pain of an attack, but also the impact migraine has on many aspects of their lives. However, many patients may not acknowledge or communicate the true impact of migraine to their healthcare providers.1 In fact, migraine remains under-recognized and undertreated.2-4 According to the American Migraine Prevalence and Prevention study, which evaluated 18,968 individuals, nearly 40% of patients with migraine are candidates for a preventive treatment, and yet only 12.4% of those eligible currently use a preventive.5

REFERENCES: 1. Mannix S, Skalicky A, Buse DC, et al. Measuring the impact of migraine for evaluating outcomes of preventive treatments for migraine headaches. Health Qual Life Outcomes. 2016;14(1):143. 2. Migraine facts. Migraine Research Foundation website. http://migraineresearchfoundation.org/ about-migraine/migraine-facts/. Accessed October 23, 2017. 3. Diamond S, Bigal ME, Silberstein S, et al. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention Study. Headache. 2007;47(3):355-363. 4. Stovner LJ, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193-210. 5. Lipton RB, Bigal ME, Diamond M, et al.; for the AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

MIGRAINE FRAMES S O M A N Y O F H E R M O M E N T S. EVEN THE ONES YOU W O U L D N ’ T S U S P E C T.

The simple 4-question Migraine Impact Identifier can help you quickly and easily assess migraine impact for a more complete picture of the burden that migraine is placing on your patients’ lives. When the impact of migraine is better understood, you and your patients can work together to develop a treatment plan with different strategies, which may include prevention, with the goal of improved management.

Download the Migraine Impact Identifier at reframemigraine.com.

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Cirugía para la enfermedad de Parkinson Por: Jaime A. Inserni, MD, FACS, FAANS Catedrático en Neurocirugia Catedrático Conjunto en Anatomía y Neurobióloga Escuela de Medicina Universidad de Puerto Rico

Resumen: La enfermedad de Parkinson es amena a cirugía cuando la levodopa y los fármacos adyuvantes han dejado de beneficiar, o han causado discinesias tardías, a los pacientes. Las cirugías aplicables al parkinsonismo consisten en lesionar o modular núcleos específicos de los ganglios basales. De las técnicas de neuromodulación, tratamiento universalmente utilizado, la cirugía se conoce como Estimulación Profunda Cerebral. ésta consiste en la inserción de un electrodo al núcleo subtalámico o al globo pálido en los ganglios basales de uno o los dos hemisferios cerebrales. Sin causar una lesión, la actividad eléctrica, impulsada por el electrodo modulador, produce un efecto benéfico al aminorar los síntomas motores de parkinsonismo. Las indicaciones para la cirugía son rigurosas, y por ello no todo paciente que padece de parkinsonismo es un candidato a ella.

Abstract: Parkinson’s Disease is amenable to surgery when levodopa and adjuvant therapies have stopped benefitting, or have caused tardive dyskinesias to the patients. Surgery for Parkinsonism consists of either lesioning or neuromodulating specific nuclei in the basal ganglia. Neuromodulation is actually the universally used modality. Known as deep brain stimulation (DBS), it consists of inserting a stimulating electrode into the subthalamic nucleus or the globus pallidus of one or both cerebral hemispheres. Without causing a lesion, the electrical impulses sent by the modulating electrode produce a beneficial effect by diminishing the abnormal motor symptoms typical of Parkinson’s Disease. The indications for surgery are rigorous and not all Parkinson’s Disease patients are candidates for it.

Palabras claves: Enfermedad de Parkinson, Ganglios Basales, Neuromodulación, Levodopa, Estimulación Profunda Cerebral

Keywords: Parkinson’s Disease, Basal Ganglia, Neuromodulation, Levodopa, Deep Brain Stimulation

Revista Puertorriqueña de Medicina y Salúd Pública

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n el tratamiento para l a en fer med ad de Park inson ex isten esencialmente dos modalidades terapéuticas: la farmacológica y la quirúrgica. Esta condición neu rológ ic a deg ener at iv a , conocida desde siglos pasados, y def inida en el 1817 por el médico y apotecario londinense James Parkinson, resulta de la disminución y eventual cese de producción del neurotransmisor dopamina en la substancia negra del mesencéfalo. Se caracteriza por desórdenes de movimiento característicos tales como la bradicinesia (enlentecimiento de movimientos de extremidades y cuerpo entero, disminución de parpadeo, pérdida de expresión facial, monotonía del habla, y enlentecimiento de las actividades del diario vivir), la rigidez, el temblor, y la disminución de estabilidad postural. Como neurotransmisor, la dopamina efectúa un papel regulador en los ganglios basales del cerebro, compuestos en cada hemisferio cerebral por el cuerpo estrellado, el globo pálido, el núcleo subtalámico, la substancia negra y el tálamo. Es en los ganglios basales en donde se regula la sincronicidad de los movimientos voluntarios del cuerpo. En ellos, la dopamina ejerce influencias tanto excitatorias como inhibitorias sobre el cuer po estrellado (putamen y núcleo caudado) que, de la misma manera, modula al globo pálido. Éste modula el núcleo subtalámico y la sustancia negra, quienes, de la misma forma,

modulan al tálamo; encargado de ejercer control sobre la corteza motora del cerebro, permitiendo m o v i m i e nt o s v o l u nt a r i o s sincronizados e inhibiendo movimientos involuntarios y antagónicos (Fig.1). La causa de la disminución de dopamina aún se desconoce, pero se atribuyen a ello causas genéticas, virales, alérgicas, tóxicas, infecciosas, o traumáticas, entre otras.

f u n d a m e nt a l m e nt e de la administración de dopamina en la formulación de carbidopa/levodopa, de agonistas de dopamina, y de otros fármacos como inhibidores de catechol-O-metil transferasa, anticolinérgicos, apomorf ina, y antivirales. El tratamiento quirúrgico del parkinsonismo habitualmente radica en la creación de una lesión en los ganglios basales, o la de modulación por inducción eléctrica de núcleos particulares en los gangliosbasales. Clasificación y tratamiento: La clasificación de la enfermedad En años recientes han surgido de Parkinson incluye cuatro modalidades no invasivas. Éstas divisiones abarcadoras. Estas crean una lesión o que modulan son: Parkinsonismo Primario la actividad neuronal por campos ( id io p á t ic o) , D e g e n e r a c i ón magnéticos o ultrasónicos, pero éstas Mu lt i s i st ém ic a (“ Pa rk i n s on aún se consideran experimentales. La cirugía para la enfermedad de Plus”), Parkinsonismo Heredodegenerativo, y Parkinsonismo Parkinson ha sido practicada desde temprano en el siglo 20. Después Secundario (adquirido). El tratamiento farmacológico de la introducción del método del park inson ismo consiste de cirugía estereotáxica, en 1947

Figura 1. Revista Puertorriqueña de Medicina y Salúd Pública

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Figura 2.

por Speigel y Wycis, el número de cirugías para parkinsonismo aumentó sustancialmente. Antes de aparecer la levodopa y los agonistas de dopamina en el 1967 y, posteriormente, la cirugía, era el único tratamiento paliativo para esta progresiva y, hasta ahora, incurable condición. Al desarrollarse los medicamentos antiparkinsonianos, la cirugía tomó un plano terapéutico secundario a estos, utilizándose mayormente solo en casos de severidad progresiva en donde ya los medicamentos no aliviaban los síntomas. Dichas cirugías consistían en ocasionar una lesión permanente en el tálamo (talamotomía), o en el globo pálido (palidotomía), o en el núcleo subtalámico (subtalamotomía). A pesar de la efectividad de levodopa para aminorar los síntomas motores de la enfermedad de Parkinson, el uso de este medicamento a largo plazo se asocia con efectos secundarios tales como: 54

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Figura 3.

las discinesias tardías (movimientos involuntarios de lengua, cara, tronco, y extremidades) y periodos largos sin efectividad, a pesar de altas dosis. Debido a la efectividad de la palidotomía, la cirugía utilizada extensamente antes del advenimiento de la levodopa, se comienza a comprobar, en la década de 1980, que en casos de discinesias y falla en efectividad por el uso de levodopa a largo plazo, el núcleo globo pálido podía ser modulado, sin ser lesionado, por altas frecuencias eléctricas. Este fenómeno se logra introduciéndole al núcleo de interés un electrodo, activándolo por un generador de impulsos intermitentes. Surge entonces la modalidad de estimulación profunda del cerebro (Deep Brain Stimulation=DBS), perfeccionada por el doctor AlimLouis Benabid y sus asociados en Grenoble, Francia. Hoy día, DBS es la cirugía universalmente aplicada a desórdenes de movimiento refractar ias a t ratam ientos

farmacológicos. De hecho, ya se está aplicando la modalidad de DBS a otras condiciones neurológicas, como la adicción, la obsesividad/ compulsividad, epilepsia, dolor intratable, isquemia cerebral, y depresión endógena. Para el parkinsonismo se suele abordar al núcleo subtalámico. También se puede escoger el globo pálido; en ambos la mejoría de los desórdenes motores es posible. La cirugía dirigida a crear una lesión en un punto particular del cerebro, como es el núcleo subtalámico, por ejemplo, se efectúa utilizando técnicas de esterotaxis. Esta técnica quirúrgica se basa en calcular -sobre un plano geométrico cartesiano- la posición anatómica precisa del área de interés, de acuerdo con imaginología y un mapa estandarizado de la anatomía cerebral. Antes de la aparición de la tomografía computarizada (CT), se utilizaba la radiografía de cráneo tomada tras la inyección

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Figura 4.

Figura 5.

de aire o tinte de contraste a los ventrículos cerebrales, en donde se medían distancias anatómicas y se calculaba matemáticamente la posición del núcleo de interés. Luego de la digitalización de la radiología, con el surgimiento de CT, y posteriormente de la resonancia magnética, la aplicación de los planos cartesianos a la imagen tridimensional del cerebro, y la adquisición de las coordenadas matemáticas ‘X’, ‘Y’, y ‘Z,’ que localizan el objetivo de interés quirúrgico, lo ejecuta un ordenador programado con la imagen cerebral digitalizada. La cirugía de DBS se lleva a cabo con el/la paciente despierto/a, bajo anestesia local y sedación endovenosa. Un ordenador especializado para la esterotaxis, conocido como neuronavegador, es programado con las imágenes tomográf icas y de resonancia magnética previamente adquiridas. Se crea una imagen tridimensional

Figura 6.

