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LXII • Año XI • 2018

Al lado de nuestros profesionales de la salud

PRESENTACIÓN ATÍPICA DE SÍNDROME DE STEVENS - JOHNSON en un paciente adulto

CONTENIDO 10

Presentación atípica de síndrome de Stevens-Johnson en un paciente adulto

Infografía síndrome Stevens - Johnson

Estadísticas de Cáncer de cabeza y cuello más comunes

Historia de la Ortopedia Pediátrica de Puerto Rico

Evaluación y tratamiento del pie diabético

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

Efectos metabólicospresentes un año luego de Roux NY gastric bypass o Sleeve Gastrectomy comocirugía bariática para reducción de peso

Intervención integral para abordar la Diabetes Mellitus Tipo 2 y la depresión concomitante en un entorno de atención primaria

El cáncer de ano en las personas con VIH/SIDA: Un riesgo en aumento

Infografía Psoriasis en Puerto Rico

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Comité Editorial Científico

Dr. Norman Ramírez Lluch, Md, FAAP, FAAOS 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). PRESIDENTE COMITÉ EDITORIAL CIENTÍFICO:

COMITÉ EDITORIAL

Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD Ileana Santiago Álvarez, MBA VICEPRESIDENTA EDITORIAL MUNDO Y FUNDADORA Laila Paloma Lorraine CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA PERIODISTAS Mayra Acevedo, Belinda Burgos, Jenny Marcela Moreno Wilches, Jessica Alejandra González Roncacio, REALIZADORA AUDIOVIZUAL Alejandra Montenegro Arango PROGRAMADOR WEB Diego Esteban Gutiérrez ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres, Pablo Bermúdez Robayo, Marcela Castro Villamarín 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

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MSP celebra duodécimo aniversario liderando el campo informativo de medicina y salud pública

Fue en noviembre de 2006 cuando se realizó el lanzamiento de la Revista Puertorriqueña de Medicina y Salud Pública en la Escuela de Medicina de Ponce con el apoyo decidido de su Programa de Salud Pública. Sin embargo, mucho antes de esa primera edición un grupo de profesionales de la salud y del periodismo se reunían con mucho entusiasmo y compromiso para planificar dicha publicación y su lanzamiento. Fue así, como hace poco más de doce años el permanente entusiasmo de estos profesionales de la salud y del periodismo, convertían en realidad uno de sus objetivos: “Editar una publicación periódica de carácter científ ico, destinada a divulgar las experiencias e investigaciones, especialmente en el área de la medicina y la salud pública, dando prioridad las realizadas en Puerto Rico”. Nace dado que, desde el extenso

campo de ejecutorias en el mundo de las publicaciones médicas, faltaba como complemento indispensable y valioso, un foro amplio que permitiera divulgar el trabajo de nuestros investigadores, el cual, le abriera las puertas de los principales laboratorios no solo a las autoridades médicas sino también a los gobernantes y a la ciudadanía interesada en conocer los resultados del trabajo científico para combatir y estudiar las enfermedades. Así, desde ese momento, nuestra revista ha mantenido su objetivo de ser una herramienta diaria imprescindible. El contenido de MSP se ha caracterizado por la originalidad y diversidad de temas médicos y de salud pública de naturaleza científ ica, técnica, humanidades, analítica, docente, ética, cultural, a r t íst ica, h istór ica, g rem ia l, profesional, informativa y social, en los que han participado desde eminentes médicos y profesionales de la salud

de Puerto Rico y el extranjero, hasta estudiantes de medicina y de salud pública bajo supervisión docente, por cuanto, hemos sido una revista abierta, empeñada en estimular la investigación y la divulgación de la información más relevante a nivel nacional como internacional. Y con mucho esfuerzo lo hemos logrado a fuerza de decisión y perseverancia indeclinables. El entusiasmo inicial continúa vigente, siendo el motor principal de todo el equipo editorial, con miras a escalar metas cada vez más elevadas. En estos doce años le hemos abierto las puertas a decenas de investigadores y médicos que no tenían la oportunidad de publicar sus años de investigación debido a las políticas editoriales de otros medios. A través de nuestras páginas, sus trabajos, han despertado el interés de la comunidad científica internacional y han obtenido el reconocimiento de sus pacientes y de la

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ciudadanía. En esta etapa, es nuestra misión facilitar la difusión del trabajo de nuestros médicos, investigadores y profesionales de la salud, potenciando su alcance, rompiendo las tendencias tradicionales de divulgación científica armonizando el conocimiento de un amplio equipo de profesionales de la salud, periodistas, diseñadores gráficos, realizadores audiovisuales, editores y programadores para presentarle al público de distintas maneras el resultado de las investigaciones y de las innovaciones médicas. La conmemoración de este a n iversar io es una ocasión privilegiada para recapitular sobre lo conseguido, celebrar su salud editorial y posicionarnos frente al futuro. Es un momento que nos permite disfrutar de una publicación

PRESIDENTE COMITÉ EDITORIAL CIENTÍFICO Norman Ramírez Lluch, MD, FAAP, FAAOS

Director Médico del Programa de Residencia del Mayagüez Medical Center (MMC) y Manatí Medical Center (MMC)

Volumen LII • Año IX

consolidada ed itor ia lmente y prestigiada entre los sectores de la academia y los profesionales de la salud más progresistas. Uno de nuest ros mayores logros ha sido mantener nuestra publicación con una frecuencia bimensual ininterrumpida. Incluso, en octubre del 2017 a menos de un mes del devastador paso del huracán María por nuestra Isla, pudimos llevarle a nuestros lectores una edición especial que le mostró al mundo no solo las dificultades a las que nos enfrentábamos como País, sino también el compromiso de los médicos y profesionales de la salud con nuestra población y especialmente con nuestros pacientes. Sin embargo, debemos resaltar que nuestro logro más visible ha sido gracias a las posibilidades

que nos brinda la internet y a las oportunidades que nos brindan las redes sociales , apostando con plataformas digitales totalmente diferentes a las que los usuarios estaban acostumbrados y logrando el posicionamiento ante millones de cibernautas de todos los lugares del mundo. Todo esto sin perder el concepto original y los principios éticos que nos impulsaron desde el primer día pero siempre buscando mejorar la calidad de nuestra Revista, adaptándola a los requisitos más exigentes e incorporando nuevas secciones y recursos. Este ha sido y seguirá siendo un proceso fascinante de cambios en lo que auguramos más cumpleaños por delante.

EDITOR

EDITOR FUNDADOR

Alberto Santiago Cornier, MD, PhD

Juan Carlos Orengo Valverde, MD, MPH, PhD

Jefe División de Genética del San Jorge Children’s Hospital en San Juan, Puerto Rico Director Centro Investigaciones Clínicas del San Jorge Children’s Hospital en San Juan, Puerto Rico Catedrático Asociado de la Universidad Central del Caribe, Departamento de Pediatría, Bayamón Puerto Rico Catedrático Asoaciado de la Esucela de Medicina de Ponce, Departamento de Bioquímica, Ponce, Puerto Rico Práctica Privada Torre Médica Hospital San Jorge y SER de Puerto Rico

Facultativo de la Escuela de Salud Pública de Ponce Health Science University

Revista Puertorriqueña de Medicina y Salúd Pública

SÍNDROME DE STEVENS-JOHNSON El síndrome de Stevens-Johnson (SJS) es una enfermedad de la piel que amenaza la vida y en la que la muerte celular hace que la epidermis se separe de la dermis.

millón año

Es una condición rara, con una incidencia de 2,6 a 6,1 casos por millón de personas por año.

Población afectada El SSJ ocurre en todas las edades, en todas las razas y en ambos sexos.

Es más frecuente en niños y adultos jóvenes del sexo masculino, con una incidencia de 1 a 6 casos por millón de personas por año.

2 a 1 es la proporción en la que los varones se ven más afectados que las mujeres.

100 veces mayor es el riesgo de que personas con VIH la padezcan frenre a la población general.

Reacción a medicamentos Los medicamentos son el agente causal más frecuente en el 60% de los casos los causantes son: + Sulfonamidas + Hidantoína + Carbamazepina + Barbitúricos

+ Fenilbutazona + Piroxicam + Alopurinol + Aminopenicilina

Se cree que el síndrome de Stevens-Johnson es una reacción severa a medicamentos, infecciones y, en contadas ocasiones, a cánceres producida en sistemas inmunológicos débiles.

Síntomas Entre su sintomatología esta: fiebre, dolor en las articulaciones, dolor ocular, picor ocular y lesiones en la piel en forma de vesículas y ampollas. En los casos más graves: deshidratación, problemas respiratorios, arritmias, pericarditis, estupor, coma e incluso la muerte.

MSP INFOGRAFÍAS

Complicaciones

Cifras

más comunes

300 nuevos diagnósticos por año se presentan en Estados Unidos

+ Infecciones + Complicaciones pulmonares + Deshidratación + Alteraciones de los electrolitos + Necrosis tubular aguda + Complicaciones oftálmicas y arritmias.

Del 5 al 15% de los casos sin tratar terminan en casos de mortalidad. En la fase aguda, la mortalidad puede ser del 10%,particularmente en los pacientes con afectación pulmonar

50%

de los casos del síndrome de Stevens-Johnson es idiopático

70%

es el alcance de mortalidad que pueden causar pese a su baja frecuencia

-10% 8% 30°32°

es el porcentaje de superficie corporal que se ve comprometido presentando despegamiento epidérmico de los pacientes tratados pueden ser graves, con formación de vesículas, ampollas, ulceración de mucosas es la temperatura ambiental que se recomienda para evitar que el paciente pierda calor a través de la piel

Primera fase

Segunda fase

Tercera fase

Edema en los párpados, fiebre, congestión ocular con picor, molestias al tragar y lesiones cutáneas en forma de pápulas rosadas, en cara, tronco, palmas de las manos y plantas de los pies.

Gran extensión de lesiones con presencia de ampollas, zonas erosionadas y necrosis. Se presentan largas áreas de desprendimiento epidérmico.

1. Hiper o hipopigmentación de la piel. 2. Inversión del párpado inferior hacia el ojo (entropión). 3. Conjuntivitis. 4. Lesiones en la mucosa bucal y esofágica. 5. Adhesión del párpado al globo ocular (simbléfaron). 6. Úlcera en la córnea del ojo. 7. Imposibilidad de cerrar completamente los ojos (lagoftalmia).

Texto:Marcela Moreno Wilches - Diseño:Marcela Villamarín9 Revista Puertorriqueña de Medicina yCastro Salúd Pública Fuente:Medicina y Salud Pública

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Presentación atípica de síndrome de STEVENS - JOHNSON EN UN PACIENTE ADULTO

Autores: Yuniet C. Moya;

1 2

Jesús Sarmiento Forastieri;

Marielys Otero Maldonado

Afiliación: Manatí Medical Center: 1

Programa de Residencia de

Medicina de Familia, PGY2; 2

Departamento de Medicina

de Familia; 3 Departamento de Medicina Interna/ Enfermedades Infecciosas. Manatí Medical Center, Carretera No.2 int. 668 Urb. Atenas Manatí, PR 00674

Resumen El síndrome de Stevens-Johnson (SJS) es una reacción de hipersensibilidad mediada por el sistema inmunológico que típicamente involucra la piel y las membranas mucosas. En los adultos con SJS la reacción a fármacos y las malignidades son la causa más común del síndrome, en contraste a los casos pediátricos en que las infecciones son las principales entidades causales. Nuestra paciente es una mujer de 66 años que presentó erupciones cutáneas con prurito y ardor de un día de evolución, que progresivamente empeoró, asociadas a malestar general leve, irritación conjuntival, ojos llorosos y secreción nasal. Inicialmente, se sospechó una reacción alérgica grave, sin embargo, no respondió a los esteroides y al tratamiento

Revista Puertorriqueña de Medicina y Salúd Pública

antihistamínico. Se sospechó SJS atípico, considerando la historia de infección respiratoria de vías aéreas superiores como una fase prodrómica de SJS. Fue entonces que se consideró la etiología infecciosa como agente causal más probable. Se ordenaron anticuerpos IgM de M. pneumoniae que regresaron positivos. Después de una buena respuesta a la doxiciclina la paciente fue dada de alta. Un alto índice de sospecha por parte del médico de atención primaria y una estrecha colaboración con el especialista en enfermedades infecciosas fue decisivo para determinar las posibles causas de esta erupción. Los clínicos deben ser conscientes de estas presentaciones más atípicas de SJS en adultos para un diagnóstico rápido y el inicio de la terapia apropiada.