"EXISTEN CONSIDERABLES RIESGOS DE COMPLICACIONES EN DBS, GENERALMENTE DE UN 10%; SERIAS COMPLICACIONES OCURREN EN HASTA 4%" del cerebro. Visualmente se identifica en el neuronavegador, el núcleo de interés y se calculan las coordenadas cartesianas pertinentes a éste. Además, se confirma la localización espacial del núcleo con la aposición de un mapa estandarizado del cerebro, creado en 1977 por Schaltenbrand y Warren. Las coordenadas estereotáxicas se traducen manualmente a un marco estereotáxico. El marco estereotáxico de aluminio y acero inoxidable (Fig. 2) se fija a la cabeza mediante cuatro tornillos estériles. Este aparato está compuesto por arcos entrelazados, calibrados milimétricamente. Los arcos se mueven cada uno independiente el uno del otro, cubriendo

geométricamente los tres planos cartesianos ‘X’, ‘Y’, y ‘Z’. La cabeza de el/la paciente queda fijada a la mesa quirúrgica a traves del marco. Una vez preparado el cuero cabelludo en forma estéril, se produce una trepanación de 1 cm de diámetro, a través de una incisión semicircular sobre el punto de entrada, previamente calculado, en el área frontal de la cabeza, aproximadamente a tres centímetros de la sutura sagital, a nivel de la sutura coronal. Utilizando el aparato estereotáxico como guía, calibrado ya con las coordenadas previamente calculadas, se insertan con lentos y precisos incrementos milimétricos unos microelectrodos hasta el núcleo de interés (Fig. 3). Durante Revista Puertorriqueña de Medicina y Salúd Pública

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"Al desarrollarse los medicamentos antiparkinsonianos, la cirugía tomó un plano terapéutico secundario a estos, utilizándose mayormente solo en casos de severidad progresiva en donde ya los medicamentos no aliviaban los síntomas"

la trayectoria de los electrodos, se registra en un ordenador dedicado a ello la señal de sonido y la imagen osciloscópica de los campos neuronales, por los cuales van atravesando los electrodos. Cuando se llega a la población de neuronas de interés, indicado por sonidos e imágenes eléctricas características de la región, se conf irma la posición de los electrodos mediante fluoroscopía. Luego se retiran los microelectrodos y se inserta un electrodo permanente al punto fijo ya estipulado electrofisiológica y f luoroscopicamente. El paciente es entonc es ex a m i n a do (a) continuamente por el neurólogo mientras se electrifica el electrodo con variables amplitudes y voltajes; la frecuencia se mantiene constante alrededor de 130Hz (Fig. 4 y 5). Cuando clínicamente se logra la aminoración de síntomas motores, según la estimulación, se documentan los parámetros de esa programación electrónica para futura referencia y programación del neuroestimulador que será implantado en una futura ocasión. Finalmente, se fija el electrodo al cráneo en un bolsillo subgaleal y se sutura la piel con cuidado de evitar estiramiento. Eventualmente, en otro momento bajo anestesia general, se conecta el electrodo al neuroestimulador implantable. El neuroestimulador se implanta en un bolsillo subcutáneo o submuscular 56

Revista Puertorriqueña de Medicina y Salúd Pública

en el área infra-clavicular ipsilateral (Fig. 6). La programación del sistema implantado es a través de la piel por un programador externo. Existen considerables riesgos de complicaciones en DBS, generalmente de un 10%; serias complicaciones ocurren en hasta 4%. Las complicaciones más comunes son infección de herida y fractura del electrodo. Como en toda invasión del cerebro, existe la posibilidad de hemorragias, infartos, convulsiones, fistula de líquido cefalorraquídeo, erosión de la piel sobre el implante, neumocefalia, y cambios cognoscitivos y de personalidad, y depresión severa. Debido a la posición del cuerpo en la mesa y el extendido tiempo en la cirugía, existe el riesgo de trombosis de venas profundas y una subsiguiente embolia pulmonar; pulmonía por aspiración puede ocurrir en el paciente con discinesia oral. Como en cualquier cirugía, siempre existe la posibilidad de complicaciones atribuibles a la anestesia, y fallo cardiaco. La cirugía de Parkinson no es para todo paciente que padezca este desorden de movimiento, por lo cual las indicaciones para este procedimiento son rigurosas. Se requiere un relativo buen estado de salud física y mental, un claro entendimiento y aceptación de que no se pretende curar la enfermedad, y un f irmemente establecido

diagnóstico en donde hubo una buena respuesta inicial a levodopa que ha eventualmente fallado. La colaboración entre neurología, neurocirugía, neuroanestesiología y neuropsicología, tiene que ser estrecha en cada caso, ya que toda decisión quirúrgica es compartida. La presencia en el quirófano de las cuatro especialidades es ideal durante el implante de electrodos. El seguimiento posoperatorio es de por vida, ya que la programación de la neuromodulación varía según progresa inexorablemente la enfermedad, y por la necesidad de cambiar la batería agotada del neuroestimulador cada tres a cinco años, según sea necesario. Los manufactureros de los implantes para DBS tienen que estar fácilmente disponibles al equipo médico, y particularmente al paciente en todo momento. Durante la cirugía de DBS, los técnicos de las compañías tienen que estar en el quirófano para garantizar el uso correcto de la tecnología, tan costosa y complicada, que permite este efectivo tratamiento. Referencias:

1. Baltuch, GH, Stern, MB, eds. Deep Brain Stimulation for Parkinson’s Disease. New York: Informa Healthcare, 2007. 2. Krauss, JK, Jankovich, J, Grossman, RG, eds. Surgery for Parkinson’s Disease and Movement Disorders. Philadelphia: Lippincott Williams & Wilkins. 2001.

HIV TREATERS

Retos para la prevención del VIH en Puerto Rico por medio de PrEP

VIH y el paciente mayor de edad

Nuevas terapias antiretrovirales: El futuro de la condición del VIH Revista Puertorriqueña de Medicina y Salúd Pública

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Retos para la prevención del VIH en Puerto Rico por medio de PrEP Por: Iván Meléndez Rivera, MD, FAAFP, AAHIVM Director Médico del Centro Ararat, Inc. Facultad del Northeast Caribbean AETC

Palabras claves: PrEP; TDF/FTC/; acceso a cuidado de prevención Keywords: PrEP; TDF/FTC; access to preventive care

Resumen: La profilaxis preexposición (PrEP) al VIH es un método efectivo para la prevención de este virus, pero su implementación puede estar amenazada por barreras estructurales como la falta de seguro de salud o el acceso al cuidado de salud. La efectividad del uso diario de tenofovir/emtricitabina (TDF/ FTC) como profilaxis preexposición en prevenir el VIH en la comunidad depende a que se tome, se mantenga un enlace continuo a cuidado y adherencia al tratamiento. Varios factores se asocian a la descontinuación de PrEP

Abstract: HIV Pre-Exposure Prophylaxis (PrEP) is an effective HIV prevention method; however, implementation may be challenged by structural barriers such as lack of insurance and healthcare access. Effectiveness of daily oral tenofovir/emtricitabine (TDF/FTC) as HIV pre-exposure prophylaxis (PrEP) in preventing HIV in community settings depends on uptake, continued eng a gement , a nd ad herence. Several factors are attributable to discontinuation of PrEP.

l uso de la modalidad de PrEP para prevenir adquirir la infección por VIH es una disponible desde el 2012. Con su aprobación, el CDC añadió otro instrumento más a la caja de herramientas disponibles para la prevención del VIH. Con el paso de los años y el uso de la PrEP, la información se ha recolectado y la sumatoria de esta nos deja una clara línea de que su uso es la alternativa para disminuir hasta eliminar las nuevas infecciones por VIH en Estados Unidos y Puerto Rico. Recientes congresos mundiales asociados a la prevención y al VIH han mostrado diferentes estudios que fortalecen lo previamente expuesto. La expansión del PrEP disminuye los casos nuevos de VIH (M. Beauchemin, et al) entre un 35 Revista Puertorriqueña de Medicina y Salúd Pública

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a un 59 por ciento. En el cohorte de 1,258 personas el continuo de cuidado de prevención es un modelo básico de 36% (450 personas) utilizó la PrEP consistentemente, 9% cinco partes que incluye: la descontinuó temporeramente y el 17% descontinuó permanentemente la PrEP. El restante de la sumatoria • Conocimiento sobre PrEP de participantes se perdió en cuidado, cosa que es común cuando hablamos de un medicamento para prevenir algo • Acceso a clínica de Prep que la persona no siente o presenta síntomas. La evaluación de múltiples literaturas relacionadas al • Receta de PrEP PrEP señalan las siguientes causas como las más comunes para que las personas no continúen en tratamiento: • Adherirse a PrEP • Dificultad en accesos a la PrEP

• Costo • No cubierta por plan medico • Falta de proveedores con conocimiento para prescribir

• Cambio en prácticas sexuales

• Entrar a una relación estable con alguien negativo al VIH.

• Entrar a una relación con una pareja positiva pero no detectable.

• Rompimiento con pareja seropositiva. • Abstinencia sexual. • Requerimiento de realizarse pruebas de laboratorio y citas frecuentes • Efectos secundarios del medicamento

• Retenerse en PrEP” En Estados Unidos, la cantidad de recetas de PrEP para el segundo trimestre de 2017 fue de 61,000. (Aron J Seingler et al) Esto equivale al 5% de los supuestos 1.2 millones de personas que debería estar utilizando la PrEP. Dentro de ese número tan bajo, las mujeres, hispanos y afroamericanos presentan un número ínfimo de beneficiarios, demostrando que la disparidad en la prevención está presente en todas las áreas. En Puerto Rico existen tres clínicas formales de PrEP. Las mismas cuentan con estructuras diferentes al igual que la gama de servicios que ofrecen a su población. A finales de 2017, 375 personas recibían servicios formales de PrEP en Puerto Rico.

“Las clínicas de PrEP aumentan la cantidad de pruebas de VIH que se realiza la población a riesgo y provee la oportunidad de un diagnóstico más certero y a tiempo”

Basado en el modelo presentado por Dawn K. Smith del CDC en Atlanta, en Puerto Rico el Need to PrEP ratio, es En Puerto Rico no tenemos data específica de por qué se decir la cantidad de personas que deberían estar en PrEP, deja la PrEP pero si sabemos que el acceso a esta terapia es comparado con la cantidad de nuevos diagnósticos por limitado por los planes médicos, especialmente por el plan cien mil habitantes es un número mayor a cualquier estado de salud del gobierno. a territorio en los Estados Unidos. Basado en las 644 personas diagnosticadas con VIH en Puerto Rico para el El continuo de cuidado de salud es uno que va más allá 2017 y los 375 pacientes que se conoce que estaban en PrEP que el que se presenta para los pacientes VIH positivo. Este para finales de ese mismo año nos deja un Need to PrEP ratio continuo también incluye a los pacientes en prevención. El de 0.58. Este número es menor que el de la región sur de 62

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

los EU (.9) donde está el número mayor de nuevos casos de VIH. No confundamos un cociente (ratio) menor con una menor necesidad. Por el contrario, lo que demuestra es que tenemos una necesidad mayor de personas en PrEP y no se está cubriendo. Las clínicas que ofrecen este tratamiento entre otras cosas aumentan la cantidad de pruebas de VIH que se realiza la población a riesgo y provee la oportunidad de un diagnóstico más certero y a tiempo y un enlace a cuidado. La ciudad de Nueva York presentó un estudio en CROI 2018 en la cual entrevistó a los 3,739 (96%) de 3,908 casos de nuevo diagnóstico entre el 2015 al 2017 en relación con su uso de PrEP. 95 personas (2.5%) reportaron uso de PrEP antes de su diagnóstico de VIH. El tiempo promedio de uso fue de tres meses con un tiempo promedio de seroconversión a los 5 meses de haberlo dejado de utilizar. Entre las características presentadas por esta población que nos deberían de abrir la mente a nuevas estrategias de prevención se encuentra que:

prescribir la PrEP.

• Acceso en los planes médicos al medicamento. • Cubierta de laboratorios relacionados a PrEP,

especialmente en el plan de salud del gobierno de Puerto Rico. • En los casos de descontinuación de PrEP:

• Evaluar las razones por las cuales los pacientes dejan de atender a sus citas de PrEP.

• Determinar la fracción de desuso relacionada

a barreras de acceso, factores del medicamento, precepción de disminución de conductas de riesgo.

• Desarrollar retención dirigida y apoyos en adherencia para la población joven.

Un Puerto Rico sin nuevas infecciones por el VIH • 33% de los usuarios de PrEP fueron depende de todos. diagnosticados con una infección aguda de VIH. • 32% fueron diagnosticados con una infección de transmisión sexual en el pasado año. • 6% reportaron haber utilizado profilaxis POST exposición (PEP). • Sostuvieron relaciones sexuales durante el año pasado:

• anales sin protección – 77% • con una persona que conocían que tenía VIH – 41%

• mientras estaban borrachos o bajo el efecto de drogas – 32%

Referencias

By Race/ethnicity, Blacks Have Highest Number Needing PrEP in the United States, 2015 Dawn K. Smith1, Michelle Van Handel1, Jeremy A. Grey1 1CDC, Atlanta, GA, USA Distribution of Active PrEP Prescriptions and the PrEP-to-Need Ratio, US Q2 2017 Aaron J. Siegler, PhD- Department of Epidemiology, Rollins School of Public Health, Emory University; Jodie L. Guest, PhDDepartment of Family and Preventive Medicine, School of Medicine, Emory University PrEP USE HISTORY OF PERSONS NEWLY DIAGNOSED WITH HIV: NEW YORK CITY, 2015-2017- Kavita Misra, PhD, MPH; Jamie S. Huang, MPH; Chi-Chi N. Udeagu, MPH HIV Epidemiology and Field Services Program, New York City Department of Health and Mental Hygiene DECREASES IN HIV INCIDENCE IN A MONTREAL CLINIC COINCIDE WITH EXPANDING PREP USE - Marieve Beauchemin, Clinique Medicale l'Actuel, Montreal, QC, Canada

Esta información nos demuestra los abismos y las oportunidades perdidas en la prevención del VIH que se deben trabajar. http://www.salud.gov.pr/Estadisticas-Registros-y-Publicaciones/ Direcciones futuras necesarias en PrEP: • Un mayor acceso a PrEP mediante:

Estadisticas_VIH/Estadísticas_Generales/2017/Diciembre_2017/ Puerto_Rico_HIVAIDS_Surveillance_Summary.pdf

• Facilidades con proveedores que conocen el Revista Puertorriqueña de Medicina y Salúd Pública

NOW APPROVED

Initiate. Advance. Protect. Help protect against resistance with the barrier to rely on from the start

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.

of patients treated with SYMTUZA™ had

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%

*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

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

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

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

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

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

MSP ARTÍCULO DE REVISIÓN

VIH y el paciente mayor de edad Por: Marisel Bosques, MD Infectóloga Vice Presidenta HIV Treaters Medical Association of Puerto Rico (HIVTMD)

Abstract: HIV patients at advanced ages require different treatment alternatives based on the time of diagnosis, preexisting conditions and other risk factors. It must be taken into account that the effective response to the treatment regimen decreases as the affected person ages.

Palabras clave: VIH, Edad Avanzada, Tratamiento, Infección.

Para esa misma fecha, en el 2017, el número de casos era 8941. Poco a poco, la prevalencia del VIH dentro de los grupos de edad avanzada está en aumento. Esto ocurre mayormente a consecuencia de dos cosas: la protección otorgada por los medicamentos antirretrovirales, pues estos ayudan a prolongar la vida, y, por un aumento en la identificación y diagnóstico de casos. Epidemiología La exposición sexual es el En Puerto Rico, hasta el 30 de abril modo más común de transmisión de 2018, la tasa acumulativa de casos del VIH en adultos mayores 2 . reportados de personas mayores de Desafortunadamente, todavía existe 55 años con VIH (no SIDA) era 937. la duda que una persona mayor de 55

años está en riesgo de contraer el VIH, por lo que es menos probable que se le haga la prueba3,4. Incluso, cuando se realiza la prueba de VIH en el paciente mayor, a menudo el diagnóstico se hace más tarde en su enfermedad, lo que aumenta el riesgo de infecciones oportunistas y de transmisión a otros. Muchos estudios han demostrado que, a pesar de la supresión viral otorgada por una terapia antirretroviral efectiva, la recuperación inmunológica es menos robusta con el aumento en edad. He aquí la importancia de diagnosticar y dar tratamiento de VIH a una edad más temprana.

Resumen: Los pacientes de VIH en edades avanzadas precisan de alternativas de tratamiento diferentes basadas en el momento del diagnóstico, condiciones preexistentes y otros factores de riesgo. Se debe tener en cuenta que la respuesta efectiva al régimen de tratamiento disminuye a medida que la persona afectada, envejece.

Las recomendaciones para el manejo y tratamiento de la infección por VIH en personas de edad avanzada son las mismas que aquellas indicadas a adolescentes y adultos. Sin embargo, se deben tomar en cuenta varios asuntos importantes. A continuación, discutiré varios puntos específicos para la población de edad avanzada que vive con VIH.

Key words: HIV, Advanced Age, Treatment, Infection.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

"A pesar de que el manejo clínico de las personas mayores de edad que viven con VIH puede ser complejo, podemos aliviar el impacto que crea sobre la vida de los pacientes dentro de este grupo de edad"

Uso de retroviales Sabemos que el régimen antirretroviral debe iniciarse independientemente del conteo de células CD4.5 Esto aplica para toda persona infectada con el virus de inmunodeficiencia humana, incluyendo la población mayor de edad. Para la selección del régimen debe tomarse en cuenta los medicamentos que ya están en uso, comorbilidades, y las posibles insuficiencias en sistemas de órganos5. Los pacientes de edad más alta pueden estar en riesgo de una función hepática o renal deteriorada, y éstas deben examinarse continuamente. Adicionalmente, la polifarmacia (el uso de 5 fármacos o más) es común en adultos mayores de edad. El potencial de interacciones entre medicamentos es una consideración primordial al momento de seleccionar y manejar los regímenes antirretrovirales en esta población.

de declive y vulnerabilidad se conoce como "fragilidad" y produce aumento en el riesgo de resultados adversos. Esta fragilidad parece afectar a la persona que vive con VIH a una edad más temprana que a las personas que no han adquirido el virus.

Morbilidad no relacionada al Sida Como se mencionó anteriormente, la terapia antirretroviral exitosa ha prolongado la supervivencia de las personas que viven con VIH y ha producido cambios en los patrones de morbilidad y mortalidad. Aunque las muertes a consecuencia del SIDA o enfermedades oportunistas han reducido, no obstante, el VIH desencadena secuelas a largo plazo que se piensan son el resultado de un estado de inflamación persistente creado por el virus. Por otro lado, la prevalencia de condiciones medicas relacionadas a la edad ha aumentado. Debido a la sobreposición epidemiológica entre las condiciones médicas asociadas a la edad y aquellas relacionadas al VIH, se generó el concepto de condiciones asociadas al VIH-no SIDA (HANA, por sus siglas en inglés). Éstas incluyen enfermedad cardiovascular, diabetes mellitus tipo 2, enfermedad pulmonar crónica obstructiva, osteopenia/osteoporosis, enfermedad crónica de riñón, enfermedad crónica de hígado, trastorno neurocognitivo asociado a VIH, y ciertos cánceres6. Por último, con el pasar de los años, el envejeciente con VIH experimenta debilidad y disminución de la reserva fisiológica. Este estado

1. HIV/AIDS Surveillance Program. Office of Epidemiology and Research, Puerto Rico Health Department. eHARS System (April 30, 2018 and April 30, 2017). 2. Centers for Disease Control and Prevention. HIV Surveillance Report, 2016; vol. 28. http://www.cdc.gov/hiv/library/reports/hivsurveillance.html. Published November 2017. 3. Management of human immunodeficiency virus infection in advanced age. Greene M, Justice AC, Lampiris HW, Valcour V. JAMA. 2013 Apr;309(13):1397-405. 4. Envejecimiento en el VIH. Bacó J. Galenus. 2018 Abril/Mayo; 69(2): 71. 5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/ AdultandAdolescentGL.pdf. 6. Guaraldi G, Falutz J, Mussi C, Silva AR. 2016. Managing the Older Adult Patient with HIV. Switzerland: Springer International Publishing. 7. Casau-Schulhof, Nathalie, et al. “HIV Infection in Older Adults.” Uptodate, 18 Jan. 2018, www.uptodate.com

Revista Puertorriqueña de Medicina y Salúd Pública

Conclusión Es importante reconocer que existe una interacción entre el envejecimiento, el VIH, sus comorbilidades asociadas, y el uso concurrente de medicamentos antirretrovirales y medicamentos de otras enfermedades crónicas. A pesar de que el manejo clínico de las personas mayores de edad que viven con VIH puede ser complejo, podemos aliviar el impacto que crea sobre la vida de los pacientes dentro de este grupo de edad. Referencias:

MSP ARTÍCULO ORIGINAL

Nuevas terapias antirretrovirales:

El futuro de la condición del VIH Por: Vilmary Sierra-Rosa, MD, AAHIVS Pasada Presidenta HIV Treaters Medical Association of Puerto Rico (HIVTMD),

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Resumen: Los avances científicos y tecnológicos buscan simplificar el tratamiento de los pacientes con VIH. Actualmente, las investigaciones están encaminadas a mejorar la eficacia del tratamiento disminuyendo dosis y perfeccionando los fármacos para que el paciente pueda elegir el tipo de tratamiento que más se adecúe a su estilo de vida.

Abstract: Scientific and technological advances seek to simplify the treatment of patients with HIV. Currently, research is aimed at improving the effectiveness of the treatment by reducing doses and improving drugs so that the patient can choose the type of treatment that best suits their lifestyle.

Palabras clave: VIH, Terapias antivirales, Fármacos, Eficacia, Investigación.

Key words: HIV, Antiviral therapies, Drugs, Efficacy, Research.

on el paso de los años, las terapias antivirales han ido cambiando y simplif icándose. En sus inicios, estas terapias eran unas de múltiples píldoras varias veces al día, actualmente se han convertido en terapias tan simples como una sola píldora una vez al día o mejor aún, un inyectable dos veces en semana. Actualmente, se persigue que estas terapias tengan los siguientes atributos: Eficacia de primera línea • Tolerabilidad y seguridad • Reducir la exposición de medicamentos • Saber cuándo comenzar la terapia • Eficacia en los cambios de segunda y tercera línea Se busca que las estrategias de manejo y tratamiento sean: • Reducir la exposición a antiretrovirales: disminuyendo dosis, frecuencia y la cantidad de estos. •Buscando nuevos agentes: A ntiretrov irales en investigación como lo son los anticuerpos monoclonales. • Estudiando nuevas formulaciones de antiretrovirales; terapias de larga duración oral, terapias implantables y terapias inyectables de larga duración. Actualmente hay una amplia gama de medicamentos en etapa de investigación desde fase 1 hasta fase 3: Inhibidores de entrada - Fostemsavir- Oral - Sifuvirtide-inyectable - Cenicriviroc-Oral - Albuvirtide – inyectable Anticuerpos Monoclonales(mAb) • UB-421(CD4 receptor) - inyectable 78

Revista Puertorriqueña de Medicina y Salúd Pública

• PRO-140(CCR5 receptor) - inyectable • Ibalizumab(TMB-355) - inyectable • VRC01- inyectable • VRC01-LS- inyectable NRTIs/NRTTIs (Nucleosidos) • EFdA(MK-8591) - oral • GS-9131- oral NNRTIs (No nucleósidos) • Doravirine (MK-1439) - oral • Elsufavirine (VM-15000) - oral • Ralpivirine-LAI(TMC-278;RPV) inyectable de larga duración • Dapivirine (TMC12;DPV) • PC-1005(MV-150/Zinc Acetate) Inhibidores de integrasas • Bictegravir(GS-9883) - oral •Cabotegravir(GSK-744;CAB) inyectable de larga duración • MK-2048 Inhibidores de Proteasas • GS-CA1 Inhibidores de Maduración • GSK2838232 Únicos/Desconocidos • MK-8507 • ABX464 • LEDGINs- aun no se encuentran bajo investigación clínica. Se ha visto que de estas nuevas modalidades de administración en el estudio LATTE-2(discutido en