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Introducción El síndrome de Stevens-Johnson (SJS, por sus siglas en inglés) es una reacción de hipersensibilidad mediada por el complejo inmune que normalmente involucra la piel y las membranas mucosas (1,2). Una reacción de hipersensibilidad retardada ha sido relacionada en la fisiopatología de esta condición. Las personas conocidas como acetiladores lentos (individuos que requieren más tiempo para metabolizar los fármacos que sufren procesos de acetilación por lo que tienden a ser más susceptibles a los efectos indeseables asociados a estos fármacos), los pacientes inmunocomprometidos (especialmente los infectados con VIH) y los pacientes con tumores cerebrales sometidos a radioterapia con fármacos antiepilépticos concomitantes figuran entre los que corren mayor riesgo (1). Varios factores etiológicos han sido relacionados en esta patología siendo los fármacos más comúnmente identificados como los causantes seguidos de infecciones, malignidades e idiopático, respectivamente (2). Los fármacos y las neoplasias malignas suelen estar implicados como la etiología en adultos y ancianos,

mientras que los casos pediátricos se relacionan más frecuentemente con infecciones (2). En el caso de los niños, el virus de Epstein-Barr y los enterovirus se identifican frecuentemente en el desarrollo de SJS (2). Más de la mitad de los pacientes con este síndrome informan de una reciente infección del tracto respiratorio superior (1). Los agentes causantes más comunes son: Mycoplasma pneumoniae, Streptococco beta-hemolítico del Grupo A, Mycobacteria y Rickettsia (1,2). M. pneumoniae es una de las causas más comunes de neumonía atípica. Entre un 25 a 33% de los pacientes con infección por M. pneumoniae pueden presentar manifestaciones cutáneas, tales como exantemas, urticaria y SJS (3). Sin embargo, SJS es una manifestación poco frecuente en la infección por M. pneumoniae solo entre el 1 y 5% de los casos, siendo reportado principalmente en niños y en adultos jóvenes (3). En los pacientes más jóvenes, el SJS puede estar precedido por síntomas de una infección del tracto respiratorio superior de 2 días a 2 semanas antes de la aparición de la erupción (1,2). Revista Puertorriqueña de Medicina y Salúd Pública

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Figura 1. Paciente de 66 años de edad que acudió a urgencias por un picor intenso y ardor en la piel de un día de evolución. El examen físico fue positivo para una erupción eritematosa generalizada con edema asociado y descamación en algunas áreas, especialmente la espalda y el torso.

Caso Clínico Este es el caso de una paciente de 66 años de edad que acudió a urgencias por un picor intenso y ardor en la piel de un día de evolución, que progresivamente empeoró, asociado a malestar general leve, inyecciones conjuntivales, ojos llorosos y secreción nasal. Una semana antes de la presentación, había visitado la Sala de Emergencias (SE) con signos y síntomas de infección de las vías respiratorias altas, después de la evaluación fue admitida con el diagnóstico de bronquitis y debido a la mala ingesta oral, se le administraron antibióticos intravenosos. Levofloxacin 500 miligramos diarios fue el antibiótico seleccionado en ese momento. La paciente fue enviada a casa después de 4 días con el mismo antibiótico, de forma oral para completar 7 días. Al día siguiente de haber terminado el curso de antibióticos notó la primera lesión cutánea. Primero notó una lesión macular roja de aproximadamente 1 cm que aumentó de tamaño rápidamente. Pocas horas después, notó una leve sensación de ardor y 12

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picazón en el pecho anterior, la espalda, el abdomen y los genitales externos lo que estaba empeorando claramente a medida que pasaba el tiempo. Una erupción cutánea generalizada con enrojecimiento asociado, una comezón muy irritante y sensación de ardor aparecieron en un período corto. Alarmada por sus síntomas visitó la SE una vez más. En la evaluación de SE, se mantuvo hemodinámicamente estable con presión arterial de 120/60 mm/Hg, pulso de 97 latidos por minuto, frecuencia respiratoria de 19 respiraciones por minuto y una temperatura de 36.3 oC. El examen físico fue positivo para una erupción eritematosa generalizada con edema asociado y descamación en algunas áreas, especialmente la espalda y el torso, conjuntivas inyectadas y lesiones de la mucosa oral (Figura 1). El resto del examen físico fue normal. La paciente constantemente se quejaba de una severa sensación de ardor y picazón. Tenía antecedentes de diabetes mellitus insulinodependiente e

hipertensión, bien controlada en el hogar con enalapril

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El diagnóstico de SJS es clínico y obtener una historia detallada del paciente es esencial para identificar y descontinuar cualquier medicamento que potencialmente pueda ser el causante

10 mg vía oral al día, insulina NPH e insulina regular. La paciente no tenía antecedentes de alergia a medicamentos y negó hábitos tóxicos, estar expuesta a irritantes o trauma, o tener antecedentes de cáncer o tratamiento de cáncer. Las pruebas iniciales revelaron electrolitos dentro del rango normal excepto por una glucosa de 292 mg / dl. Un hemograma completo mostró un recuento de glóbulos blancos de 15,2 x 106/μL con 81,3% de neutrófilos, hemoglobina de 14,1 g/dl, hematocrito de 42,5 g/dl y conteo plaquetario de 182 x 103/ μL. Tasa de sedimentación de 49 mm/hora, sugestiva de un proceso inflamatorio. La paciente fue admitida con medidas de aislamientos protectores con un diagnóstico de síndrome de Steven Johnson (ICD10, L51.1) debido a lo sugestivo de las lesiones y el período prodrómico de una semana con síntomas respiratorios superiores usualmente encontrados en pacientes con SJS. Las órdenes iniciales fueron una solución salina al 0,45% a 60 ml/h, metilprednisolona 60 mg intravenosa cada 8 horas, difenhidramina 50 mg IV cada 8 horas, Famotidina 20 mg intravenosa cada 12 horas y sus medicamentos habituales en el hogar. La especialista en enfermedades infecciosas fue consultada iniciando a la paciente en Doxiciclina 100 mg IV cada 12 horas y ordenando laboratorios para descartar M. pneumoniae como causa de SJS

también. IgG e IgM para M. pneumoniae se ordenaron como parte de las pruebas diagnósticas y los resultados fueron positivos para IgM para M. pneumoniae, confirmando el diagnostico de SJS por un agente infeccioso. Después de varios días de tratamiento, la paciente mejoró notablemente, los síntomas de picazón desaparecieron dos días después del inicio de la terapia y entre el quinto y sexto día las lesiones de piel desaparecieron prácticamente. Discución Nuestra paciente es un caso muy atípico porque SJS causado por M. pneumoniae es poco común y se suele ver en los niños, no en los adultos. En pacientes más jóvenes, SJS puede estar precedida por síntomas de infección del tracto respiratorio superior de 2 días a 2 semanas antes de la aparición de la erupción. La mayoría de los adultos, generalmente desarrollan síntomas y erupciones casi simultáneamente, probablemente debido a una reacción inmune a una exposición previa. Las lesiones orales están presentes en el 100% de los casos, lesiones genitales en el 75% 3 y lesiones oculares en el 66% (2,3). La SJS inducida por M. pneumonia se asocia con complicaciones menos graves y menor envolvimiento de órganos internos que las resultantes por otras causas (3). Los pacientes con SJS asociada a M. pneumonia frecuentemente

han recibido antibióticos temprano durante su enfermedad, antes de la aparición de las manifestaciones cutáneas y esto puede ser un factor de confusión importante para determinar la etiología precisa de SJS (2,3). M. pneumoniae ha sido aislado ocasionalmente de lesiones de pacientes afectados, sin embargo, se cree más comúnmente que estas lesiones resultan del daño vascular mediado por el complejo inmune, la reacción autoinmune y la respuesta inmune mediada por células (1). El diagnóstico de SJS es clínico y obtener una historia detallada del paciente es esencial para identificar y descontinuar cualquier medicamento que potencialmente pueda ser el causante. Los laboratorios para M. pneumoniae deben considerarse en pacientes que presentan SJS particularmente, si no hay antecedentes de uso reciente de medicamentos como en el caso de nuestro paciente. El manejo de SJS asociado a M. pneumoniae incluye especial atención al equilibrio de líquidos y electrolitos (4). Los antibióticos se han utilizado especialmente para SJS debido a infección por M. pneumoniae o casos con compl ic a c iones sec u nd a r i a s o sepsis (4). El papel de los corticosteroides en el tratamiento de SJS es controversial debido a la posibilidad de infecciones secundarias (4). Sin embargo, los datos publicados recientemente de un estudio observacional sugieren Revista Puertorriqueña de Medicina y Salúd Pública

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un posible efecto beneficioso en pacientes tratados con corticosteroides (4). Inmunoglobulina intravenosa (dosis total de 3 g divididas durante 3 días) puede considerarse en casos graves (4). Creemos que este caso es único en algunos aspectos. El SJS asociado a M. pneumoniae es más común en niños y adultos jóvenes < 21 años de edad y es inusual en pacientes con edades mayores a este rango (2). Nuestra paciente desarrolló infección respiratoria superior una semana antes de las lesiones cutáneas, que es el período típico de retraso antes de la erupción en pacientes más jóvenes. Se encontraron altos niveles de anticuerpos IgM para M pneumoniae lo que no es común para infecciones primarias en adultos. Considerando estos hallazgos, las infecciones por M. pneumoniae pueden tener una presentación atípica en adultos por lo que

sugerimos que deben ser consideradas en el diagnóstico diferencial de SJS. El historial y el examen físico son la parte más importante del diagnóstico de cualquier patología, especialmente aquellos con presentación atípica como en nuestra paciente. En nuestro caso, la historia detallada obtenida en la entrevista inicial fue esencial para el resultado positivo de la paciente. Un alto índice de sospecha por parte del médico de atención primaria y una estrecha colaboración con el especialista en enfermedades infecciosas fue decisivo para determinar las posibles causas de esta erupción. Los clínicos, deben ser conscientes de estas presentaciones más atípicas de SJS en adultos para un diagnóstico rápido y el inicio de la terapia apropiada.

Referencias Rotunda A, Hirsch RJ, Scheinfeld N, Weinberg JM. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol. 2003. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int. 2006 Mar. Sendi P, Graber P, Lepère F, Schiller P, Zimmerli W. Mycoplasma pneumoniae infection complicated by severe mucocutaneous lesions. Lancet Infect Dis. 2008 Apr. 8(4):268. Hillebrand-Haverkort ME, Budding AE, bij de Vaate LA, van Agtmael MA. Mycoplasma pneumoniae infection with incomplete Stevens-Johnson syndrome. Lancet Infect Dis. 2008 Oct. 8 14

Revista Puertorriqueña de Medicina y Salúd Pública

Â© Janssen Biotech, Inc. 2017 07/17 071251-170417

NOW APPROVED A first-in-class treatment that selectively blocks IL-23*

FOR THE TREATMENT OF ADULTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS WHO ARE CANDIDATES FOR SYSTEMIC THERAPY OR PHOTOTHERAPY

STAND FOR SUPERIOR SKIN CLEARANCE

AND THERAPEUTIC LONGEVITY Superior Skin Clearance VOYAGE 1: CO-PRIMARY ENDPOINTS AT WEEK 161,2† PASI 90

73%

‡

(n=241/329) TREMFYA™

(n=5/174)

PLACEBO

IGA 0/1

85%

‡

(n=280/329) TREMFYA™

(n=12/174)

PLACEBO

Placebo-controlled period. P<0.001 vs placebo. Based on the results of an analysis of the 101 global sites from VOYAGE 1 (including North American sites [ie, US and Canada]).

† ‡

VOYAGE 2: Co-primary Endpoints at Week 161,4 • 70% of patients taking TREMFYA™ (347/496) achieved PASI 90 vs 2% (6/248) with placebo • 84% of patients taking TREMFYA™ (417/496) achieved IGA 0/1 vs 8% (21/248) with placebo P<0.001 vs. placebo. Based on the results of an analysis of the 115 global sites from VOYAGE 2 (including North American sites [ie, US and Canada]). *IL=interleukin.

TREMFYA™ is administered as a 100 mg subcutaneous injection once every 8 weeks, after starter doses at Weeks 0 and 4. TREMFYA™ is intended for use under the guidance and supervision of a physician. Patients may self-inject with TREMFYA™ after physician approval and proper training.

Therapeutic Longevity VOYAGE 1: MAJOR SECONDARY ENDPOINT AT WEEKS 16, 24, AND 48 (NORTH AMERICAN ANALYSIS)1,3 PASI 90 VS HUMIRA® (adalimumab)

PERCENTAGE OF PATIENTS

ONLY 7 TREMFYA™ DOSES THROUGH WEEK 48 100 80

80§

73§

60 40

20 0

TREMFYA™ Humira®

TREMFYATM (84/115) Humira® (47/115)

TREMFYATM (92/115) Humira® (51/115)

TREMFYATM (84/115) Humira® (53/115)

WEEKS P<0.001 vs Humira®.

Based on the results of an analysis of 38 North American sites (US=27, Canada=11) from VOYAGE 1 that used US-licensed Humira®. The same patients may not have responded at each time point. VOYAGE 2: Major Secondary Endpoints at Week 241,3

• At Week 24, 71% of patients taking TREMFYA™ achieved PASI 90 (113/160) vs 51% (41/81) with Humira®; P=0.003 vs Humira®

Based on the results of an analysis of 41 North American sites (US=31, Canada=10) from VOYAGE 2 that used US-licensed Humira®.

IMPORTANT SAFETY INFORMATION

Infections TREMFYA™ may increase the risk of infection. Treatment with TREMFYA™ should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated. Consider the risks and beneﬁts of treatment prior to prescribing TREMFYA™ in patients with a chronic infection or a history of recurrent infection. Instruct patients receiving TREMFYA™ to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection, or is not responding to standard therapy, closely monitor and discontinue TREMFYA™ until the infection resolves. Pre-Treatment Evaluation for Tuberculosis (TB) Evaluate patients for TB infection prior to initiating treatment with TREMFYA™. Initiate treatment of latent TB prior to administering TREMFYA™. Monitor patients for signs and symptoms of active TB during and after TREMFYA™ treatment. Do not administer TREMFYA™ to patients with active TB infection. Immunizations Prior to initiating TREMFYA™, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TREMFYA™.

Adverse Reactions Most common (≥1%) adverse reactions associated with TREMFYA™ include upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections. Please see the Brief Summary of the full Prescribing Information for TREMFYA™ on the following page. References: 1. TREMFYA™ (guselkumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc. 2. Blauvelt A, Papp KA, Griffiths CEM, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76(3): 405-417. 3. Data on file. Janssen Biotech, Inc. 4. Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431. TTREMFYA™ (guselkumab) is a trademark of Janssen Biotech, Inc. Humira® (adalimumab) is a registered trademark of AbbVie Inc.

067010-170208

B:11.75 in

T:11.5 in

S:10.3667 in

In VOYAGE 1, 837 patients were randomized to placebo (n=174), TREMFYA™ 100 mg every 8 weeks (q8w) after Weeks 0 and 4 (n=329), or Humira® 80 mg at Week 0, 40 mg at Week 1, and 40 mg every 2 weeks thereafter (n=334). Eligible patients (≥18 years of age) had moderate to severe plaque psoriasis (ie, Investigator Global Assessment [IGA] score ≥3, Psoriasis Area and Severity Index [PASI] score ≥12, body surface area involvement ≥10%) for at least 6 months and were candidates for systemic therapy or phototherapy. The study comprised a placebo-controlled period (Weeks 0 to 16) after which patients taking placebo crossed over to receive TREMFYA™ at Weeks 16 and 20 and q8w thereafter through Week 48 and an active-comparator–controlled period when TREMFYA™ was compared with Humira® from Week 0 through Week 48.1 In VOYAGE 2, 992 patients were randomized to placebo (n=248), TREMFYA™ 100 mg q8w after Weeks 0 and 4 (n=496), or Humira® 80 mg at Week 0, 40 mg at Week 1, and 40 mg every 2 weeks thereafter (n=248). The study design was identical to VOYAGE 1 through Week 28. Inclusion criteria were consistent with VOYAGE 1. The study comprised a placebocontrolled period (Weeks 0 to 16) after which patients taking placebo crossed over to receive TREMFYA™ at Weeks 16 and 20. The study also included an active-comparator– controlled period with Humira® (Weeks 0 to 24). At Week 28, subjects who were randomized to TREMFYA™ 100 mg q8w at Week 0 and those who were PASI 90 responders were re-randomized either to placebo or TREMFYA™ 100 mg q8w in a 1:1 ratio.

Brief Summary of Prescribing Information for TREMFYATM (guselkumab) TREMFYATM (guselkumab) injection, for subcutaneous use See package insert for full Prescribing Information. INDICATIONS AND USAGE TREMFYA™ is indicated for the treatment of adults with moderateto-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infections: TREMFYA may increase the risk of infection. In clinical trials, infections occurred in 23% of subjects in the TREMFYA group versus 21% of subjects in the placebo group through 16 weeks of treatment. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the TREMFYA group than in the placebo group [see Adverse Reactions]. The rate of serious infections for the TREMFYA group and the placebo group was ≤ 0.2%. Treatment with TREMFYA should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing TREMFYA. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TREMFYA until the infection resolves. Pre-treatment Evaluation for Tuberculosis: Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TREMFYA. Initiate treatment of latent TB prior to administering TREMFYA. In clinical studies, 105 subjects with latent TB who were concurrently treated with TREMFYA and appropriate TB prophylaxis did not develop active TB (during the mean follow-up of 43 weeks). Monitor patients for signs and symptoms of active TB during and after TREMFYA treatment. Consider anti-TB therapy prior to initiating TREMFYA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer TREMFYA to patients with active TB infection. Immunizations: Prior to initiating therapy with TREMFYA, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TREMFYA. No data are available on the response to live or inactive vaccines. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of labeling: • Infections [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. In clinical trials, a total of 1748 subjects with moderate-to-severe plaque psoriasis received TREMFYA. Of these, 1393 subjects were exposed to TREMFYA for at least 6 months and 728 subjects were exposed for at least 1 year. Data from two placebo- and active-controlled trials (VOYAGE 1 and VOYAGE 2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of TREMFYA (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 8 weeks). Weeks 0 to 16: In the 16-week placebo-controlled period of the pooled clinical trials (VOYAGE 1 and VOYAGE 2), adverse events occurred in 49% of subjects in the TREMFYA group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of the TREMFYA group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of U.S. licensed adalimumab group (9.9 events per 100 subject-years 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 TREMFYA group than in the placebo group during the 16-week placebo-controlled period. Table 1: Adverse Reactions Occurring in ≥1% of Subjects through Week 16 in VOYAGE 1 and VOYAGE 2 TREMFYAa 100 mg N=823 n (%)

Adalimumabb N=196 n (%)

Placebo N=422 n (%)

118 (14.3) 38 (4.6) 37 (4.5)

21 (10.7) 2 (1.0) 15 (7.7)

Arthralgia

22 (2.7)

4 (2.0)

Diarrhea

13 (1.6)

3 (1.5)

Gastroenteritisf

11 (1.3)

4 (2.0)

54 (12.8) 14 (3.3) 12 (2.8) 9 (2.1) 4 (0.9) 4 (0.9)

Upper respiratory infectionsc Headached Injection site reactionse

Tinea infectionsg 9 (1.1) 0 0 Herpes simplex infectionsh 9 (1.1) 0 2 (0.5) a subjects receiving 100 mg of TREMFYA at Week 0, Week 4, and every 8 weeks thereafter. b U.S. licensed adalimumab c Upper respiratory infections include nasopharyngitis, upper respiratory tract infection (URTI), pharyngitis, and viral URTI. d Headache includes headache and tension headache. e Injection site reactions include injection site erythema, bruising, hematoma, hemorrhage, swelling, edema, pruritus, pain, discoloration, induration, inflammation, and urticaria. f Gastroenteritis includes gastroenteritis and viral gastroenteritis. g Tinea infections include tinea pedis, tinea cruris, tinea infection, and tinea manuum infections. h Herpes simplex infections include oral herpes, herpes simplex, genital herpes, genital herpes simplex, and nasal herpes simplex. Adverse reactions that occurred in < 1% but > 0.1% of subjects in the TREMFYA group and at a higher rate than in the placebo group through Week 16 in VOYAGE 1 and VOYAGE 2 were migraine, candida infections, and urticaria. Specific Adverse Reactions: Infections: Infections occurred in 23% of the TREMFYA group compared to 21% of the placebo group. The most common (≥ 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of TREMFYA. Elevated Liver Enzymes: Elevated liver enzymes were reported more frequently in the TREMFYA group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver

TREMFYATM (guselkumab) injection enzymes in the TREMFYA group, all events except one were mild to moderate in severity and none of the events led to discontinuation of TREMFYA. Safety through Week 48: Through Week 48, no new adverse reactions were identified with TREMFYA use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment. Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity with TREMFYA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab with the incidences of antibodies to other products may be misleading. Up to Week 52, approximately 6% of subjects treated with TREMFYA developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions. DRUG INTERACTIONS Live Vaccinations: Avoid use of live vaccines in patients treated with TREMFYA [see Warnings and Precautions]. CYP450 Substrates: The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, interferon) during chronic inflammation. Results from an exploratory drug-drug interaction study in subjects with moderate-to-severe psoriasis suggested a low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19 and CYP1A2 but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6. However, the results were highly variable because of the limited number of subjects in the study. Upon initiation of TREMFYA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: There are no available data on TREMFYA use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, TREMFYA may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD (see Data). The clinical significance of these nonclinical findings is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated 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: In a combined embryofetal development and pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on a mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on a mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on a mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-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 guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TREMFYA and any potential adverse effects on the breastfed infant from TREMFYA or from the underlying maternal condition. Pediatric Use: The safety and efficacy of TREMFYA in pediatric patients (less than 18 years of age) have not been established. Geriatric Use: Of the 1748 subjects with plaque psoriasis exposed to TREMFYA, a total of 93 subjects were 65 years or older, and 4 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received TREMFYA. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer 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 starting TREMFYA therapy, and each time the prescription is renewed, as there may be new information they need to know. 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 an infection [see Warnings and Precautions]. Instruction on Injection Technique: Instruct the patient or caregivers to perform the first self-injection under the supervision and guidance of a qualified healthcare professional for proper training in subcutaneous injection technique. Instruct patients who are self-administering to inject the full dose of TREMFYA [see Medication Guide and Instructions for Use]. Instruct patients or caregivers in the technique of proper needle and syringe disposal. Needles and syringes should be disposed of in a puncture-resistant container. Advise patients and caregivers not to reuse needles or syringes. Remind patients if they forget to take their dose of TREMFYA to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time.

MSP INFOGRAFÍAS

Dr. Manuel García Ariz

Dr. Norman

Ramírez Lluch

La facultad de Ortopedia Pediátrica del Hospital Pediátrico integrada por el Dr. John Flynn, el Dr. Manuel García Ariz y el Dr. Néstor Ramos, se caracterizó por su dinamismo.

Este dinamismo, estimuló que los doctores Pablo V. Marrero, José Aníbal Collazo, Samuel Fernández y Norman Ramírez regresaran a Puerto Rico en los años 90 con el entrenamiento de “Fellow” en Ortopedia Pediátrica.

Dr. John Flyn

Historia de la Ortopedia Pediátrica en Puerto Rico 1920 al 1930, no había en Puerto Rico médicos ortopedas.

Dr. Espinosa y el Dr. Ferraioli eran cirujanos generales que se dedicaban a trauma, principalmente, y a la ortopedia.

1940

1968 Bajo la dirección del doctor Aníbal

Año en el que Puerto Rico contó con el primer ortopeda; el Dr. Kraft, quien vino a la Isla con el Ejército de Estados Unidos.

Lugo, se establece la Residencia en Ortopedia de la Escuela de Medicina de la UPR.

1960

en adelante comienzan a practicar en PR médicos entrenados en Ortopedia como el Dr. Llompart, el Dr. Bonilla, el Dr. Suárez Alvarez y el Dr. Guzmán Acosta, entre otros.

4 Médicos residentes comienzan el programa; el Dr. José Abreu Deliz, el Dr. Juan Rodríguez Colón, el Dr. Carlos Grovas y el Dr. César Cintrón del Valle.

1971

Es el año donde la primera clase completa su residencia.

Dr. Fernández Feliberti, fue el primer graduado de la Escuela de Medicina de la UPR en hacerse ortopeda.

1976

Asume la dirección del Departamento el Dr. Rafael Fernández Feliberti. Bajo

su liderazgo se desarrolló la rotación de ortopedia pediátrica dentro del Programa de Entrenamiento en Ortopedia.

2000

El Dr. Rafael Fernández Feliberti clave en el desarrollo del Departamento de Cirugía Ortopédica de la Escuela de Medicina de la Universidad de PR.

1966

Dr. Fernández Feliberti culmina su residencia en Ortopedia en la Clínica Mayo. Regresa a Puerto Rico como Profesor Asistente en la Escuela de Medicina. Luego de pasar los Boards, lo nombran Profesor Asociado.

El Dr. Rafael Fernández Feliberti se retira de la Escuela de Medicina.

Dr. Manuel García

Ariz

Asume la dirección del Programa el doctor Manuel García Ariz. A partir de la década del 2000 se integran a la práctica los doctores Onix Reyes, Humberto Guzmán, Gladys Ramos, Lissette Salgueiro y Leah Cobb.

2017 En reconocimiento a su campo educativo como en la investigación, la Sociedad Puertorriqueña de Ortopedia y Traumatología

El Dr. Francisco López dirige el Programa de Entrenamiento en Ortopedia UPR.

que lleva su nombre. Centro Médico.

Puerto Rico contaba con el Sistema de Niños Lisiados del Departamento de Salud de Puerto Rico el cual ofrecía servicios de primera calidad y estimulaba a muchos médicos a inclinarse por la Ortopedia Pediátrica.

MSP CASO CLÍNICO

Revista Puertorriqueña de Medicina y Salúd Pública

MSP CASO CLÍNICO

Fibrilación atrial secundario

A MIXOMA GRANDE

en un hombre de 68 años

Autores: Raúl García Rinaldi MD PhD FACS, Héctor Martínez MD FACC,Ruth Barosy MD PGY2 FM, Roberto López MD PGY2 FM,Lourdes Aguiló MD PGY1 FM

Revista Puertorriqueña de Medicina y Salúd Pública

MSP CASO CLÍNICO

“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 22

Revista Puertorriqueña de Medicina y Salúd Pública

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

MSP CASO CLÍNICO

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 primaria debido a una hematuria inexplicable acompañada de mareos, debilidad y disuria de 1 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, pero 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 calcif icado 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 ingresada 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 resolvió espontáneamente y no ha vuelto a aparecer. El paciente también se sometió a una cistoscopia ambulatoria que no reveló ningún hallazgo significativo. Revista Puertorriqueña de Medicina y Salúd Pública

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Discusión Este caso clínico destaca la importancia de considerar el diagnóstico de un mixoma cardiaco 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 intracardiaco. 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

Revista Puertorriqueña de Medicina y Salúd Pública

“DEBIDO A SU NATURALEZA INTRA-VASCULAR 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.

MSP CASO CLÍNICO

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 myxoma familiar pueden tener una variedad de características llamadas síndrome de myxoma 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 cardiaca 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. Estas células 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”

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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 26

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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

10 mg NOW APPROVED: For the reduction in the risk of recurrence of DVT/PE in patients at continued risk of DVT/PE* *After 6 months initial treatment.

The ONLY NOAC to demonstrate a major bleeding rate as low as aspirin with superior efﬁcacy

Convenient 30-day Starter Pack for the initial treatment of DVT and/or PE

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

IMPORTANT SAFETY INFORMATION Factors that can increase the risk of developing epidural WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, or spinal hematomas in these patients include: (B) SPINAL/EPIDURAL HEMATOMA Use of indwelling epidural catheters

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.