MSP ARTÍCULO ORIGINAL

"Se ha visto que de estas nuevas modalidades de administración en el estudio LATTE-2(discutido en CROI 2017-18), los pacientes prefieren los medicamentos inyectables CAB/ RPV a los medicamentos en pastillas u orales"

CROI 2017-18), los pacientes prefieren los medicamentos inyectables CAB/RPV a los medicamentos en pastillas u orales. Por tanto, dentro de los factores de efectividad de un medicamento además de los puntos perseguidos por la FDA: Carga vital <50 c/ml el cual es determinado por la carga viral de inicio y la barrera genética del medicamento, también se deberían fijar para que sea más efectivo el proceso del tratamiento del paciente en: pt que abandonan tratamiento y por qué, tolerabilidad del fármaco, seguridad de este (efectos secundarios). Perseguir que las pruebas se extiendan mas allá de 48 semanas, para así tener una data más abundante del medicamento e incluir en los estudios más pacientes: mayores, adolescentes, mujeres, usuarios de drogas intravenosas, trans y cis-trans, pt coinfectados con HCV-HBV, diversidad étnica y con comorbilidades. Por tanto, para que estas nuevas terapias sean aún más efectivas, se debe perseguir de cara a los próximos años: Aumentar el enlace a tratamiento haciendo medicamentos más convenientes: una sola pastilla que contenga la dosis de varios medicamentos o bien medicamentos inyectables de dosis semanales, bisemanales y hasta mensuales. Para que el paciente no abandone el tratamiento una vez se logra enlazar hay que: • Trabajar con el estigma, tener diferentes modalidades de tratamientos (ver cual es más conveniente para el paciente), monitoría de pares y a través de las redes, y llevar a cabo más intervenciones de salud mental. • Perseguir que los medicamentos tengan menos efectos secundarios a nivel renal, de hueso, cardiovascular y de sistema nervioso central. Luego de tener al paciente en tratamiento ya estable, si es necesario cambiar medicamentos debemos preguntarnos: se está cambiando por seguridad, por necesidad de simplificar, se ha evaluado el genotipo de ese paciente, las posibles interacciones, si hay coinfección. Se ha considerado

Prueba y análisis de VIH.

cambio a triple o doble terapia. Viendo este panorama se puede esperar en un futuro: • Cambio a nuevas moléculas • Cambios mejorando la seguridad de los medicamentos y reducción de dosis • El paciente podrá escoger terapia oral o inyectable • Mejores costos y acceso a los medicamentos Esto es un futuro altamente prometedor y de más seguridad en el tratamiento y manejo de esta población. De nosotros como proveedores depende que este paciente alcance lo que en los estudios persiguen todos los estudiosos del tema, el cuarto noventa: Vivir bien y en salud. La autora es médico en el Concilio de salud integral de Loíza, tiene practica en Carolina y es facultativa del Northeast Caribbean AETC. Referencias:

1.CAb,cabotegravir,LA,Long acting,RPV,rilpivirine,Margolis CA, Lancet 2017:390;1499-1510 2. Ergs J, et al at IAS 2017. Paris, France, abstract MOAX0005LB 3. Integrating new antiretroviral therapies, Chloe Orkin, et al, CROI 2018 abstract presentation Revista Puertorriqueña de Medicina y Salúd Pública

The NOAC you choose for stroke risk reduction in NVAF matters Only XARELTO® provides all of the following: Once daily,* 24-hour stroke risk reduction1,2 *Taken with evening meal.

Class-leading coverage

Proven data in high-risk patients with a mean CHADS2 score of 3.5†1: Comorbidities included: Elderly (≥75 years) CHF Diabetes Prior stroke, TIA, or non-CNS SE Hypertension Moderate renal impairment‡

Extensive clinical trial and real-world evidence— time and time again1,3-16

The most affordable NOAC with the lowest average out-of-pocket cost17

As demonstrated in ROCKET AF. CrCl 30 mL/min-49 mL/min; as calculated by the Cockcroft-Gault formula.

† ‡

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.

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 procedures. Factors that can increase the risk of developing 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,

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. 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.

CHADS2 = CHF; hypertension; aged ≥75 years; diabetes mellitus; prior stroke or TIA; CHF = congestive heart failure; CrCl = creatinine clearance; NOAC = non-vitamin K antagonist oral anticoagulant; non-CNS SE = non-central nervous system systemic embolism; NVAF = nonvalvular atrial fibrillation; TIA = transient ischemic attack.

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

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2017 December 2017 067421-171110

Janssen Pharmaceuticals, Inc.

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 CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the 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 CYP3A4 inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk. Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase the risk of bleeding. 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. 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 with an anticoagulant that is not readily reversible. 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. • 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 the use of XARELTO® 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. 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. 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 Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. 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. ADVERSE REACTIONS IN CLINICAL STUDIES The most common adverse reactions with XARELTO® were bleeding complications. Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS, or visit www.XareltoHCP.com/PI.

083074-171026

B:11.75 in

T:11.5 in

S:10.3667 in

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS AND PRECAUTIONS (cont’d) 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 XARELTO® in patients with active pathological hemorrhage. • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. • Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). 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 the 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 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), or 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 (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO® in patients who develop acute renal failure while on XARELTO®. • 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. • 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. 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. Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A4 inhibitors. Avoid concomitant use of XARELTO® with drugs that are known combined P-gp and strong CYP3A4 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 nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). 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.

References: 1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Kubitza D et al. Clin Pharmacol Ther. 2005;78(4):412-421. 3. Camm AJ et al. Eur Heart J. 2016;37(14):1145-1153. 4. Coleman CI et al. Curr Med Res Opin. 2016;32(12):2047-2053. 5. Peacock WF et al. Ann Emerg Med. doi:10.1016/j.annemergmed.2016.09.032. 6. Coleman CI et al. Int J Cardiol. 2016;203:882884. 7. Abraham NS et al. BMJ. doi:10.1136/bmj.h1857. 8. Beyer-Westendorf J et al. Blood. 2014;124(6):955-962. 9. Chang H-Y et al. BMJ. doi:10.1136/bmj.h1585. 10. Graham DJ et al. JAMA Intern Med. 2016;176(11):1662-1671. 11. Laliberté F et al. Curr Med Res Opin. 2014;30(7):13171325. 12. Lauffenburger JC et al. Am J Cardiol. 2015;115(8):1095-1101. 13. Ogawa S et al. J Stroke Cerebrovasc Dis. 2014;23(10):2520-2526. 14. Olesen JB et al. Europace. 2015;17(2):187-193. 15. Staerk L et al. Eur Heart J. doi:10.1093/eurheartj/ ehw496. 16. Yao X et al. J Am Heart Assoc. doi:10.1161/JAHA.116.003725. 17. Data on file. Janssen Pharmaceuticals, Inc. Source: Managed Markets Insight and Technology, LLC™, a trademark of MMIT, as of September 15, 2017, and is subject to change.

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 (2.3, 2.8), 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. 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 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 (2.3, 2.8) 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, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory 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 CYP3A4 inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

XARELTO® (rivaroxaban) tablets Reversal of Anticoagulant Effect: A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be 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. Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated. 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 longterm 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 (2.4) 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]. 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 CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A4 inhibitors [see Drug Interactions]. Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A4 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 nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). 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]

XARELTO® (rivaroxaban) tablets

• Bleeding risk [see Warnings and Precautions] • Spinal/epidural hematoma [see Boxed Warning and 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. During clinical development for the approved indications, 18560 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; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3). 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. Table 1: Bleeding Events 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. Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Enoxaparin/ XARELTO† VKA† 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) 3 (<0.1) 10 (0.2) Intracranial‡ 1 (<0.1) 8 (0.2) Retroperitoneal‡ 3 (<0.1) 2 (<0.1) Intraocular‡ 0 4 (<0.1) Intra-articular‡ 27 (0.7) 37 (0.9) Non-fatal non-critical organ bleeding§ 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

Parameter Major Bleeding†

XARELTO N=7111 n (%/year) 395 (3.6)

Warfarin N=7125 n (%/year) 386 (3.5)

XARELTO vs. Warfarin HR (95% CI) 1.04 (0.90, 1.20)

Intracranial 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Hemorrhage (ICH)‡ 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) Hemorrhagic Stroke§ 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) Gastrointestinal (GI)¶ 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) Fatal Bleeding# 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) 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

Parameter

XARELTO† Acetylsalicylic Acid 10 mg (aspirin)† 100 mg N=1127 N=1131 n (%) n (%) 5 (0.4) 3 (0.3) 0 1 (<0.1) 2 (0.2) 1 (<0.1) 3 (0.3) 1 (<0.1) 22 (2.0) 20 (1.8)

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.

XARELTO® (rivaroxaban) tablets

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 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3) XARELTO Enoxaparin† 10 mg

Table 5: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies (continued) Body System Adverse Reaction 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 Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1-3 studies are shown in Table 6. Table 6: Other Adverse Drug Reactions* Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies

Total treated patients

N=4487 n (%)

N=4524 n (%)

14 (0.3) 1 (<0.1) 2 (<0.1) 7 (0.2) 4 (0.1)

9 (0.2) 0 3 (0.1) 5 (0.1) 1 (<0.1)

261 (5.8) N=3281 n (%) 7 (0.2) 1 (<0.1) 1 (<0.1) 2 (0.1) 3 (0.1)

251 (5.6) N=3298 n (%) 3 (0.1) 0 1 (<0.1) 1 (<0.1) 1 (<0.1)

201 (6.1) N=1206 n (%) 7 (0.6) 0 1 (0.1) 5 (0.4) 1 (0.1)

191 (5.8) N=1226 n (%) 6 (0.5) 0 2 (0.2) 4 (0.3) 0

Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 60 (5.0) 60 (4.9) 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. 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 5. Table 5: 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 10 mg N=4487 n (%)

Enoxaparin† N=4524 Body System n (%) Adverse Reaction 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 double-blind 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 INTERACTIONS General Inhibition and Induction Properties: Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events. Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Interaction with Combined P-gp and Strong CYP3A4 Inhibitors: Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A4 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 CYP3A4 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 CYP3A4 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 CYP3A4 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 3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

XARELTO® (rivaroxaban) tablets

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 with an anticoagulant that is not readily reversible. 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 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: 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 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.4) and 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 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. 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. A specific antidote for rivaroxaban is not available. 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. 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

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Palabras clave: Fibrilación atrial, Mixoma, Tumor, Cardiología. Key words: Atrial fibrillation, Myxoma, Tumor, Cardiology.