Concomitant use of other drugs that affect hemostasis, such as non-steroidal 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.

NOAC = non-vitamin K antagonist oral anticoagulant.

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

IMPORTANT SAFETY INFORMATION (cont’d) CONTRAINDICATIONS Active pathological bleeding Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions) WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events After Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. 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).

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS AND PRECAUTIONS (cont’d)

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.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2017 November 2017 070524-170906

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• 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. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated 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

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/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.

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

MSP ARTÍCULO ORIGINAL

Efectos metabólicos presentes un año luego de Roux NY gastric bypass o Sleeve Gastrectomy como CIRUGÍA BARIÁTRICA para reducción de peso . Por: Héctor Núñez , MD. Pablo I. Altieri, MD. Albert Suarez, MD Departamento de Medicina y Fisiología Universidad de Puerto Rico-Recinto Ciencias Médicas, San Juan Puerto Rico

Resumen Describimos la data de cirugía bariátrica de la UPR -roux -n- y -sleeve incluyendo los cambios metabólicos después de la cirugía.

Revista Puertorriqueña de Medicina y Salúd Pública

Abstract Description of metabolic changes seen in roux -n y surgery and sleeve surgery with possible cure of diabetes mellitus.

MSP ARTÍCULO ORIGINAL

Palabras clave Cirugía bariátrica, cambios metabólicos, cura diabetes mellitus Keywords Bariatric surgery, metabolic changes, diabetes mellitus cure Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO ORIGINAL

Infografía Cirugía Bariátrica A

B E

Estómago Bolsa gástrica

Manga gástrica

Banda gástrica

Reservorio subcutáneo

Varios métodos

En las imágenes de la izquierda y la superior pueden observarse varios de los métodos que se utilizan actualmente dentro del campo de la cirugía bariátrica para tratar la obesidad mórbida (n o t r i b u t a r i a d e te r a p i a farmacológica o diabetológica):

D Estómago

Bolsa gástrica

Sección de Roux

Región biliopancreática

Canal común

Región biliopancreática

Sección alimentaria

Canal común

A: Banda gástrica laparoscópica ajustable B: Gastrectomía en manga C: En Y de Roux de bypass gástrico D: Derivación biliopancreática con cruce duodenal E: Bolsa gástrica superior separada del resto del estómago

Fuente: Centro Médico Láser en Quirón

L 36

a obesidad fue reconocida 15 años1 con un aumento exponencial como una epidemia mundial en la prevalencia desde entonces. En p or l a O r g a n i z a c ión Estados Unidos, estudios nacionales Mundial de la Salud hace han demostrado un aumento en la

Revista Puertorriqueña de Medicina y Salúd Pública

proporción de adultos con un BMI mayor de 25 a 29% en 1980 a 34% en el 2013. En Puerto Rico las tasas de obesidad

MSP ARTÍCULO ORIGINAL

son aún más alarmantes. Datos del Departamento de Salud muestran una prevalencia de 66.2%, afectando en mayor proporción a personas entre 45-64 años de edad, colocando la Isla entre los diez estados con mayor prevalencia de obesidad en la nación. Actualmente, dicha condición se considera un grave riesgo para la salud y un factor de riesgo para diabetes mellitus, hipertensión arterial, gastroesofágico, apnea del sueño, entre otras2. Dentro del grupo de personas obesas la proporción de obesidad mórbida ha ido en aumento y de igual forma el impacto económico y social de las comorbilidades de dicha condición en el sistema de salud 3. Múltiples intervenciones para atacar este problema se han desarrollado a lo largo de los años, principalmente

con el uso de diversas intervenciones quirúrgicas para la reducción de peso. Estudios que han demostrado el impacto a largo plazo de estas intervenciones en la reducción de factores de riesgo cardiovascular y resolución de condiciones crónicas como hipertensión arterial y diabetes4. Dentro de los principales tipos de cirugía bariátrica se encuentra el Rouxn-N-Y gastric bypass(RouxN-Y) y la Vertical Sleeve Gastrectomy (LSG). Ambos tipos de intervenciones varían en los mecanismos de reducción de peso y parámetros metabólicos dentro los cuales se encuentran, la reducción de ingesta calórica y espacio gástrico, aumento en saciedad, malabsorción de nutrientes y cambios neuroendocrinos incluyendo aumento en GLP-1, PPY, OXM y reducción en Leptina y Grelina, todos hormonas gastrointestinales asociadas a la

ingesta oral 5 . Estudios sobre la efectividad de ambos procedimientos a corto y largo plazo han demostrado el éxito de ambas intervenciones, siendo ambas igualmente efectivas en la reducción de peso y resolución de Diabetes Mellitus pero con una mayor efectividad de Roux N-Y en la cantidad de pérdida de peso y resolución de comorbilidades incluyendo hipertensión arterial, artritis6. Ambos procedimientos tienen ventajas y desventajas en relación a los efectos metabólicos por lo cual, no hay una postura clara en la literatura sobre la superioridad de uno sobre el otro. La decisión de cual tipo de para el paciente tiene que tomar en cuenta entonces las comorbilidades presentes y las complicaciones operator ias inherentes a cada

Tabla 1.

79.4 89.5 FÉMINAS

Roux-NY

38.2 23.5 Roux-NY

LSG

HIPERTENSIÓN ARTERIAL

50.9 50.0 Roux-NY

APNEA DE SUEÑO OBSTRUCTIVA

70.5 76.5 Roux-NY

LSG

DIABETES MELLITUS

LSG

DISLIPIDEMIA

6.8 5.9

Roux-NY

LSG

Grupo Operatorio: Roux-NY (Porciento) n=102 LSG (Porciento) n=34

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“AMBAS FUERON INDEPENDIENTEMENTE EFECTIVAS EN DISMINUIR SIGNIFICATIVAMENTE LOS NIVELES DE TG Y FBS Y ELEVAR EL HDL. POR OTRA PARTE, LAS DIFERENCIAS DEL CAMBIO POST OPERATORIO NO FUERON SIGNIFICATIVAS ENTRE AMBAS INTERVENCIONES” de la intervención quirúrgica. Los valores de interés fueron: Índice de masa corporal (BMI), Colesterol total , LDL-C, HDL-C, Triglicéridos y Glucosa en ayuna (FBS). Un total de 34 pacientes del grupo del mientras que si al momento de la grupo de LSG y 102 del grupo de intervención la meta principal es Roux-N-Y fueron utilizados para la pérdida de peso LSG es la mejor análisis estadístico dado a contar opción dado a la simplicidad de la con la totalidad de datos en los tres intervención y menos complicaciones periodos de evaluación. Se utilizo post-operatorias7. En este trabajo cada paciente como su propio control investigativo se evaluó la diferencia para evaluar los cambios luego de entre los cambios metabólicos intervención. presentes en dos grupos de pacientes que recibieron dichas intervenciones Resultados Un total de 34 pacientes del grupo identif icar la intervención más de LSG y 102 pacientes del grupo de efectiva. Roux N-Y completaron seguimiento un año tras la intervención quirúrgica. Metodología y Materiales Los grupos no fueron diferentes S e r e a l i z ó u n a e v a lu a c i ón en términos de las comorbilidades retrospectiva de todos los pacientes presentes antes del procedimiento de cirugía bariátrica en el Hospital bariátrico y alto porcentaje de féminas Universitario de Carolina durante participantes. Las comorbilidades presentes más comunes fueron, un total de 134 pacientes que se diabetes mellitus tipo 2, hipertensión sometieron a LSG y 102 pacientes arterial, apnea obstructiva de sueño a Roux N-Y. Para ambos grupos se y dislipidemia; porcentajes descritos utilizaron datos de evaluación pre- en tabla 1. No hubo diferencias operatoria, un mes y un año luego técnica quirúrgica. Se postula que, dado la evidencia a largo plazo de Roux N-Y en resolución de comorbilidades dicho procedimiento es una mejor alternat iva para

Revista Puertorriqueña de Medicina y Salúd Pública

los valores pre-operatorios de BMI, Colesterol Total, LDL-C, HDL-C y FBS entre ambos grupos. En el grupo de Roux-N-Y se observó una diferencia estadísticamente del colesterol total y LDL-C un año luego de la cirugía en comparación con la reducción presente luego de LSG; datos en tabla 1. El promedio de LDL-C en Roux NY fue 86.2 mg/ dL(25.3) con una reducción de 14.99 % versus un promedio en LSG de 99.29 mg/dL (± 24.3) y 7.63 % de reducción. El promedio de Colesterol Total en Roux NY fue 151.8 mg/dL (±24.6) con una reducción de 9.2 % versus un promedio en LSG de 167.1 mg/dL (± 24.6) y 1.8 % de reducción. Ambas intervenciones por separado en BMI, TG, FBS y un aumento en HDL -C. Sin embargo, no se entre la reducción de BMI, TG, FBS y aumento en HDL-C un año luego de las intervenciones quirúrgicas al comparar los cambios entre ambos procedimientos; datos en tabla 2. Discusión Rou x N Y gast r ic by pass ha demostrado tener un mayor impacto que la LSG en términos de reducción en parámetros metabólicos asociados con enfermedad cardiovascular. L os ha l lazgos de este estud io demostraron una mayor reducción en los niveles de colesterol total y LDL -C en comparación con los cambios presentes luego de LSG

MSP ARTÍCULO ORIGINAL

Tabla 2.

Cambios post-operatorios un año luego de Roux N-Y y LSG Parámetros evaluados

Promedio Pre-Operatorio (SE)

Promedio Post-Operatorio (SE)

% Reducción

Roux-N-Y

LSG

Valor P

Roux-N-Y

LSG

Valor P

Roux-N-Y

LSG

BMI (kg/m2)

47.6 (±9.1)

45.97 (±7.30)

0.3453

33.3 (±7.5)

32.14 (±5.96)

0.9315

-30.04

-30.08

Colesterol Total (mg/dL)

169.6 (± 30.8)

170.20 (±30.83)

0.9218

151.8 (±30.9)

167.13 (±24.62)

0.0096

-10.49

-1.80

Triglicéridos 112.7 (mg/dL) (±47.3)

114.88 (±46.77)

0.8158

84.0 (±22.9)

86.57 (±47.62)

0.9576

-25.46

-24.64

HDL-C (mg/dL)

44.3 (± 10.4)

41.94 (± 9.52)

0.2443

49.5 (± 13.9)

51.63 (± 10.6)

0.9319

+11.73

+23.00

LDL-C (mg/dL)

101.4 (± 27.6)

107.49 (±26.17)

0.9037

86.2 (± 25.3)

99.29 (± 24.3)

0.0093

-14.99

-7.62

FBS (mg/dL)

98.9 (±25.0)

101.1 (±23.44)

0.9615

87.6 (±20.6)

87.21 (±15.05)

0.9916

-11.42

-13.74

aunque no se observó una diferencia en otros parámetros como los niveles de H DL - C . Dichos ha l lazgos cor relac iona n con resu lt ados obtenidos en un meta-análisis que comparó los efectos de cada procedimiento en comorbilidades asociadas a obesidad en donde se observó un mayor impacto de Roux N-Y sobre LSG en disminución de dislipidemia. 2 La pato-f isiología de estos cambios no es totalmente clara al momento. Hipótesis sobre el mecanismo incluyen disminución en la absorción de colesterol en el tracto alimentario deprivado de secreciones pancreáticas8 y cambios en la cinética de sales biliares incluyendo un mayor nivel de procesamiento y niveles en sangre, causando así menores secreciones hepáticas de partículas necesarias para la síntesis de lípidos.8 LSG por su parte es una técnica restrictiva con menor impacto en

la absorción de nutrientes aunque, estudios han demostrado igual impacto en términos de la resolución en dislipidemia.2 Nuestro estudio falló entre los cambios observados en la reducción de BMI, TG, FBS, e incremento en HDL. En términos de la reducción de BMI, ambas intervenciones sugieren tener un impacto similar en términos de la capacidad reductora de peso un año posterior a la intervención. Dichos resultados ref lejan lo encontrado en la literatura en donde se ha descrito similar efectividad al año de intervención pero con una mayor reducción de peso luego de dos años post operatorio en pacientes de Roux N-Y.4 Ambas intervenciones fueron independientemente efectivas en disminuir signif icativamente los niveles de TG y FBS y elevar el HDL. Por otra parte, las diferencias

del cambio post operatorio no fueron significativas entre ambas intervenciones. Estos resultados están parcialmente alineados con la literatura en donde se ha demostrado un mayor impacto en la resolución de Diabetes Mellitus tipo 2 en RouxN-Y sobre LSG.4 La información obtenida con nuestro estudio nos brinda herramientas para decidir qué tipo de procedimiento es el es imperativo tomar en cuenta no tan solo los cambios metabólicos inherentes a cada intervención, sino que también las peculiaridades técnicas de cada procedimiento. LSG es una intervención más simple, rápida y con menos complicaciones post operatorias tales como hernias i nter na s , ú lcer a s ma r g i na les , estrecheces en áreas de anastomosis, def iciencias de vitaminas, todas complicaciones asociadas a Roux

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MSP ARTÍCULO ORIGINAL

“EL UTILIZAR ROUX N-Y LLEVA CONSIGO UNA SERIE DE POSIBLES COMPLICACIONES CUYO RIESGO SOLO DEBERÍA SER TOMADO POR AQUELLOS QUE TENGAN MAYOR CANTIDAD DE COMORBILIDADES ASOCIADAS A LA OBESIDAD” N-Y. En LSG se ha obser vado en un 12 porciento de los pacientes9. La preservación del píloro y no alteración del vaciado gástrico también disminuye síndromes de vaciado gástrico y permite un acceso endoscópico completo2 , todo eso siendo benef icios de LSG sobre Roux N-Y. Por tal razón, el utilizar Roux N-Y lleva consigo una serie de posibles complicaciones cuyo riesgo solo debería ser tomado por aquellos que tengan mayor cantidad de comorbilidades asociadas a la obesidad, dado el mejor impacto en estos parámetros luego de esta inter vención. Pacientes en los cuales la perdida de peso es la meta principal, se benef ician en mayor manera de LSG dado que, el impacto que tiene sobre la pérdida de peso es igual al de Roux N-Y pero sin las complicaciones post operatorias asociadas con dicha intervención.

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5. Andrew J. Beamish, Torsten

of bariatric surgery. Nature Reviews. (2016) 13:730-743. 6. Ricci C., et al. Long-Term Ef fects of Bariatric Surgery on Type II Diabetes, Hypertension and Hyperlipidemia: A Meta-Analysis and Referencias 1. Katherine M. Flegal M. K, et al. Meta-Regression Study with 5-Year Trends in obesity Among Adult in Follow-Up. Obesity Surgery, (2015) the United States 2005-2014. JAMA. 25:397–405. 7. Golomb I., et al. Long-term 2016;315(21):2284-2291. 2. Jianfang L.,Dandan L., Dongping W., et al. Laparoscopic Roux-en-Y Sleeve Gastrectomy. JAMA Surg. Gastric Bypass Versus Laparoscopic 2015;150(11):1051-1057. 8. Quezada N, Hernández J, Sleeve Gastrectomy to Treat Morbid Obesity-Related Comorbidities: León F, Brañes A, Gabrielli M, a Systematic Review and Meta- et al. (2015) Long-term Results of analysis. Obesity Surgery (2016) Dyslipidemia After Bariatric Surgery: A Comparison Between Gastric 26:429–442. 3. Oster, G., Thompson, D., Bypass and Sleeve Gastrectomy. Edelsberg, J., Bird, A. P. & Colditz, Obesity, Open Access 1(2). 9. Rosenthal, R. J. et al. International G, et a l. L ifet ime hea lt h and economic benef its of weight loss Sleeve Gastrectomy Expert Panel among obese persons. Am. J. Public Consensus Statement: best practice guidelines based on experience of Health 89, 1536–1542 (1999). 4. Zhang Y., et al. Laparoscopic >12,000 cases. Surg. Obes. Relat. S l e e v e G a s t r e c t o m y Ve r s u s Dis. 8, 8–19 (2012). Laparoscopic Roux-En-Y Gastric Bypass for Morbid Obesity and Related Comorbidities: A MetaAnalysis of 21 Studies. Obesity Surgery, (2015) 25:19–26.

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

T:11.5 in

B:11.75 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

XARELTO® (rivaroxaban) tablets

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)

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)

XARELTO® (rivaroxaban) tablets

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

XARELTO 10 mg N=4487 n (%)

XARELTO® (rivaroxaban) tablets

Psoriasis

en Puerto Rico La psoriasis es un trastorno inmunológico y crónico que altera las articulaciones, generando inflamaciones y lesiones serias en la piel 1 de cada 3 personas en el mundo tienen la enfermedad De 80 a 100 mil personas podrían tener esta condición en Puerto Rico

Factores de riesgo:

Diagnóstico:

MSP INFOGRAFÍAS

-Estudio de la historia clínica del paciente -Examen físico o análisis microscópico de las lesiones en la piel -Un análisis de sangre podría diferenciar la enfermedad de una artritis reumatoide

30 %

Infecciones crónicas, artritis reumatoide, cambios hormonales, traumatismos, obesidad, alcoholismo y estrés.

Niños: Tienen una elevada prevalencia de la enfermedad 30% de estos pacientes presentan artritis psoriásica y otro 40% tienen síndrome metabólico.

Tipos de psoriasis: Psoriasis leve: afecta un 2% o menos de la piel en zonas como codos, rodillas, manos, pies y cuero cabelludo.

Psoriasis moderada: afecta de un 2 a un 10% de la piel y se presenta en zonas como rodillas, codos, manos, pies, cuero cabelludo y otras partes del cuerpo.

Tratamiento: Psoriasis Grave: afecta más del 10% de la piel, genera sangrados.

Esteroides tópicos, fototerapia, medicamentos orales (metotrexato, acitretin, ciclosporina, entre otros) o los biológicos inyectables aprobados por la FDA. Estos últimos son efectivos para pacientes con psoriasis de moderada a severa Cada tratamiento debe ser personalizado de acuerdo a la situación clínica del paciente.

Revista Puertorriqueña de Medicina y Salúd Pública

MSP INFOGRAFÍAS

Síntomas:

Recomendaciones: Medir la presión, el pulso, el índice de masa corporal cada dos años, azúcar en ayunas y niveles de lípidos cada 5 años o cada dos años si el paciente tiene otros factores de riesgo Revisar las articulaciones en cada visita al médico

Piel rojiza, hinchazón, dolor, lesiones genitales en los hombres, caspa, uñas más gruesas y de color amarillo a marrón ¡Cuidado! Los síntomas pueden desaparecer temporalmente y luego volver con mayor fuerza.

Se recomienda evaluación por un profesional de la salud mental si el paciente muestra síntomas emocionales

Uñas amarillas

Sarpullido

Medicamentos tópicos (cremas y lociones) Hinchazón

Caspa

Esteroides: imitan la acción de las hormonas naturales del organismo y son comunes para tratar la psoriasis leve y moderada Retinoides: Derivados de la vitamina A y suelen combinarse con esteroides Antralina: No tiene efectos secundarios y se utiliza para tratar la psoriasis leve o moderada

Alquilantes: Con un olor particular, son los tópicos más utilizados para la psoriasis Calcipotriol: forma sintética de la vitamina D, que actúa a largo plazo. En algunas zonas como el rostro, genera irritación Ácido salicílico: Elimina las escamas de las placas generadas por la psoriasis y prepara la piel para recibir medicamentos cremas o lociones

Otro tipo de medicación: Retinoides orales: Especiales para tratamientos a largo plazo y se pueden combinar con otros medicamentos para la psoriasis

Metotrexato: Limpia las zonas que afecta la psoriasis. Sin embargo, genera náuseas, pérdida del apetito y llagas en la boca

Ciclosporina: Es una de las opciones más fuertes, controla el sistema inmunológico y actúa de manera rápida. Puede generar hipertensión o lesiones renales

Fuente: Leticia Lopez Directora Ejecutiva de la Asociación Puertorriqueña de Ayuda al Paciente de Psoriasis (APAPP) Periodista: Andrea Ramos León Diseño & diagramación: Nicolás Gaitán Avila

Revista Puertorriqueña de Medicina y Salúd Pública

NOW AVAILABLE

FOR ADULT PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RA

IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Patients should be tested for tuberculosis (TB) before KEVZARA use and during therapy. Treatment for latent TB infection should be initiated prior to KEVZARA use. Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection. CONTRAINDICATION Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients. WARNINGS AND PRECAUTIONS • Infections. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents for rheumatoid arthritis (RA). The most

frequently observed serious infections with KEVZARA included pneumonia and cellulitis. Among opportunistic infections, TB, candidiasis, and pneumocystis were reported with KEVZARA. — Patients with latent TB should be treated with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA 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 having risk factors for TB infection. — Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: chronic or recurrent infection, a history of serious or opportunistic infections, underlying conditions in addition to RA that may predispose them to infection, been exposed to TB, or lived in or traveled to areas of endemic TB or endemic mycoses. — Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster occurred in greater proportion of KEVZARA-treated patients than placebotreated patients. • Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters

KEVZARA is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

To learn more, please visit KEVZARAhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals. • Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms. • Immunosuppression. Treatment with immunosuppressants may result in an increased risk of malignancies. • Active Hepatic Disease and Hepatic Impairment. Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations. • Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections.

ADVERSE REACTIONS • The most common adverse reactions are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.

theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate. USE IN SPECIFIC POPULATIONS • KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA. • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KEVZARA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. • Use caution when treating the elderly. Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

DRUG INTERACTIONS • Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or

KEVZARA® (sarilumab) injection, for subcutaneous use

Rx Only

Brief Summary of Prescribing Information WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before KEVZARA use and during therapy. Treatment for latent infection should be initiated prior to KEVZARA use. • Invasive fungal infections, such as candidiasis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral and other infections due to opportunistic pathogens. Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection.

1 INDICATIONS AND USAGE KEVZARA® is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection. Reduce dose to 150 mg once every two weeks for management of neutropenia, thrombocytopenia and elevated liver enzymes [see Dosage and Administration (2.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 2.2 General Considerations for Administration • KEVZARA initiation is not recommended in patients with an absolute neutrophil count (ANC) less than 2000 per mm3, platelet count less than 150,000 per mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN) [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. • Prior to initiating KEVZARA, test patients for latent tuberculosis (TB). If positive, consider treating for TB prior to KEVZARA use [see Warnings and Precautions (5.1)]. • Avoid using KEVZARA with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of KEVZARA with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators has not been studied. • Avoid KEVZARA use in patients with active infections [see Warnings and Precautions (5.1)]. 2.3 Important Administration Instructions • KEVZARA is intended for use under the guidance of a healthcare professional. A patient may self-inject KEVZARA or the patient’s caregiver may administer KEVZARA. Provide proper training to patients and/or caregivers on the preparation and administration of KEVZARA prior to use according to the Instructions for Use (IFU). • Allow the pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. KEVZARA solution should be clear and colorless to pale yellow. Do not use if the solution is cloudy, discolored or contains particles, or if any part of the pre-filled syringe appears to be damaged. • Instruct patients to inject the full amount in the syringe (1.14 mL), which provides 200 mg or 150 mg of KEVZARA, according to the directions provided in the IFU. • Rotate injection sites with each injection. Do not inject into skin that is tender, damaged, or has bruises or scars. 2.4 Dosage Modifications for Laboratory Abnormalities or Serious Infection If a patient develops a serious infection, hold treatment with KEVZARA until the infection is controlled. Modify dosage in case of neutropenia, thrombocytopenia or liver enzyme elevations (see Table 1). For treatment initiation criteria, see [Dosage and Administration (2.2)].

Table 1: KEVZARA Dosage Modification for Neutropenia, Thrombocytopenia, or Elevated Liver Enzymes Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) in the full prescribing information] Lab Value (cells/ mm3)

Recommendation

ANC greater than 1000

Maintain current dosage of KEVZARA.

ANC 500–1000

Hold treatment with KEVZARA until ANC greater than 1000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate.

ANC less than 500

Discontinue KEVZARA.

Low Platelet Count [see Warnings and Precautions (5.2)] Lab Value (cells/ mm3)

Recommendation

50,000–100,000

Hold treatment with KEVZARA until platelets greater than 100,000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate.

Less than 50,000

If confirmed by repeat testing, discontinue KEVZARA.

Liver Enzyme Abnormalities [see Warnings and Precautions (5.2)] Lab Value

Recommendation

ALT greater than ULN to 3 times ULN or less

Consider dosage modification of concomitant DMARDs as clinically appropriate.

ALT greater than 3 times ULN to 5 times ULN or less

Hold treatment with KEVZARA until ALT less than 3 times ULN. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate.

ALT greater than 5 times ULN

Discontinue KEVZARA.

4 CONTRAINDICATIONS KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including KEVZARA for rheumatoid arthritis (RA). The most frequently observed serious infections with KEVZARA included pneumonia and cellulitis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with KEVZARA. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids, which in addition to RA may predispose them to infections. While not reported in KEVZARA clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA. Avoid use of KEVZARA in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: • chronic or recurrent infection; • a history of serious or opportunistic infections; • underlying conditions, in addition to RA, that may predispose them to infection; • been exposed to tuberculosis; or • lived in or traveled to areas of endemic tuberculosis or endemic mycoses. Closely monitor patients for the development of signs and symptoms of infection during treatment with KEVZARA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.4), Adverse Reactions (6.1)]. Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection. Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with KEVZARA; initiate appropriate antimicrobial therapy, and closely monitor the patient.