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Fibrilación atrial secundaria

A MIXOMA GRANDE

en un hombre de 68 años Por: Raúl García Rinaldi, MD, PhD, FACS Héctor Martínez, MD, FACC Ruth Borosy, MD, PGY2 Roberto López, MD, PGY2 FM, Lourdes Aguiló, MD, PGY1 FM

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“Como esta fibrilación era de novo, se consultó a un cardiólogo y se ordenó un ecocardiograma. El ecocardiograma reveló una masa gigante abultada en la aurícula izquierda y una fracción de eyección del 55%”

Resumen Este es el caso de un varón de 68 años sin comorbilidades, que acudió al servicio de sala de emergencias debido a una hematuria sin explicacion con disuria acompañada de mareos y malestar de un día de duración. El historial familiar mostró que su madre había muerto de un infarto al miocardio a los 74 años de edad. El paciente era chofer jubilado y negó cualquier hábito tóxico o uso crónico de medicamentos. El examen físico fue normal excepto para edema de la extremidad inferior izquierda, grado 1. Los resultados de laboratorio de emergencia revelaron un análisis de orina con hematuria. El paciente fue ingresado con el diagnóstico de hematuria macroscópica, y complicada con una infección del tracto urinario. A l d ía sig u iente de la hospitalización, un EKG reveló fibrilación atrial con respuesta ventricular adecuada. Se consultó a un cardiólogo y se ordenó un ecocardiograma, lo que demostró una gran masa abultada en la aurícula izquierda y una fracción de eyección del 55%. El paciente fue sometido a cateterismo cardíaco y posteriormente resección de un mixoma grande atrial izquierdo. Este caso se seleccionó para su presentación debido a la naturaleza coincidente de la hematuria macroscópica y el posterior hallazgo

incidental de un mixoma cardiaco asintomático con fibrilación atrial de novo. Además, el tamaño del tumor hace que el caso sea particularmente interesante.

myxoma.This case was selected for presentation due to the coincidental nature of gross hematuria and the subsequent incidental finding of an asymptomatic cardiac myxoma with resultant atrial fibrillation de novo. Abstract Also, the size of the tumor makes This is the case of a 68 male the case particularly interesting. without comorbidities, who came to the Emergency Department due Introducción to unexplained hematuria with Un mixoma auricular es un tumor dysuria accompanied by dizziness no canceroso en el lado superior and malaise of 1 day duration. The izquierdo o derecho del corazón, family history was significant for a que tiende a crecer en el septo mother who died of a myocardial auricular (7). Los tumores cardiacos infarction at 74 years of age. The primarios son raros y los myxomas patient was a retired chauffeur and son los más comunes. Alrededor denied any toxic habits or chronic del 75% de los mixomas ocurren en use of medications. The physical la aurícula izquierda del corazón examination was unremarkable generalmente comenzando en el except for left lower extremity septo auricular. El 25% restante edema, grade 1. Emergency se origina en el atrio derecho. Los laboratory results revealed a urine mixomas de la aurícula derecha analysis with hematuria. The a veces se asocian con estenosis patient was admitted with the tricúspide y fibrilación auricular diagnosis of gross hematuria, (7). Estos tumores son más comunes and complicated Urinary Tract en las mujeres, y alrededor de 1 de Infection. cada 10 son hereditarios y se llaman On the following day of the mixomas familiares. Estos tienden hospitalization, an EKG revealed a ocurrir en más de una parte del atrial fibrillation with adequate corazón a la vez, y a menudo se ventricular response. A cardiologist presentan a una edad más temprana was consulted and a 2D echo was (7). Los mixomas son el tipo más ordered, which demonstrated a large común de tumores cardíacos en mass bulging into the left atrium todas las edades yrepresentan de un and an ejection fraction of 55%. tercio a la mitad de los casos post The patient underwent cardiac mortem y de aproximadamente catheterization and subsequent tres cuartos de los tumores tratados resection of a large left atrial quirúrgicamente.

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Descripción del caso Este es el caso de un hombre de 68 años sin historial médico pasado, que fue enviado a la sala de emergencias por su médico primario debido a una hematuria inexplicable acompañada de mareos, debilidad y disuria de un día de evolución. El paciente negó fiebre, dolor abdominal, náuseas, vómitos o trauma reciente. La historia familiar fue significativa para una madre que murió de un infarto al miocardio a los 74 años de edad. El paciente era un chofer jubilado que negaba cualquier hábito tóxico o uso crónico de cualquier medicamento. El examen físico fue normal excepto por el edema de la extremidad inferior izquierda +1. Los resultados del laboratorio de sala de emergencia revelaron un CBC y CMP dentro de límites normales, y un análisis de orina con hematuria y leucocitosis . La radiografía de pecho reveló un ligero agrandamiento cardíaco y una aorta torácica ligeramente tortuosa. Una radiografía de tórax abdominal sin contraste fue negativa para cálculos renales o hidronefrosis. Sin embargo, el radiólogo recomendó una CT de tórax debido a los hallazgos de congestión vascular pulmonar, pequeños nódulos subpleurales en el lóbulo medio lateral derecho y un pequeño foco de cicatrices parénquimales. El CT posteriormente sin contraste mostró un granuloma calcificado del lóbulo superior derecho, ganglios linfáticos en mediastino y un ganglio linfático más grande en la región paratraqueal derecha de 1.3 cm de tamaño. Después de estos hallazgos, el paciente fue evaluado por un hematólogo que determinó que los hallazgos observados eran ganglios linfáticos reactivos debido a una posible infección. El paciente fue ingresado con el diagnóstico de hematuria macroscópica, infección del tracto urinario complicado.

Fue evaluado por el urólogo que recomendó una cistoscopia y estudios del tracto urinario superior con contraste IV. Al día siguiente de la hospitalización, durante la evaluación de la cama, se auscultaba un ritmo cardiaco irregular para el cual se hizo un EKG. Los resultados revelaron fibrilación auricular con respuesta ventricular adecuada. Como esta fibrilación era de novo, se consultó a un cardiólogo y se ordenó un ecocardiograma. El ecocardiograma reveló una masa gigante abultada en la aurícula izquierda y una fracción de eyección del 55%. Posteriormente, el paciente fue sometido a un cateterismo cardíaco que reveló una gran masa interseptal en la aurícula consistente con un mixoma, pero sin obstrucción coronaria. El paciente fue colocado en telemetría para monitorización cardiaca. La anticoagulación se evitó debido a la hematuria persistente. Se consultó a un cirujano cardiovascular que después, de obtener la evaluación del neumólogo, serealizó una resección del enorme mixoma auricular izquierdo. El paciente se complicó con una hemorragia postoperatoria y se tuvo que re-intervenir quirúrgicamente. El paciente fue transfundido 2 unidades de PRBC, FFP y crioprecipitado para estabilizar los niveles sanguíneos. Posteriormente, el informe patológico de una muestra del mixoma tomada en la sala de operaciones reveló una masa benigna de 38g, 7 x 3.5 x 1.5 cm. Después de la cirugía, el paciente ha tenido recuperación completa y recibe seguimiento regular en la clínica de Medicina Familiar en Mayagüez PR. La hematuria se resolvió espontáneamente y no ha vuelto a aparecer. El paciente también se sometió a una cistoscopia ambulatoria que no reveló ningún hallazgo significativo.

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Discusión Este caso clínico destaca la importancia de considerar el diagnóstico de un mixoma cardíaco en presencia de fibrilación auricular que no se explica por otras causas. También, nos recuerda la naturaleza asintomática de estos tumores, que suele ser el caso en el 20% de los pacientes (8). Cuando los mixomas cardíacos presentan síntomas, éstos varían desde síntomas no específicos o constitucionales a la muerte súbita (8). Los síntomas de estenosis mitral, endocarditis, regurgitación mitral y enfermedad vascular de colágeno pueden ser similares que los síntomas de mixomas auriculares (8), Sin embargo, un alto índice de sospecha ayuda en el diagnóstico. Los síntomas de los mixomas cardiacos se producen por interferencia mecánica con la función cardiaca o la embolización. De hecho, debido a su naturaleza intra-vascular y friable, los mixomas representan la mayoría de los casos de embolismo tumoral. La embolización ocurre en el 30-40% de los pacientes con mixomas cardiacos. El sitio del émbolo depende de la localización (aurícula izquierda o derecha) y de la presencia de un defecto intracardíaco. Los mixomas cardiacos pueden causar síntomas a través de una variedad de mecanismos: Embolización Obstrucción de la circulación a través de las válvulas del corazón. Interferencia con la válvula cardíaca, causando regurgitación. Invasión directa del miocardio, resultando en una alteración de la función ventricular izquierda, arritmias, bloqueo cardíaco o derrame pericárdico con o sin taponamiento. La invasión del pulmón adyacente puede causar síntomas pulmonares (10). Los síntomas de insuficiencia cardíaca izquierda incluyen disnea al esfuerzo (75%) que puede progresar a ortopnea, disnea paroxística nocturna y edema pulmonar (8). Los síntomas son secundarios a la obstrucción en el orificio de la válvula mitral y el daño de la válvula puede resultar en regurgitación mitral. La insuficiencia cardíaca derecha puede presentarse

“DEBIDO A SU NATURALEZA INTRAVASCULAR Y FRIABLE, LOS MYXOMAS REPRESENTAN LA MAYORÍA DE LOS CASOS DE EMBOLISMO TUMORAL”

con fatiga y edema periférico. La distensión abdominal debida a la ascitis aunque rara, es más común en tumores de lado derecho y de crecimiento lento. Estos síntomas también se observan en la etapa posterior de insuficiencia cardíaca progresiva asociada con los mixomas de la aurícula izquierda. El vértigo o síncope severo es experimentado por aproximadamente el 20% de los pacientes. La causa más frecuente del vértigo en los pacientes con mixoma auricular izquierdo es la obstrucción de la válvula mitral. Los síntomas pueden cambiar a medida que el paciente cambia de posición. La embolización al sistema nervioso central puede resultar en un ataque isquémico transitorio, un accidente cerebrovascular o una convulsión. Además, la participación de las arterias retinianas puede resultar en pérdida de la visión. Los síntomas constitucionales que incluyen fiebre, pérdida de peso, artralgias y fenómeno de Raynaud se observan en el 50% de los pacientes. Estos síntomas pueden estar relacionados con la sobreproducción de interleucina-6. En adición, el mixoma auricular puede infectarse si la vegetación está unida a su superficie (8). Los hallazgos en el examen físico incluyen una presión venosa yugular elevada, y una onda A prominente puede estar presente en el EKG. A la auscultación, un S1 fuerte causado por un retraso en el cierre de la válvula mitral debido al prolapso del tumor en el orificio de la válvula mitral (imitando estenosis mitral) y retraso de P2 puede estar presente (8). Su intensidad puede ser normal o aumentada, dependiendo si hay presencia de hipertensión pulmonar. En muchos casos, se oye un sonido diastólico temprano, llamado plop tumoral.

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ste sonido se produce por el impacto del tumor contra la pared endocárdica o cuando su excursión se detiene. Un S3 o S4 puede ser escuchado y un ruido auricular diastólico también se puede oír si el tumor está obstruyendo la válvula mitral o tricúspide. Si hay daño valvular del tumor, la regurgitación mitral puede causar un soplo sistólico en el ápice. El examen general puede revelar fiebre, cianosis, “clubbing,” erupciones cutáneas o petequias (8). Los pacientes con mixoma familiar pueden tener una variedad de características llamadas síndrome de mixoma o síndrome de Carney, que se presenta con: Mixomas en mama, piel, glándula tiroides o tejido neural Pigmentación irregular, lunares pigmentados o ambos Hiperactividad endocrina, como el síndrome de Cushing Aneurismas fusiformes cerebrales múltiples (8). Aunque la ecocardiografía transesofágica es más sensible, una ecocardiografía bidimensional que permite la evaluación de la localización, tamaño y movilidad del tumor es adecuada para el diagnóstico. Debido a que los tumores pueden estar en múltiples lugares, las cuatro cámaras deben ser visualizadas (8). El mixoma auricular debe diferenciarse de un trombo auricular izquierdo que suele situarse en la porción posterior de la aurícula y presenta un aspecto estratificado. La presencia de un tallo y la movilidad favorece el mixoma auricular. La ecocardiografía con Doppler puede demostrar las consecuencias hemodinámicas del mixoma auricular, que suelen ser consistentes con estenosis mitral o regurgitación (8). El tratamiento convencional del mixoma auricular es la extirpación quirúrgica mediante esternotomía mediana. Otra opción, es la mini toracotomía con cirugía asistida por robotización, que se trata de una estancia hospitalaria más corta y se considera un método seguro y factible para la extirpación del mixoma de la aurícula (8). Generalmente, la evaluación se puede realizar de forma ambulatoria. Después de la resección,

los pacientes deben ser evaluados regularmente de forma ambulatoria y someterse a un ecocardiograma transtorácico anual para evaluar si hay recurrencia del tumor (8). Otras lesiones cardíacas benignas comunes incluyen fibroelastomas papilares y lipomas (10). Sin embargo, los mixomas son la neoplasia cardíaca primaria más común. Histológicamente, estos tumores se componen de células dispersas dentro de un estroma mucopolisacárido. Estas células se originan a partir de un mesénquima multipotente que es capaz de realizar la diferenciación neuronal y endotelial. Además producen el factor de crecimiento endotelial vascular, que probablemente contribuye a la inducción de la angiogénesis y las primeras etapas del crecimiento del tumor. Los mixomas típicos son pedunculados, de consistencia gelatinosa, con una superficie lisa, vellosa o friable. Lo que hace este caso particularmente interesante es el hallazgo coincidente del mixoma durante la hospitalización por un conjunto de síntomas totalmente no relacionados. Sin la presentación espontánea e inexplicada de la hematuria del paciente, la fibrilación auricular resultante probablemente no habría sido detectada. De no atenderse esto, habría dejado al paciente vulnerable a la embolización, entre otros resultados catastróficos. Además, la accesibilidad de un eco bidimensional y un cardiólogo hicieron posible el diagnóstico. La resección exitosa del tumor fue un esfuerzo de equipo liderado por la participación del cirujano cardiovascular, cuya intervención oportuna y eficaz salvó la vida del paciente.

“LO QUE HACE ESTE CASO PARTICULARMENTE INTERESANTE ES EL HALLAZGO COINCIDENTE DEL MIXOMA DURANTE LA HOSPITALIZACIÓN POR UN CONJUNTO DE SÍNTOMAS TOTALMENTE NO RELACIONADOS”

MSP CASO CLÍNICO

Conclusión Los m i xomas, aunque a s i ntomát icos , pueden ser catastróficos. En pacientes con nueva f ibrilación auricular sin explicación deben considerarse como un diagnóstico diferencial los mixomas. Tienen una tasa de recurrencia de 1-3% en los pacientes con mixomas esporádicos, pero tasas de recurrencia tan altas como 10-

20% se han reportado en pacientes con mixomas familiares. También se sabe que estos tumores recurren debido a la escisión incompleta (8). Esto resalta la importancia de un seguimiento clínico estrecho en las personas diagnosticadas con miomas bronco-cardiacos. Se recomiendan ecocardiogramas transtorácicos anuales ambulatorios para evaluar la recurrencia del

Referencias 1.Larsson S, Lepore V, Kennergren C. Atrial myxomas: results of 25 years’ experience and review of the literature. Surgery. 1989 Jun. 105(6):6958. [Medline]. 2.Obrenovic-Kircanski B, Mikic A, Parapid B, et al. A 30-year-single-center experience in atrial myxomas: from presentation to treatment and prognosis. Thorac Cardiovasc Surg. 2013 Sep. 61(6):530-6. [Medline]. 3.Dong A, Lu J, Zuo C. Multiple peripheral pulmonary artery aneurysms in association with a right atrial myxoma. Circulation. 2016 Jan 26. 133 (4):444-6. [Medline]. 4.Ha JW, Kang WC, Chung N. Echocardiographic and morphologic characteristics of left atrial myxoma and their relation to systemic embolism.Am J Cardiol. 1999. 83:1579-1582. [Medline]. 5.Hasdemir H, Alper AT, Arslan Y, Erdinler I. [Left atrial myxoma with severe neovascularization: role of preoperative coronary angiography]. Turk Kardiyol Dern Ars. 2011 Mar. 39(2):163-5. [Medline] 6.Lone

tumor. El paciente presentado en este relato de caso está siendo seguido actualmente en el Centro de Medicina Familiar de Mayagüez Medical Center en Mayagüez Puerto Rico para la anticoagulación a largo plazo para su fibrilación auricular persistente. Se estará sometiendo a su ecocardiograma anual para su reevaluación.

RA, Ahanger AG, Singh S, et al. Atrial Myxoma: Trends in Management. International Journal of Health Sciences. 2008; 2(2):141-151. 7.Lenihan DJ, Yusuf SW. Tumors affecting the cardiovascular system. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier Saunders; 2015: chap 85. 8.Gyanendra K Sharma, MD, FACC, FASE Professor, Department of Medicine, Section of Cardiology, Medical College of Georgia, Georgia Regents University 9.Raith EP. Heart: Cardiac Myxoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2):164-168. 10.William H. Gaasch, MD Thomas J Vander Salm MD. Cardiac Tumors. Up to Date 11.Reined K. Frequency of primary tumors of the heart. Am J Cardiology 1996; 77:7 12.Salcedo EE, Cohen GI, White RG Davison MB. Cardiac Tumors: diagnosis and management. Curt Probl cardio 1992

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia

Fecha 24 de agosto de 2018 24 al 26 de Agosto

Título 2do Simposio de Trauma

Maratón de educaión médica continua-temas mandatorios

MSP ARTÍCULO DE REVISIÓN

Puerto Rico

Lugar

Coordinador o Contacto 787-777-3760 prfact2012@gmail.com

Centro Criollo de Ciencia y Tecnología Caguas, PR Restaurante El Buen Café Hatillo, PR

Legal Medical Educational Workshop

787-514-5633 787-904-6544

Comentarios SIMPOSIO

CURSO

25 de agosto 2018

8th Annual Pediatric Gastroenterology Symposium- Asociación de Gastroenterología y Hepatología Pediátrica de PR

Hotel La Concha San Juan, PR

IC Planners Ivette Colón

(787)504-3655 ivettecolon@ icplannerspr.com.

CONVENCIÓN

25 de agosto 2018

Mayagüez Medical Center Cardiovascular Innovation Forum 2018

Mayagüez Resort & Casino Mayagüez, PR

AMEC

787-289-8989 amec@amec-pr.com

CONFERENCIAS

25 de agosto 2018

Puerto Rico Cancer Conference Series: Non-Small Cell Lung Cancer 2018

Condado Plaza Hilton Hotel 999 Ashford Avenue, San Juan PR 00907

High Education Health

787-964-6394 heh@hehpr.com

CONFERENCIAS

26 de agosto 2018

Disaster Management Symposium

IntercontinentalHotel Isla Verde

Sociedad Puertorriqueña de Pediatría

939-642-2011 939-639-3119

SIMPOSIO

59th Annual Convention Sociedad de Médicos Graduados de la Escuela de Medicina UPR

San Juan Marriot Resort San Juan, PR

Sociedad de Médicos Graduados de la Escuela de Medicina UPR

787-758-2525 ext 2038 sgem.rcm@upr.edu

CONVENCIÓN

La Concha Hotel San Juan, PR

AMEC

787-289-8989 amec@amec-pr.com

CONVENCIÓN

31 de agosto al 2 de septiembre 1 de septiembre 2018

Convención Anual Academia de Neurología de PR

1 al 3 de septiembre 2018

36 ta Convención Anual Asociación de Médicos Pediatras Región Oeste (AMPRO)

Mayagüez Resort & Casino Mayagüez, PR

Mignaliz Vega

302-893-2136 amprodirectiva@gmail.com ampropediatras@gmail.com

CONVENCIÓN

8 de septiembre 2018

Update in liver diseases 2018 - Asociación Puertoriqueña de Gastroenterología

La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com www.aceppr.org

CONFERENCIA

8 de septiembre 2018

35ta Conferencia Epilepsia del CaribeSociedad Puertorriqueña de Epilepsia

Intercontinental Hotel Isla Verde

Sociedad Puertorri- 787-782-6200 queña de Epilepsia 787-782-3991 info@sociedadepilepsiapr.org

13 al 16 de Septiembre 2018

Convención Anual Sociedad Radiológica de PR

Condado Plaza Hotel San Juan, PR

Serra & Serra Group

787-640-5776 787-748-6022 info@serrayserra.com

CONVENCIÓN

14 al 16 de septiembre 2018

Cursos obligatorios para médicos

Club de Leones Mayagüez, PR

High Education Health Inc.

787-964-6394 heh@hehpr.com/ www.hehpr.com

CURSOS

15 de septiembre 2018

Convención Anual Sociedad de Nefrología de PR

Hotel Marriot San Juan, PR

AMEC

787-289-8989 amec@amec-pr.com

CONVENCIÓN

22 de septiembre de 2018

Simposio Negligencia, Imprudencia o Impericia Médica

Club Rotario Río Piedras, PR

High Education Health

787-964-6394 heh@hehpr.com

SIMPOSIO

22 de septiembre de 2018

Excellence In GI Nursing - Sociedad Puertoriqueña de asistentes de Gastroenterología

La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com www.aceppr.org

28 al 30 de septiembre de 2018

Convención anual Asociación de Hematología y Oncologìa Médica de PR (AHOMPR)