Tuberculosis Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with KEVZARA. Treat patients with latent TB with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA 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 having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate. Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA [see Adverse Reactions (6.1)]. The risk of Hepatitis B reactivation with KEVZARA is unknown since patients who were at risk for reactivation were excluded. 5.2 Laboratory Abnormalities Neutropenia Treatment with KEVZARA was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia [see Adverse Reactions (6.1)]. • Assess neutrophil count prior to initiation of KEVZARA and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2) in the full prescribing information]. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on ANC results see Dosage and Administration (2.2 and 2.4). • Based on the pharmacodynamics of the changes in ANC [see Clinical Pharmacology (12.2) in the full prescribing information], use results obtained at the end of the dosing interval when considering dose modification. Thrombocytopenia Treatment with KEVZARA was associated with a reduction in platelet counts in clinical studies [see Adverse Reactions (6.1)]. • Assess platelet count prior to initiation of KEVZARA and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on platelet counts see Dosage and Administration (2.2 and 2.4). Elevated Liver Enzymes Treatment with KEVZARA was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies [see Adverse Reactions (6.1)]. Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. • Assess ALT/AST levels prior to initiation of KEVZARA and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on transaminase elevations see Dosage and Administration (2.2 and 2.4). Lipid Abnormalities Treatment with KEVZARA was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides [see Adverse Reactions (6.1)]. • Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with KEVZARA, then at approximately 6 month intervals. • Manage patients according to clinical guidelines for the management of hyperlipidemia. 5.3 Gastrointestinal Perforation Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms [see Adverse Reactions (6.1)]. 5.4 Immunosuppression Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies were reported in clinical studies [see Adverse Reactions (6.1)]. 5.5 Hypersensitivity Reactions Hypersensitivity reactions have been reported in association with KEVZARA [see Adverse Reactions (6.1)]. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab [see Contraindications (4) and Adverse Reactions (6.1)]. 5.6 Active Hepatic Disease and Hepatic Impairment Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. 5.7 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections; clinical safety of live vaccines during

KEVZARA® (sarilumab) injection, for subcutaneous use KEVZARA treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. The interval between live vaccinations and initiation of KEVZARA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Drug Interactions (7.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Serious infections [see Warnings and Precautions (5.1)] • Neutropenia, thrombocytopenia, elevated liver enzymes, lipid abnormalities [see Warnings and Precautions (5.2)] • Gastrointestinal perforation [see Warnings and Precautions (5.3)] • Immunosuppression [see Warnings and Precautions (5.4)] • Hypersensitivity reactions [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. All patients in the safety data described below had moderately to severely active rheumatoid arthritis. The safety of KEVZARA in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received KEVZARA for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to KEVZARA. In this population, 582 patients, 579 patients, and 579 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. The 52-week placebo-controlled population includes patients from one Phase 2 study of 12 week duration and two Phase 3 efficacy studies (one of 24 week duration and the other of 52 week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used. The most common serious adverse reactions were infections [see Warnings and Precautions (5.1)]. The most frequent adverse reactions (occurring in at least 3% of patients treated with KEVZARA in combination with DMARDs) observed with KEVZARA in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with KEVZARA 200 mg, KEVZARA 150 mg, and placebo, respectively. The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia. The use of KEVZARA as monotherapy was assessed in 132 patients, of which 67 received KEVZARA 200 mg and 65 patients received KEVZARA 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. Overall Infections In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg KEVZARA + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with KEVZARA 200 mg + DMARD, 0.6% (4 patients) treated with KEVZARA 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster [see Warnings and Precautions (5.1)]. The overall rate of infections with KEVZARA + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. Serious Infections In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported [see Warnings and Precautions (5.1)].

Gastrointestinal Perforation In the 52-week placebo-controlled population, one patient on KEVZARA therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to KEVZARA in the development of GI perforations is not known [see Warnings and Precautions (5.3)]. Hypersensitivity Reactions In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with KEVZARA (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving KEVZARA 200 mg, 6% receiving KEVZARA 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving KEVZARA. Laboratory Abnormalities Decreased neutrophil count In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm3 occurred in 6% and 4% of patients in the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm3 occurred in 0.7% of patients in both the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including serious infections. In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies [see Warnings and Precautions (5.2)]. Decreased platelet count In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm3 occurred in 1% and 0.7% of patients on 200 mg and 150 mg KEVZARA + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events. In the long-term safety population, the observations on platelet counts were consistent with what was seen in the placebo-controlled clinical studies [see Warnings and Precautions (5.2)]. Elevated liver enzymes Liver enzyme elevations in the pre-rescue placebo-controlled population (KEVZARA + DMARD or placebo + DMARD) are summarized in Table 2. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of KEVZARA or reduction in dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.4)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment [see Warnings and Precautions (5.2)]. Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active Rheumatoid Arthritis* Placebo + DMARD N=579

KEVZARA 150 mg + DMARD N=579

KEVZARA 200 mg + DMARD N=582

Greater than ULN to 3 times ULN or less

15%

27%

30%

Greater than 3 times ULN to 5 times ULN

Greater than 5 times ULN

0.7%

0.2%

Greater than ULN to 3 times ULN or less

25%

38%

43%

Greater than 3 times ULN to 5 times ULN

Greater than 5 times ULN

0.7%

AST

ALT

ULN = Upper Limit of Normal *Phase 3 placebo-controlled safety population through the pre-rescue period

KEVZARA® (sarilumab) injection, for subcutaneous use Lipid Abnormalities Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of KEVZARA + DMARDs in the placebo-controlled population. Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below: • Mean LDL increased by 12 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 16 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group. • Mean triglycerides increased by 20 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 27 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group. • Mean HDL increased by 3 mg/dL in both the KEVZARA 150 mg every two weeks + DMARD and KEVZARA 200 mg every two weeks + DMARD groups. In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies. Malignancies In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving KEVZARA+ DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years). In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period [see Warnings and Precautions (5.4)]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on KEVZARA + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3. Table 3: Common Adverse Reactions* in Adults with Moderately to Severely Active Rheumatoid Arthritis † Preferred Term

Placebo + DMARD (N=579)

KEVZARA 150 mg + DMARD (N=579)

KEVZARA 200 mg + DMARD (N=582)

0.2%

10%

Injection site erythema

0.9%

Injection site pruritus

Neutropenia Alanine aminotransferase increased

0.2%

Upper respiratory tract infection

Urinary tract infection

Hypertriglyceridemia

0.5%

0.9%

Leukopenia

*Adverse reactions occurring in 2% or more in the 150 mg KEVZARA + DMARD or 200 mg KEVZARA + DMARD groups and greater than observed in Placebo + DMARD †Pre-rescue, placebo-controlled population Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with KEVZARA in controlled studies was oral herpes. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to sarilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In the pre-rescue population, 4.0% of patients treated with KEVZARA 200 mg + DMARD, 5.7% of patients treated with KEVZARA 150 mg + DMARD and 1.9% of patients treated with placebo + DMARD, exhibited an anti-drug antibody (ADA) response. Neutralizing antibodies (NAb) were detected in 1.0% of patients on KEVZARA 200 mg + DMARD, 1.6% of patients on KEVZARA 150 mg + DMARD, and 0.2% of patients on placebo + DMARD. In patients treated with KEVZARA monotherapy, 9.2% of patients exhibited an ADA response with 6.9% of patients also exhibiting NAbs. Prior to administration of KEVZARA, 2.3% of patients exhibited an ADA response. No correlation was observed between ADA development and either loss of efficacy or adverse reactions. 7 DRUG INTERACTIONS 7.1 Use with Other Drugs for Treatment of Rheumatoid Arthritis Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on sarilumab clearance. KEVZARA has not been investigated in combination

with JAK inhibitors or biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)]. 7.2 Interactions with CYP450 Substrates Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations. The modulation of IL-6 effect on CYP enzymes by KEVZARA may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of KEVZARA, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed. Exercise caution when coadministering KEVZARA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of KEVZARA on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3) in the full prescribing information]. 7.3 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA [see Warnings and Precautions (5.7)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KEVZARA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. Risk Summary The limited human data with KEVZARA in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers [see Clinical Considerations and Data]. In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD) [see Data]. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to KEVZARA in utero [see Warnings and Precautions (5.7)]. From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers [see Data]. Data Animal Data In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta. Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with KEVZARA.

KEVZARA® (sarilumab) injection, for subcutaneous use Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. 8.2 Lactation Risk Summary No information is available on the presence of sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of KEVZARA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KEVZARA and the potential adverse effects on the breastfed child from KEVZARA or from the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of KEVZARA in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients in clinical studies of KEVZARA [see Clinical Studies (14) in the full prescribing information], 15% were 65 years of age and over, while 1.6% were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infection among KEVZARA and placebo-treated patients 65 years of age and older was higher than 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. 8.6 Hepatic Impairment The safety and efficacy of KEVZARA have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology [see Warnings and Precautions (5.6)]. 8.7 Renal Impairment No dose adjustment is required in patients with mild to moderate renal impairment. KEVZARA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY U.S. License # 1752 Marketed by: sanofi-aventis U.S. LLC (Bridgewater, NJ 08807) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) KEVZARA® is a registered trademark of Sanofi Biotechnology ©2017 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC Issue Date: May 2017 SAI-BPLR-SA-MAY17

MSP ARTÍCULO DE REVISIÓN

Estadísticas de cáncer de cabeza y cuello más comunes en Puerto Rico Por: Elba C. Díaz DMD, MSD, MPH Prostodoncista Catedrática Escuela de Medicina Dental RCM, UPR Directora Área de Servicios Dentales Oncológicos Hospital de Investigación del Centro Comprensivo de Cáncer Universidad de Puerto Rico

Palabras claves Cáncer oro faringe Cáncer de cabeza y cuello Cáncer de tiroides Incidencia y mortalidad de cáncer en Puerto Rico Keywords Oro pharynx cancer Head and neck cancer Puerto Rico cancer incidence and mortality Thyroid cancer

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

10 el número de cánceres principales en

Puerto Rico. La incidencia en hombres es el de cavidad oral y faringe y entre mujeres el de tiroides.

Diagnosticados anualmente con cáncer [2010-2014].

324

hombres

115

mujeres

Murieron por este tipo de cáncer en ese mismo período.

hombres

mujeres

4% de todos los cánceres 4.7% es el riesgo de son en hombre. muer te en hombres 1.6% en mujeres comparado con mujere

1.6%

Summary Head and neck cancer is one of the tumors affecting the Puerto Rican adult population according to statistics of the Central Cancer Registry of Puerto Rico 2010-2014. Oro pharynx cancer to be the 5th most-diagnosed cancer in men and is the 6th in mortality; and thyroid cancer the third most diagnosed in women and unlike oro pharynx cancer isn’t on mortality among the first 15 cancers in women. Oro pharynx cancer has a better prognosis if it is detected, diagnosed and treated in time, yet an average, 324 men and 115 women were diagnosed annually with this cancer in Puerto Rico, but on average, 94 men and 26 women die from this cancer each year on the island. The risk of developing this cancer is 3.4 times higher in men than in women (95% CI: 3.1, 3.7) and the risk of dying from this cancer in Puerto Rico is 4.7 times higher in men than in women (95% CI: 3.8, 5.7). In relation to thyroid cancer an average of 173 men and 787 women were diagnosed annually in Puerto Rico although on average, 7 men and 8 women die from this cancer each year, being the low cancer mortality compared with the oro pharynx cancer mortality. Contrary to the Oro pharynx that the incidence is higher in men, in the thyroid is the risk of developing this cancer of 4.1 times higher in women than in men (95% CI: 3.8, 4.4), but the risk of dying from this cancer was 1.1 times higher in men than in Women (95% CI: 0.5, 1.5). Resumen El cáncer de cabeza y cuello es uno de los tumores que más afecta a la población adulta puertorriqueña, según las estadísticas del Registro Central de Cáncer de Puerto Rico 2010-2014. El cáncer de oro faringe es el quinto cáncer más diagnosticado en los hombres y es el sexto en mortalidad; y el cáncer de tiroides el tercero más diagnosticado en las mujeres y a diferencia del cáncer de orofaringe, no aparece en mortalidad entre los primeros 15 cánceres en mujeres. El cáncer de orofaringe tiene una mejor prognosis si es detectado, diagnosticado y tratado a tiempo, aun así, un promedio de 324 hombres y 115 mujeres fueron diagnosticados anualmente con este cáncer en Puerto Rico, pero en promedio, 94 hombres y 26 mujeres mueren por este cáncer cada año en la Isla. El riesgo de desarrollar este cáncer es 3.4 veces mayor en hombres que en mujeres (95% CI: 3.1, 3.7) y el riesgo de morir por este cáncer en Puerto Rico es 4.7 veces más alto en hombres que en mujeres (95% CI: 3.8, 5.7) Con relación al cáncer de tiroides un promedio de 173 hombres y 787 mujeres fueron diagnosticados anualmente en Puerto Rico, aunque en promedio, 7 hombres y 8 mujeres mueren por este cáncer cada año, es una mortalidad baja comparada con los indices de muerte del cáncer de orofaringe. Contrario al de oro faringe que la incidencia es más alta en hombres, en el de tiroides el riesgo de desarrollar este cáncer es 4.1 veces mayor en mujeres que en hombres (95% CI: 3.8, 4.4), pero el riesgo de morir por este cáncer es de 1.1 veces más alto en hombres que en mujeres (95% CI: 0.5, 1.5).i Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

El cáncer de cabeza y cuello es uno de los tumores que más afecta a la población adulta puertorriqueña, según las estadísticas del Registro Central de Cáncer de Puerto Rico. Siendo el cáncer de orofaringe el quinto cáncer más diagnosticado en los hombres y el cáncer de tiroides el tercero más diagnosticado en las mujeres. El cáncer de orofaringe tiene una mejor prognosis si es detectado, diagnosticado y tratado a tiempo.

Cáncer de la cavidad oral y faringe (2010 al 2014) ✓✓Responsable del 4.0% de todos los cánceres

en hombres y 1.6% de todos los cánceres en mujeres. ✓✓Responsable de 3.2% de todas las muertes por cáncer en hombres y de 1.1% de todas las muertes por cáncer en mujeres. ✓✓En promedio, 324 hombres y 115 mujeres fueron diagnosticados anualmente con este cáncer. ✓✓En promedio, 94 hombres y 26 mujeres mueren por este cáncer cada año. ✓✓El riesgo de desarrollar este cáncer es de 3.4 veces mayor en hombres que en mujeres (95% CI: 3.1, 3.7). ✓✓El riesgo de morir por este cáncer es de 4.7 veces más alto en hombres que en mujeres (95% CI: 3.8, 5.7). ✓✓Sexto entre todos los cánceres en Puerto Rico. ✓✓Cuarto cáncer más común y la sexta en causas de muerte en hombres. ✓✓Cáncer 2.5 veces más común en los puertorriqueños que en los hispanos en los EU.

“El cáncer de cabeza y cuello es uno de los tumores que más afecta a la población adulta puertorriqueña”

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

“Un promedio de 324 hombres y 115 mujeres fueron diagnosticados anualmente con cáncer de orofaringe en Puerto Rico”

Cáncer de Tiroides (2010 al 2014)

✓✓Responsable del 2.1% de todos los cánceres en hom-

bres y 10.8% de todos los cánceres en mujeres. ✓✓Responsable de 0.2% de todas las muertes por cáncer en hombres y de 0.3% de todas las muertes por cáncer en mujeres. ✓✓En promedio, 173 hombres y 787 mujeres fueron diagnosticados anualmente con este cáncer. ✓✓En promedio, 7 hombres y 8 mujeres mueren por este cáncer cada año. ✓✓El riesgo de desarrollar este cáncer es de 4.1 veces mayor en mujeres que en hombres (95% CI: 3.8, 4.4). ✓✓El riesgo de morir por este cáncer es de 1.1 veces más alto en hombres que en mujeres (95% CI: 0.5, 1.5).

Referencias 1. Puerto Rico Cancer Registry: (February, 2017), 2. Puerto Rico Demografic Registry (October, 2016) 3. Puerto Rico Census, 2015

Revista Puertorriqueña de Medicina y Salúd Pública

CMY

SYNTHROID® (sin-throyd)(levothyroxine sodium) tablets, USP WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS Thyroid hormones, including SYNTHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects [see Adverse Reactions, Drug Interactions, and Overdosage]. INDICATIONS AND USAGE Hypothyroidism SYNTHROID is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression SYNTHROID is indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use: • SYNTHROID is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with SYNTHROID may induce hyperthyroidism [see Warnings and Precautions]. • SYNTHROID is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. CONTRAINDICATIONS SYNTHROID is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate SYNTHROID therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Use in Specific Populations]. Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive SYNTHROID therapy. Monitor patients receiving concomitant SYNTHROID and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the SYNTHROID dose or withhold for one week and restart at a lower dose. Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma. Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with SYNTHROID [see Contraindications]. Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism SYNTHROID has a narrow therapeutic index. Over- or undertreatment with SYNTHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of SYNTHROID carefully and monitor response to titration to avoid these effects. Monitor for the presence of drug or food interactions when using SYNTHROID and adjust the dose as necessary [see Drug Interactions]. Worsening of Diabetic Control Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing SYNTHROID [see Drug Interactions]. Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in postmenopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of SYNTHROID that achieves the desired clinical and biochemical response to mitigate this risk. ADVERSE REACTIONS Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions and Overdosage]. They include the following: • General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating • Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia • Musculoskeletal: tremors, muscle weakness, muscle spasm • Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest • Respiratory: dyspnea • Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests • Dermatologic: hair loss, flushing, rash • Endocrine: decreased bone mineral density

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• Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse Reactions in Children Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height. Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. DRUG INTERACTIONS Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to SYNTHROID (see Tables 1-4 below). Table 1. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Calcium Carbonate Calcium carbonate may form an Ferrous Sulfate insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. Bile Acid Sequestrants Bile acid sequestrants and ion - Colesevelam exchange resins are known to decrease - Cholestyramine levothyroxine absorption. Administer - Colestipol SYNTHROID at least 4 hours prior to Ion Exchange Resins these drugs or monitor TSH levels. - Kayexalate - Sevelamer Other drugs: Gastric acidity is an essential Proton Pump Inhibitors requirement for adequate absorption Sucralfate of levothyroxine. Sucralfate, antacids Antacids and proton pump inhibitors may cause - Aluminum & Magnesium hypochlorhydria, affect intragastric pH, Hydroxides and reduce levothyroxine absorption. - Simethicone Monitor patients appropriately. Table 2. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate These drugs may increase serum thyroxine-binding globulin (TBG) Estrogen-containing oral concentration. contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen Androgens / Anabolic Steroids These drugs may decrease serum TBG concentration. Asparaginase Glucocorticoids Slow-Release Nicotinic Acid Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Other drugs: These drugs may cause protein-binding site displacement. Furosemide has Carbamazepine been shown to inhibit the protein Furosemide (> 80 mg IV) binding of T4 to TBG and albumin, Heparin causing an increase free T4 fraction Hydantoins in serum. Furosemide competes for Non-Steroidal Anti-inflammatory T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose Drugs can acutely lower the total T4 level. - Fenamates Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

Table 3. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. Drug or Drug Class Effect Phenobarbital Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases Rifampin L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. Table 4. Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic In patients treated with large doses of propranolol antagonists (> 160 mg/day), T3 and T4 levels change, TSH (e.g., Propranolol levels remain normal, and patients are clinically > 160 mg/day) euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. Glucocorticoids Short-term administration of large doses (e.g., Dexamethasone of glucocorticoids may decrease serum T3 ≥ 4 mg/day) concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). Other drugs: Amiodarone inhibits peripheral conversion of Amiodarone levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. Antidiabetic Therapy Addition of SYNTHROID therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions]. Oral Anticoagulants SYNTHROID increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the SYNTHROID dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. Digitalis Glycosides SYNTHROID may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and SYNTHROID may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. SYNTHROID may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on SYNTHROID may result in increased SYNTHROID requirements. Ketamine Concurrent use of ketamine and SYNTHROID may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. Sympathomimetics Concurrent use of sympathomimetics and SYNTHROID may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. Drug-Food Interactions Consumption of certain foods may affect SYNTHROID absorption thereby necessitating adjustments in dosing. Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of SYNTHROID from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Experience with levothyroxine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages [see Data]. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since

TSH levels may increase during pregnancy, TSH should be monitored and SYNTHROID dosage adjusted during pregnancy [see Clinical Considerations]. There are no animal studies conducted with levothyroxine during pregnancy. SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase SYNTHROID requirements. Serum TSH levels should be monitored and the SYNTHROID dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the SYNTHROID dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration ]. Data Human Data Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women. Lactation Risk Summary Limited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNTHROID and any potential adverse effects on the breastfed infant from SYNTHROID or from the underlying maternal condition. Pediatric Use The initial dose of SYNTHROID varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters. In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue SYNTHROID administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted. Congenital Hypothyroidism Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate SYNTHROID therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. Closely monitor infants during the first 2 weeks of SYNTHROID therapy for cardiac overload, arrhythmias, and aspiration from avid suckling. Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height. Geriatric Use Because of the increased prevalence of cardiovascular disease among the elderly, initiate SYNTHROID at less than the full replacement dose [see Warnings and Precautions]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly. OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions and Adverse Reactions]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the SYNTHROID dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org. PATIENT COUNSELING INFORMATION Inform the patient of the following information to aid in the safe and effective use of SYNTHROID: Dosing and Administration • Instruct patients to take SYNTHROID only as directed by their healthcare provider. • Instruct patients to take SYNTHROID as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. • Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take SYNTHROID tablets within 4 hours of these agents. • Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking SYNTHROID. Important Information • Inform patients that it may take several weeks before they notice an improvement in symptoms. • Inform patients that the levothyroxine in SYNTHROID is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life. • Inform patients that SYNTHROID should not be used as a primary or adjunctive therapy in a weight control program. • Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations. • Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking SYNTHROID. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently. • Instruct patients to notify their physician or dentist that they are taking SYNTHROID prior to any surgery.

Adverse Reactions • Instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. • Inform patients that partial hair loss may occur rarely during the first few months of SYNTHROID therapy, but this is usually temporary. AbbVie Inc. North Chicago, IL 60064, U.S.A. Ref: 03-A648 Revised February 2017 605-1901463 MASTER

5600-1930320

MSP ARTÍCULO DE REVISIÓN

Estadísticas en Puerto Rico

550,000

Pacientes aproximadamente con diagnóstico de diabetes.

2,500

Amputaciones anuales de la extremidad inferior se hacen en Puerto Rico de las cuales el 70% son en pacientes diabéticos

AMPUTACIONES no traumáticas de la extremidad inferior ocurren debido a problemas vasculares.

Evaluación y tratamiento del pie diabético Por: Dra. Lourdes Kutbi, Cirujana Ortopeda Presidenta de la Sociedad para la Prevención de Enfermedades Cardiovasculares

Palabras claves Neuropatía, motilidad, estenosis, prevención, amputación, úlceras Keywords Neuropathy, motility, stenosis, prevention, amputation, ulcers

Resumen Los problemas de pie diabético son una preocupación importante en la atención médica y una causa común de hospitalización. La mayoría de los problemas de pie que enfrentan las personas con diabetes surgen a raíz de dos complicaciones serias de la enfermedad: daño de los nervios y mala circulación. Las complicaciones vasculares de la diabetes mellitus representan la principal causa de morbi-mortalidad entre la población diabética y dan lugar a un importante número de secuelas invalidantes como son la ceguera, la de la extremidad inferior, lo que provoca

Revista Puertorriqueña de Medicina y Salúd Pública

Doctor midiendo la presión arterial para hacer un diagnóstico.

un marcado deterioro de la calidad de vida de los pacientes y un elevado costo económico y social. En Puerto Rico existen cerca de 550,000 pacientes con un diagnóstico de diabetes y 2,500 amputaciones anuales de las cuales el 70% se realiza en pacientes diabéticos. El 85 % de las amputaciones no traumáticas de la extremidad inferior ocurren debido a problemas vasculares. El riesgo de mortalidad a los 5 años de un paciente amputado es aproximadamente de un 70%. Por ello, la importancia de diagnosticar de manera precoz al paciente diabético con enfermedad vascular.

Abstract Puerto Rico is the number one country in diagnosis of diabetes. It is estimated that the number of diabetics continue in ascent due to a diet high in calories, fat, sugar and carbohydrates. Diabetic foot is a health problem of great importance because of its high prevalence and consequences that may result. Knowledge of risk factors, design prevention plans and the creation of multidisciplinary teams with dedication to this pathology is the best option available today to improve living conditions of people.

MSP ARTÍCULO DE REVISIÓN

$30-$60

mil dólares

costo aproximado en el período periamputación.

Discusión Un procedimiento de amputación viene precedido de problemas de circulación, tumores cancerosos, trauma o úlcera en el pie, lo que disminuye considerablemente la calidad de vida de los pacientes ya que tan solo un tercio de los que sufren la amputación de la extremidad vuelve a caminar usando una prótesis. La evolución de los diabéticos con una amputación mayor es negativa, ya que el 30% fallece en el primer año desde la intervención y al cabo de 5 años un 50% sufren la amputación de la otra extremidad inferior. Se ha demostrado que una prevención adecuada de las lesiones en el pie del diabético, así como un correcto tratamiento puede reducir esta tasa de amputación entre un 50 y un 85%. Dadas las incapacidades, las repercusiones sociales y el elevado coste económico que origina la pérdida de la extremidad, se han propuesto la creación de equipos multidisciplinares expertos en este tipo de patología que sepan reconocer los factores de riesgo para desarrollar estrategias preventivas y de tratamiento precoz. Estadísticas En Puerto Rico existen apro-ximadamente 550,000 pacientes con diagnóstico de diabetes. Los pacientes con esta condición están a un mayor riesgo de sufrir amputación de su extremidad. El 70% de los pacientes con amputación de extremidad inferior son diabéticos. El costo aproximado en el período periamputación es entre $30-$60 mil dólares. En los 3 años post-amputación el costo promedia entre los $40-$60 mil. Esto se debe al costo de terapias, prótesis, hospitalizaciones y complicaciones post procedimiento. El riesgo de mortalidad a los 5 años de un paciente amputado es aproximadamente de un 70%. Un paciente diabético tiene niveles de azúcar elevados, que con el tiempo afectan cómo los nervios envían un mensaje.

$40-$60

mil dólares

es el costo promedio de 3 años post-amputación.

Esto se debe al costo de terapias, prótesis, hospitalizaciones y complicaciones post procedimiento.