Wyndham Rio Mar Río Grande, PR

AHOMPR Germaine Quiñones

6 de octubre 2018

3rd Electrophysiology Symposium- American College of Cardiology, PR Chapter

Ponce Hilton Hotel Ponce, PR

787-706-7495 American College of Cardiology-PR Chapter accprchapter@gmail.com

10 de octubre 2018

American Psychiatric Academy Annual Convention

*Por Confirmar lugar

AMEC

787-608-1477 ahomprgq@gmail.com

CONFERENCIA

CURSO

CONVENCIÓN

SIMPOSIO

Revista Puertorriqueña de Medicina y Salúd Pública

787-289-8989 amec@amec-pr.com

CONVENCIÓN

8 de Update in liver diseases 2018 - Asociación septiembre Puertoriqueña de Gastroenterología 2018 1 de septiembre Convención Anual Academia de Neurología de PR 2018 8 de 35ta Conferencia Epilepsia del Caribeseptiembre Sociedad Puertorriqueña de Epilepsia 2018 1 al 3 de 36 ta Convención Anual Asociación de septiembre Médicos Pediatras Región Oeste (AMPRO) 2018 13 al 16 de Convención Anual Sociedad Septiembre Radiológica de PR www.medicinaysaludpublica.com 8 de 2018 Update in liver diseases 2018 - Asociación septiembre Puertoriqueña de Gastroenterología 2018 14 al 16 de Cursos obligatorios para médicos septiembre 8 de 2018 35ta Conferencia Epilepsia del Caribeseptiembre Sociedad Puertorriqueña de Epilepsia 2018 15 de Convención Anual Sociedad de septiembre Nefrología de PR 13 al 16 de 2018 Convención Anual Sociedad Septiembre Radiológica de PR 2018 22 de Simposio Negligencia, septiembre Imprudencia o Impericia Médica 14 16 de deal2018 Cursos obligatorios para médicos septiembre 2018 Excellence In GI Nursing - Sociedad 22 de Puertoriqueña de asistentes de septiembre Fecha Título Gastroenterología dede 2018 15 Convención Anual Sociedad de septiembre 28 al 30 de Nefrología deanual PR Asociación de Convención 2018 septiembre Hematología y Oncologìa Médica de 2018 de PR (AHOMPR) 22 de Simposio Negligencia, septiembre Imprudencia o Impericia Médica 3rd Electrophysiology de 6 de2018 Symposium- American College of octubre Cardiology, Excellence InPRGIChapter Nursing - Sociedad 2018 22 de Puertoriqueña de asistentes de septiembre 10 Gastroenterología de de 2018 American Psychiatric Academy octubre Annual Convention 2018 28 al 30 de Convención anual Asociación de septiembre Hematología y Oncologìa Médica 13 14 de de al 2018 Acupuntura, más qeu una de PR (AHOMPR) octubre medicina alternativa 2018 3rd Electrophysiology 6 de 18 al 20 de SymposiumAmerican College octubre 68 Annual Meeting - Puerto Ricoof octubre Cardiology, PR Chapter 2018 Urological Association 2018 10 de American Psychiatric Academy octubre Annual ObligatoriosConvention Asociación 21 al 22 de Cursos 2018 octubre de Puertorriqueña de Gastroenterología 2018 13 al 14 de Acupuntura, más qeu una octubre 27 al 28 de medicina alternativa Annual Convention Puerto Rico HIV 2018 de octubre Treaters Medical Association 2018 18 al 20 de 68 Annual Meeting - Puerto Rico octubre Urological Association 27 de 2018 2018 Annual Allergy and Immunology octubre Congress de 2018 21 al 22 de Cursos Obligatorios- Asociación octubre de Puertorriqueña de Gastroenterología 2 al 4 de 2018 Convención Anual Asociación de Médicos Noviembre Pediatras Región Este (AMPRE) 2018 27 al 28 de Annual Convention Puerto Rico HIV octubre de Treaters Medical 2018 17 de 2018 ACP ClinicalAssociation Vignettes and Research Noviembre Competition Program - American College 2018 of Physicians 27 de 2018 Annual Allergy and Immunology octubre Congress 7deal2018 9 de Convención Anual Colegio de Médicos Diciembre Cirujanos de PR 2018 2 al 4 de Convención Anual Asociación de Médicos Noviembre Pediatras Región Este (AMPRE) 72018 al 10 de Digestive Diseases of the Caribbean 2019 Febrero 2019 17 de 2018 ACP Clinical Vignettes and Research Noviembre Competition Program - American College 8 al 10 de American College of Physicians-PR 2018 of Physicians Marzo 2019 Chapter Meeting 7 al 9 de Convención Anual Colegio de Médicos Diciembre Fecha Título Cirujanos de PR 2018

2018

Agenda Médica

MSP Somos Ciencia

La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR La Concha Hotel San Juan, PR Intercontinental Hotel Isla Verde Mayagüez Resort & Casino Mayagüez, PR Condado Plaza Hotel San Juan, PR La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR Club de Leones Mayagüez, PR Intercontinental Hotel Isla Verde Hotel Marriot San Juan, PR Condado Plaza Hotel San Juan, PR Club Rotario Río Piedras, PR Club de Leones Mayagüez, PR La Concha Renaissace Resort Lugar 1077 Ashford Avenue, San Juan PR Hotel Marriot San Juan, PR Wyndham Rio Mar Río Grande, PR Club Rotario Río Piedras, PR Ponce Hilton Hotel Ponce, PR La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR *Por Confirmar lugar

Puerto Rico

Wyndham Rio Mar Río Grande, PR Club Rotario Río Piedras

Medicina UPR RiVS Marketing

info@rivsmarketing.com www.aceppr.org 787-289-8989 AMEC amec@amec-pr.com Sociedad Puertorri- 787-782-6200 queña de Epilepsia 787-782-3991 info@sociedadepilepsiapr.org 302-893-2136 amprodirectiva@gmail.com Mignaliz Vega ampropediatras@gmail.com 787-640-5776 Serra & Serra 787-748-6022 Group 787-548-0047 info@serrayserra.com RiVS Marketing info@rivsmarketing.com www.aceppr.org 787-964-6394 High Education heh@hehpr.com/ Health Inc. www.hehpr.com Sociedad Puertorri- 787-782-6200 queña de Epilepsia 787-782-3991 info@sociedadepilepsiapr.org 787-289-8989 AMEC amec@amec-pr.com 787-640-5776 Serra & Serra 787-748-6022 Group info@serrayserra.com 787-964-6394 High Education heh@hehpr.com Health 787-964-6394 High Education heh@hehpr.com/ Health Inc. www.hehpr.com 787-548-0047 RiVS Marketing Coordinador oinfo@rivsmarketing.com Contacto www.aceppr.org 787-289-8989 AMEC AHOMPR amec@amec-pr.com 787-608-1477 Germaine ahomprgq@gmail.com Quiñones 787-964-6394 High Education heh@hehpr.com Health 787-706-7495 American College of Cardiology-PR Chapter accprchapter@gmail.com 787-548-0047 RiVS Marketing info@rivsmarketing.com www.aceppr.org 787-289-8989 AMEC amec@amec-pr.com AHOMPR 787-608-1477 Germaine ahomprgq@gmail.com Quiñones 787-964-6394 High Education heh@hehpr.com Health

CONFERENCIA CONVENCIÓN CONFERENCIA CONVENCIÓN CONVENCIÓN CONFERENCIA CURSOS CONFERENCIA CONVENCIÓN CONVENCIÓN SIMPOSIO CURSOS CURSO Comentarios CONVENCIÓN CONVENCIÓN SIMPOSIO SIMPOSIO CURSO CONVENCIÓN CONVENCIÓN CURSOS

Ponce Hilton Hotel Hotel and Casino Sheraton Ponce, PRPuerto Rico 200 Convention Boulevard, San Juan PR 00907

American College of Puerto Rico Urological Cardiology-PR Chapter Association

787-706-7495 787-277-0674 accprchapter@gmail.com Aixa Vélez

SIMPOSIO CONVENCIÓN

*Por Confirmar lugar Intercontinental Hotel San Juan, PR

AMEC RiVS Marketing

787-289-8989 amec@amec-pr.com 787-548-0047 info@rivsmarketing.com

CONVENCIÓN CURSO

Club Rotario Río Piedras Embassy Suites Hotel Dorado, PR Sheraton Puerto Rico Hotel and Casino 200 Convention Boulevard, San Juan PR 00907 Intercontinental Hotel San Juan

787-964-6394 High Education Educational Partners heh@hehpr.com Health & Coaching, Inc. 787-646-0780 Vilma Pérez Puerto Rico Urological 787-277-0674 Association Aixa Vélez 787-504-3655 IC Planners ivettecolon@icplannerspr.com Ivette Colón 787-548-0047 RiVS Marketing info@rivsmarketing.com 787-706-0442 BPlanner Merna Morales Educational Partners bplanner21@gmail.com & Coaching, Inc. 787-646-0780 Vilma Pérez 787-548-0047 RiVS Marketing info@rivsmarketing.com www.aceppr.org 787-504-3655 IC Planners ivettecolon@icplannerspr.com Ivette Colón Colegio de Médicos Cirujanos 787-751-5979 www.colegiomedicopr.org de PR 787-706-0442 BPlanner bplanner21@gmail.com Merna Morales 787-548-0047 RiVS Marketing info@rivsmarketing.com 787-548-0047 RiVS Marketing info@rivsmarketing.com 787-548-0047 www.aceppr.org RiVS Marketing info@rivsmarketing.com

Intercontinental Hotel San Juan, PR Intercontinental Hotel San Juan, PR Embassy Suites Hotel Dorado, PR La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR Intercontinental Hotel San Juan Sheraton Convention Center Hotel Intercontinental Hotel San Juan, PR Sheraton Convention Center San Juan, PR La Concha Renaissace Resort 1077 Ashford Avenue, San Juan PR La Concha Resort San Juan, PR

2019 Agenda Médica

Sheraton Convention Center Hotel Lugar

Colegio de Médicos Cirujanos o787-751-5979 Coordinador Contacto www.colegiomedicopr.org de PR

CURSOS CONVENCIÓN CONVENCIÓN CONGRESO CURSO CONVENCIÓN CONVENCIÓN CONFERENCIA CONGRESO CONVENCIÓN CONVENCIÓN CONVENCIÓN CONFERENCIA CONVENCIÓN

Comentarios CONVENCIÓN

7 al 10 de Febrero 2019

Digestive Diseases of the Caribbean 2019

Sheraton Convention Center San Juan, PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com

CONVENCIÓN

8 al 10 de Marzo 2019

American College of Physicians-PR Chapter Meeting

La Concha Resort San Juan, PR

RiVS Marketing

787-548-0047 info@rivsmarketing.com

CONVENCIÓN

Revista Puertorriqueña de Medicina y Salúd Pública

2018

www.medicinaysaludpublica.com

Agenda Médica

MSP Somos Ciencia 01 al 04 de agosto de 2018

25th Annual Summer Conference on Obstetrics and Gynecology

08 al 10

Global Conference on Ageing de agosto Título Fecha de 2018

MSP ARTÍCULO DE REVISIÓN

Internacional

The Naples Beach Hotel Naples, FL, USA

Chelsea Hotel Ryerson University

Lugar Toronto, Canadá

http://symposiamedicus.org sduchen@ifa-fiv.org

Coordinador o Contacto

24 al 25 de agosto de 2018

V Simposio Nacional de Crianza y Salud

Armenia Bogotá, Colombia

Sociedad Colombiana de Pediatría

Tel: 6495352 Tel:7464706/07 http://plandeactividades.com/eventos/

03 al 08 de septiembre de 2018

Congreso-Curso Internacional de Urología

Centro de Convenciones Julio Cesar Turbay Ayala Cartagena, Colombia

Sociedad Colombiana de Urología

Tel: 2186700 http://www.scu.org.c o/Congreso%20SCU %202018c6.pdf

5 al 7 de septiembre de 2018

2018 ACS Cancer Programs Annual Conference: Learn, Interact, Transform

Hilton Chicago, Chicago, IL

American College of Surgeons

www.facs.org

12 al 16 de septiembre de 2018

17th World Congress on Pain

Boston Convention & Exhibition Center Boston, MA, USA

www.iaspworldcongressonpain.org

Mayo Clinic Multidisciplinary Simulation Center, Rochester, MN

American College of Surgeons

14 al 15 de septiembre de 2018

11 th Annual ACS-AEI Postgraduate Course

Comentarios

CONFERENCIA

CONGRESO

www.facs.org

26 al 29 septiembre de 2018

XV Congreso Colombiano y IX Congreso Internacional de Genética Humana

Hotel Dann Barranquilla, Colombia

Asociación Colombiana Tel. 310 699-2532 De Gerontología Y info@acgh.com.co Geriatría (ACGG)

01 al 02 de octubre de2018

International Workshop on HIV &amp; Aging

New Yorker Wyndham New York, NY

info@virology-education.com

01 al 04 de octubre de 2018

2018 World Cancer Congress

Kuala LumpurConvention Centre Kuala Lumpur, Malasia

01 al o4 de octubre de 2018

American College of Emergency Physicians Annual Conference 2018

San Diego Convention Center San Diego, CA

17 al 20 de octubre de 2018

World Stroke Congress

Palais des Congrés, Montreal, Canadá

17 al 21 de octubre de 2018

22nd WONCA World Conference of Family Doctors

Coex, Seoul, Korea

The Korean Academy of Family Medicine http://www.wonca2018.com/ World Organization of Family Doctors

19 al 24 de octubre de 2018

2018 ACR/ARHP Annual MeetingAmerican College of Rheumatology

McCormick Place, Chicago, IL

American College of Rheumatology

www.rheumatology.org

21 al 24 de octubre de 2018

2018 ASTRO Annual Meeting (American Society for Radiation Oncology)

Henry B. Gonzalez Convention Center San Antonio, TX, USA

Astro

www.astro.org

ANNUAL MEETING

14 al 17 de noviembre de 2018

15 th International Congress of Behavioral Medicine (ICBM)

Santiago, Chile

International Society of Behavioral Medicine

www.isbm.info

CONGRESO

14 al 17 de noviembre de 2018

XXXVI Congreso Panamericano de Otorrinolaringología y Cirugía de Cabeza y Cuello

Swisshotel, San Isidro Lima, Perú

www.panamorlperu.com

16 al 18 de noviembre de 2018

TQIP Annual Scientific Meeting and Training

Anaheim Convention Center Anaheim, CA

American College of Surgeons

25 al 30 de noviembre de 2018

Radiological Society of North America-RSNA Annual Meeting

McCormick Place Chicago, Il, USA

www.rsna.org

7 al 9 de diciembre de 2018

New York Cardiovascular SymposiumAmerican College of Cardiology

New York Hilton Midtown New York, NY

American College of Cardiology

congress@uicc.irg American College of Emergency Physicians (ACEP)

acep.conference2018.com

CONGRESO

www.facs.org

www.acc.org

Revista Puertorriqueña de Medicina y Salúd Pública

Convenciones 2018

Revista

Convención Anual de la Academia de Medicina de Familia de PR Dra. Sonia Ortiz, presidenta de la Academia de Medicina de Familia de Puerto Rico durante su convención anual, donde inició su cargo como presidenta de la entidad.

Annual Lung Cancer Conference-Hospital Auxilio Mutuo El Hospital Auxilio Mutuo celebró el Puerto Rico Lung Cancer Symposium, donde se ofrecieron los últimos avances y futuros enfoques en el tratamiento de cáncer en el pulmón.

Dra. Sonia Ortiz, presidenta entrante Academia de Medicina de Familia de PR.

Dr. José Lozada, director del Departamento de Oncología del Hospital Auxilio Mutuo.

Conveción Anual Asociación de Reumatólogos de PR

Convención Anual American College of Surgeons, PR Chapter Durante el encuentro se celebró el avance c ient í f ico que ha permitido que la cirugía bariátrica se realice de forma laparoscópica y mínimamente invasiva.

Durante la Convención, se reunieron conferencistas que ofrecieron información sobre enfermedades infecciosas, manejo clínico y avances en los tratamientos. Dra. Ana Quintero, anterior presidenta Asociación de Reumatólogos de PR.

Simposio Diagnosis of Skin Conditions Fundación Puertorriqueña para el Mejoramiento de la Dermatología Se realizó por primera vez un simposio en donde se ofrecieron conferencias sobre las afecciones que hoy representan un reto para la dermatología. Dr. Luis Ortiz Espinosa, presidente Fundación Puertorriqueña para el Mejoramiento de la Dermatología.

Revista Puertorriqueña de Medicina y Salúd Pública

Dr. Bolívar Arboleda, anterior presidente American College of Surgeons PR Chapter y Dr. Guillermo Bolaños, especialista en Cirugía Bariátrica.

Caribbean Congress on Emergency Medicine Durante el evento, los mé d ic o s r e c ibier on entrenamientos directos que ayudan a mejorar la respuesta en salas de emergencia, ante escenarios cardiovasculares y de cuidado crítico. Dr. Luis Serrano, presidente Colegio de Emergenciólogos de PR.

Convenciones 2018

Revista

Convención Semianual de la Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED) Las enfermedades asociadas a la tiroides y los nuevos avances en cuanto a la prevención, diagnóstico y manejo de la diabetes, fueron algunos de los temas destacados durante la convención semianual de la Sociedad Puertorriqueña de Diabetología y Endocrinología (SPED). Dr. José García Mateo y Dr. Luis Ruiz, presidente Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED).

Convención Anual Sociedad Radiológica de PR (SOCRAD) Durante la últ ima Convención Anual los conferencistas expusieron temas de neurorradiología, imágenes cardiotorácicas y hasta inteligencia artificial.

Dr. Gory Ballester, presidente Sociedad Radiológica de PR (SOCRAD).

Convención Anual Academia de Medicina General de PR Durante la Convención de la Academia de Medicina General, los médicos se nutrieron con temas en el área de reumatología, antibióticos, causas y efectos de la fibrilación atrial. Dr. José Rivera Guilbe, presidente electo Academia de Medicina General de PR.

Junta Asociación Puertorriqueña de Medicina Física y Rehabilitación Con el fin de dar a conocer las nuevas tendencias, retos e innovaciones asociadas al tratamiento de manejo del dolor, se realizó la Convención Anual de la Asociación Puertorriqueña de Medicina Física y Rehabilitación. Este evento agrupó aproximadamente 125 médicos de diversas subespecialidades y contó con exponentes, locales e internacionales. Miembros junta de Asociación Puertorriqueña de Medicina Física y Rehabilitación, de izquierda a derecha: Dr. Fernando Sepúlveda, presidente entrante, Dra.Carla Matos Rodríguez, tesorera, Dra. Marimie Rodríguez Campos, presidenta de la asociación, Dra. Eileen Bravo, secretaria de la Asociación, Dr. Eduardo Nadal, presidente saliente, Dr. Carlos Calvo, director de Educación de la asociación.

Revista Puertorriqueña de Medicina y Salúd Pública

Convenciones 2018

Revista

Convención Anual de la Sociedad Dermatológica de PR (SDPR) Conferencias sobre el manejo de condiciones ampollosas, el diagnóstico de tumores de tejido blando y tratamientos para las cicatrices secundarias al acné, fueron algunos de los temas tratados en la Convención Anual de la Sociedad Dermatológica de Puerto Rico. Dra. Lilian Ramírez, presidenta entrante Sociedad Dermatológica de PR y Dra. Elena Montalván, presidenta saliente.

Convención Anual Asociación de Gastroenterología de PR Reconocer los nuevos hallazgos sobre la profesión y dar a conocer todo lo que está aconteciendo en el campo de la gastroenterología, fue el principal objetivo de la Convención. Dr. Carlos Micames, presidente Asociación de Gastroenterología de PR.

Convención anual de la Sociedad Puertorriqueña de Gastroenterología Con el fin de brindar información sobre manejo, diagnóstico y tratamiento de las enfermedades cardiovasculares, la Sociedad Puertorriqueña de Cardiología celebró su congreso. Dr. Gilberto Rivera, presidente Sociedad Puertorriqueña de Gastroenterología.

Convención Sunshine Seminar 2018 Bajo el tema de “Resiliencia en la salud de la mujer” se llevó a cabo el Sunshine Seminar 2018, denominada como la reunión científica más importante de la región del Caribe, dedicada a la medicina femenina. Cerca de 400 ginecólogos participaron de este evento del Puerto Rico Obstetrics and Ginecology (PROGyn), cuyo objetivo es proveer información actualizada en temas sobre la salud preventiva de la mujer. Dr. Nabal Bracero, presidente PRO Gyn.

100

Revista Puertorriqueña de Medicina y Salúd Pública

Convenciones 2018

Revista

Best of ASCO 2018

Conferencia Hispana de Salud Pública (CHISPA)

En las convenciones Best of ASCO y Caribbean Breast Symposium, los asistentes conocieron lo más reciente sobre los tumores cancerosos.

La conferencia se centró en el análisis del estado en que se encuentra el sistema de salud del país, tras el impacto del fenómeno atmosférico María.

Dr. Bolívar Arboleda, presidente Sociedad Puertorriqueña de Senología.

Dr. Javier Morales, infectólogo y director del Clinical Research Puerto Rico.

Convención Anual del Colegio de Farmacéuticos de PR

Congreso de Coalición de Asma de PR

Los cambios en la prestación de los servicios de salud en el país y la importancia de la labor del farmacéutico, fueron parte de los temas discutidos durante la Convención. Lcdo. Alfredo Román, presidente Colegio de Farmacéuticos de PR.

Los cambios en la prestación de los servicios de salud en el país y la importancia de la labor del farmacéutico, fueron parte de los temas discutidos durante la Convención. Dr. Álvaro Aranda, presidente Coalición de Asma de PR.

Convención anual de la Sociedad de Enfermedades Infecciosas de PR (SEINPR) El uso adecuado de los antibióticos para evitar la resistencia a los mismos, el panorama del VIH, la epidemiología de las infecciones respiratorias virales en personas hospitalizadas y las infecciones en pacientes trasplantados, fueron el foco de la Convención anual de la Sociedad de Enfermedades Infecciosas de PR (SEINPR). En esta oportunidad los asistentes contaron con la presencia de los principales exponentes en el campo de la infectología del país. Dr. Jorge Santana Bagur, presidente Sociedad de Enfermedades Infecciosas de PR (SEINPR).

Revista Puertorriqueña de Medicina y Salúd Pública

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Médico cirujano Rafael A. Couto y su paciente Katie Stubblefield tras el trasplante de rostro.

El Dr. Rafael A. Couto, primer cirujano puertorriqueño en participar de un trasplante de rostro

l Dr. Rafael Couto no pasará en vano por la historia. Gracias a su destacada labor, este médico puertorriqueño hizo parte del equipo de cirugía plástica que participó del trasplante de rostro realizado a la persona más joven en nuestros días. El procedimiento se llevó a cabo en Cleveland Clinic, Estados Unidos y duró 31 horas en completarse.

parte del proceso posoperatorio y realizó otras operaciones de revisión. Para el Dr. Couto, la posibilidad de hacer parte de una de las cirugías más modernas de la medicina lo llena de gratitud con su profesión y sus colegas.

“Para mí fue fascinante como la grandeza de este evento se extendía más allá de la medicina. La paciente fue Katie Stubblefield, una Por ejemplo, la valentía de la paciente, el amor joven que perdió la mayoría de su rostro en un incondicional que tenía la familia y sobre todo el intento de suicidio. En la cirugía se corrigieron trabajo del equipo de Cleveland Clinic” estructuras óseas y se ajustaron tejidos blandos, especialmente en el área maxilar para facilitar Sin duda, el doctor ha sentado un precedente el movimiento de la lengua y labios. El cirujano, para la medicina de Puerto Rico, que se destaca egresado de la Escuela de Medicina de la nuevamente en el ámbito internacional por las Universidad de Puerto Rico (UPR), supervisó extraordinarias capacidades de sus profesionales.

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Revista Puertorriqueña de Medicina y Salúd Pública

UNDERLYING THROMBOTIC RISK PERSISTS In stable CAD/PAD patients, major cardiovascular events doubled over two years despite guidelines-based therapy1

To learn more about Underlying Thrombotic Risk, register for a virtual program by visiting ThrombosisAdvisorUS.com/Meetings

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www.ThrombosisAdvisorUS.com

CAD = coronary artery disease; PAD = peripheral artery disease. Reference: 1. Alberts MJ, Bhatt DL, Mas J-L, et al; REduction of Atherothrombosis for Continued Health Registry Investigators. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J. 2009;30(19):2318-2326. ÂŠ Janssen Pharmaceuticals, Inc. 2018

Janssen Pharmaceuticals, Inc.

May 2018

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