Esto quiere decir, que estos pacientes eventualmente desarrollan síntomas de: adormecimiento y debilidad cosquilleo y hormigueo dolor punzante ardor y quemazón Estos síntomas son más marcados en pacientes con un nivel de azúcar mayor de 150mg/dL y en pacientes con niveles de azúcar controlados pero con un período de diagnóstico de más de 8 años. Neuropatía Se sabe que la presencia de neuropatía,

de los pacientes tienen riesgo de mortalidad a los 5 años de una amputación.

zonas pre-ulcerativas. Estas se pueden convertir en úlceras donde se pierde la protección provista por la piel y aumenta el riesgo de infección -grosor excesivo de las uñas/estas ocasionan presión en el área periungal lo que aumenta riesgo de ulceración -cambio de color en la uñas/pueden sanguíneo -áreas enrojecidas por presión indebida/

propenso a ulceración. -deformidad ósea/se consideran puntos de presión excesivos y pueden estar Semmes-Weinstein, o la presencia de relacionados a cambios neuropáticos enfermedad arterial periférica, determinada El paciente debe estar alerta a: por la medición de la presión transcutánea - áreas enrojecidas de oxígeno menor de 30 mmHg. Ambos, - callosidades y aperturas son los factores predictivos de principal - presencia de secreciones importancia para el desarrollo de úlceras. - manchas irregulares en la piel y Igualmente se destaca la presencia de hematomas deformidades óseas, de alteraciones en el - incapacidad de caminar apoyo plantar y la historia previa de úlceras. distancias cortas por dolor De los factores de riesgo socio-económicos sólo se ha podido demostrar relación Disminución de Circulación directa con la duración de la diabetes. Existen diferencias muy notables según extremidad es el causante del 85% de las sea la atención sanitaria de que disponga amputaciones. Esto se debe al daño en el paciente. el epitelio de las arterias, que causa que El paciente con neuropatía demuestra insensibilidad a tacto que hace que su pisada piernas. La amputación es prevenible si se tenga puntos de presión anormales que aumentan su riesgo de ulceración. De igual presenten síntomas en etapa temprana de la enfermedad vascular. Algunas señales de un problema objetos extraños que los lastimen. La neuropatía es el causante de úlceras número uno. La presencia de ulceración -pérdida de vello multiplica el riesgo de amputación y -calambres al caminar complicación de la extremidad. -pulsos disminuídos o no palpables Cambios en piel -dolor intenso en reposo Observar la piel es de suma importancia -presencia de úlceras para la prevención. El médico debe estar -pies enrojecidos alerta a los siguientes cambios: -disminución de vellos/ puede indicar la resultados falsos. Especialmente, aquellos que no tienen un componente de lectura -zonas de presión callosas/se consideran digital (i.e. fotopletismografía) y en pacientes

Revista Puertorriqueña de Medicina y Salúd Pública

MSP ARTÍCULO DE REVISIÓN

y cualquier cambio de temperatura. lectura del índice de presión tobillo-braquial. Debe estudiarse también la presencia de neuropatía y de enfermedad arterial y tratar a los pacientes antes de que estos periférica. Para estas dos últimas patologías desarrollen gangrena, cambios isquémicos se considera que con una revisión anual y amputaciones. Algunas formas de tratamiento para restaurar flujo sanguíneo a las piernas Enfermedad arterial periférica. son los procedimientos endovasculares La arterioesclerosis obliterante de las para romper placas estenóticas, posicionar extremidades inferiores es la complicación mallas”stents” y bypass. vascular más frecuente observada entre los diabéticos. Al diagnosticar la diabetes Deformidades está presente en un 8% y la cifra se eleva La corrección de deformidades como hasta el 45% a los 20 años del diagnóstico. lo son los dedos de martillo y juanetes Estas lesiones ateroescleroticas pueden son importantes en un paciente diabético. permanecer asintomáticas o conducir a la Usualmente, el paciente no puede sentir roce necrosis y a la pérdida de la extremidad, excesivo debido a los cambios neuropáticos dependiendo de la localización y extensión y esto puede provocar el surgimiento de de las lesiones y de la capacidad de suplencia úlceras. Debido al poco tejido que hay de la circulación colateral. entre la piel y los huesos en los dedos, el potencial de desarrollar una infección osea/ Motilidad y Calidad de vida osteomielitis es muy alto. La calidad de vida de un paciente diabético depende de las complicaciones que surjan Cuidado del Paciente/Prevención por su condición. Las complicaciones que El paciente debe utilizar el calzado llevan a la pérdida de una extremidad, no apropiado que no haga roce excesivo en sólo afectan al paciente sino a todo su entorno. su pie. No se recomienda el uso de zapato Esto incluye a su familia y la sociedad. abierto ni andar d scalzo. No utilizar Mientras más proximal sea el nivel medicamentos que contengan ácidos para de amputación, más limitado se hace el remover callosidad. movimiento del paciente. Una amputación El uso de medias de color claro ayudan digital o a nivel de metatarso, permite que el paciente tenga movilidad adecuada con el Se recomienda que sean de materiales de uso del zapato apropiado para la amputación. algodón con pocas áreas de costura. La amputación bajo la rodilla (BKA) permite El uso de piedras pómez al bañarse con la que el paciente ambule con el uso de prótesis piel húmeda ayuda a disminuir callosidad. y permite que el paciente pueda tener No se debe utilizar navajas, ni instrumento mejores movimientos de traslados de silla afilados para remover las callosidades. y en la cama. La amputación sobre rodilla El corte de uñas por parte del especialista (AKA) es sumamente incapacitante para el paciente, ya que limita su capacidad de áreas de posibles uñas encarnadas o de traslado y está relacionada a un mayor riesgo presión excesiva en la cama de la uña que de mortalidad. pueden ocasionar ulceración. Mantener Un paciente diabético, ya sea amputado los niveles de glucosa controlados ayuda a o con úlcera, es un paciente con un menor disminuir el riesgo de complicaciones por nivel de productividad debido al cuidado que infección y por neuropatía. conlleva y sus limitaciones. Estos tendrán Control de la glucemia. El buen un mayor potencial de desempleo, carga control de la diabetes, manteniendo cifras socioeconómica, depresión y ansiedad. de HbA1C por debajo de 7% de la Hb total, Los números de amputación en Puerto disminuye la presencia de neuropatía tanto Rico son de aproximadamente 2,000 al año. asintomática como la clínica. Examen del pie. El examen del pie Un problema de Salud es fundamental para corregir los factores Pública/Conclusión de riesgo y disminuir la incidencia de Puerto Rico es el país número uno en úlceras y de amputación. Este examen diagnóstico de diabetes y se estima que el debe incluir aspectos como el estado de la número de diabéticos continúe en ascenso piel, la presencia de grietas o callosidades debido a una dieta alta en calorías, grasas, 66

Revista Puertorriqueña de Medicina y Salúd Pública

azúcares y carbohidratos, acompañado de un alto grado de sedentarismo. Si calculamos que un paciente con úlcera y en proceso de amputación cuesta entre $30,000 - $60,000 y luego este mismo paciente ha de gastar entre $40,000 - $60,000 en los 3 años post-amputación,- nos damos cuenta del impacto económico que esto conlleva. No de menor importancia, recalcar que se limita la capacidad productiva del paciente e impacta su núcleo familiar al hacerlo más dependiente y disminuir su capacidad funcional. Los números demuestran que hemos fallado en desarrollar protocolos de prevención que deben estar enfocados en la educación desde etapas tempranas, preferiblemente en la niñez. En resumen, el pie del diabético es un problema sanitario de gran importancia por su elevada prevalencia y las secuelas que puede originar. El conocimiento de los factores de riesgo, el diseño de planes de prevención y la creación de equipos multidisciplinares con dedicación a esta patología es la mejor opción de que disponemos hoy en día para mejorar las condiciones de vida y las expectativas de los pacientes diabéticos. Referencias Rogers LC, Lavery LA, Armstrong DG. The right to bear legs - An amendment to healthcare; how preventing amputations can save billions to the US healthcare system. J Am Podiatr Med Assoc. 2008;98(2) Miranda-Palma B, Sosenko JM, Bowker JH, Mizel MS, Boulton AJ. A comparison of the for foot ulcer susceptibility. Diabetes Res Clin Pract. Oct 2005;70(1):8-12 Vickie R. Driver, Matteo Fabbi, Lawrence A. Lavery, and Gary Gibbons (2010) The Costs of Diabetic Foot. Journal of the American Podiatric Medical Association: September 2010, Vol. 100, No. 5, pp. 335-341. Lee C. Rogers, DPM (2010) Preventing Amputation In Patients With Diabetes.Podiatry Today.March 2008, Volume 21, no. 3 Resumen seminal de la salud en PR 20042013/Ana Rius

MSP INFOGRAFÍAS

Diabetes en Puerto Rico

550,000

AMPUTACIONES no traumáticas

personas

Pacientes aproximadamente con diagnóstico de diabetes.

de la extremidad inferior ocurren debido a problemas vasculares.

en la isla son diagnosticadas con diabetes cada año.

La DIABETES es la tercera causa de muerte en Puerto Rico.

2,500

Amputaciones anuales de la extremidad inferior se hacen en Puerto Rico de las cuales el 70% son en pacientes diabéticos.

1 de cada 6

adultos en Puerto Rico padece de DIABETES.

65 A 74 AÑOS

Según el CDC

mayor prevalencia

niños hispanos

nacidos después del 2000 van a desarrollar diabetes en algún momento de su vida.

particularmente en las MUJERES.

1 de cada 3 adultos de

65 años+

MAYOR TASA DE MUERTES en los hombres en comparación con las mujeres.

padece de diabetes.

ESCUELAS ESPECIALIZADAS EN ENDOCRINOLOGÍA : Recinto de Ciencias Médicas y el Hospital Municipal de San Juan, de donde salen aproximadamente dos especialistas al año.

es la prevalencia de diabetes en adultos puertorriqueños.

Por cada

100,000

población adulta en Puerto Rico sufre de

murieron murieron alrededor alrededor de 90 de 80 debido a la debido a la DIABETES. DIABETES.

Puerto Rico es la jurisdicción de EU con la prevalencia de casos de diabetes.

casos son de TIPO 2.

DIABETES TIPO 1.

más alta

En adultos entre las edades de

20 a 79 años,

en comparación con otras regiones de América del Sur y Centro América, Puerto Rico reporta una prevalencia de 13%.

66.6

puertorriqueños

13.5 casos por

cada 100,000 niños y/o jóvenes menores de 20 años, entre 1995 a 2003.

Fuentes:

1,130

921

278

659

*Los datos adquiridos para el año 2012, son preliminares.

en niñas (69%).

entre las edades de 15 a 19 años y

Muertes por diabetes en Puerto Rico por grupo de edad, 2012 7

en el grupo de jóvenes

27.9

MAYOR PREVALENCIA

sobrepeso (38.7%). está

Edad 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80+

como obeso.

puertorriqueños no realiza actividad física mensualmente.

66.4

no realiza actividad física aeróbica de 150 minutos o más por semana.

Asociación Americana de Diabetes • Federación Internacional de Diabetes • Departamento de Salud. (2014). Resumen General de la Salud en Puerto Rico. San Juan, Puerto Rico. • International Diabetes Federation.Revista IDF Diabetes Atlas. 6th ed.de Brussels, Belgium: Revista Puertorriqueña de Medicina Salúd Pública Pública Puertorriqueña Medicina yy Salúd International Diabetes Federation; 2014. • Pérez-Perdomo R, Pérez-Cardona C, Allende-Vigo M, Rivera-Rodríguez M, Rodríguez-Lugo L. Type 2 diabetes mellitus among young in Puerto Rico, 2003. P R Health Sci J. 2005; 24(2):111-7. • Frances M. Colon Pratts: Pharm D., CDE - Datos epidemiológicos de la diabetes en Puerto Rico, Revista Puertorriqueña de Medicina y Salud Pública Volumen IV año X.

67 31

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Intervención integral para abordar la Diabetes Mellitus Tipo 2 y la depresión concomitante en un entorno de atención primaria Por: Felix M. Marti Rivera, MD PGY-31; Fares Yasin, MD, PGY-31; Yanira Maldonado Allende, BHE2; Diana Núñez Padín, PsyD3; María de los Ángeles De Jesús, PhD4; Martha L. Villarreal Morales, PhD5; Yadira Reyes, MD4;

1 Programa de Residencia de Medicina Familiar, Manatí Medical Center. 2Programa de Educación del Paciente, Atlantic Medical Center, Barceloneta. 3Departamento de Medicina del Comportamiento, Atlantic Medical Center, Barceloneta. 4Departamento de Medicina de Familia, Manatí Medical Center, Manatí. 5Departamento de Educación Médica, Manatí Medical Center.

de estos pacientes en nuestra comunidad. Para esto un estudio, en dos etapas, fue realizado entre los pacientes diabéticos tipo 2 que acuden a Atlantic Medical Center (AMC), Barceloneta. En la Etapa 1 a cada participante se le administró el cuestionario sobre la salud del paciente PHQ-9, se le midió el nivel de hemoglobina glucosilada (HbA1c) y se recogieron datos biopsicosociales. En la etapa 2, fue realizada una intervención de atención integral durante 6 meses por un equipo multidisciplinario. El nivel de HbA1c fue utilizado para medir el control glucémico y la puntuación PHQ-9 para evaluar la depresión. Hubo 152 personas al inicio del estudio con una edad media de 62,8 (± 12,26), HbA1c media de 7,97% (± 1,7) de los cuales el 66,9% eran mujeres. Entre los participantes 52,7% tenían depresión mínima, el 28,7% tenía depresión leve y 18.42% depresión entre moderada y severa. El 49,7% de los sujetos no entendía lo que

era DM. Sólo el 40.78% completaron la segunda fase del estudio; sin embargo, el grupo que abandonó y el que terminó no iniciales. Entre los que completaron el estudio hubo una disminución ligera pero no estadísticamente significativa en la en la puntuación del cuestionario PHQ-9 (p <0,001). Existe una correlación positiva y 0,08 a 0,53 p = 0,01). Un enfoque integrado para el tratamiento de la diabetes tipo 2 y la depresión puede mejorar los resultados clínicos de los pacientes en el ámbito de la atención primaria. Nuestros resultados ponen un mayor énfasis en la necesidad de programas clínicos que ayuden al paciente a comprender mejor su enfermedad, a mejorar la adherencia al tratamiento y prevención de las complicaciones de la diabetes.

Palabras claves Diabetes Mellitus tipo 2, depresión, comorbilidad, la atención primaria de salud, Puerto Rico

De acuerdo con el sistema de vigilancia de los factores de riesgo de los Centros para el Control y la Prevención de Enfermedades (CDC), en el 2014 Puerto Rico

Lugar

Resumen La depresión está asociada a un autocuidado deficiente de la diabetes Mellitus (DM) lo que resulta en un empeoramiento de los resultados clínicos del paciente. Este estudio tiene como objetivo evaluar el impacto de una intervención educativa multidisciplinaria en pacientes diabéticos tipo 2 con depresión en un entorno de atención primaria. El objetivo secundario es describir las

• prevalencia de la diabetes • prevalencia del trastorno depresivo mayor y general

21 y 85 años Edad de los sujetos fueron reclutados entre la población diabética de tipo II del Atlantic Medical Center (AMC), Barceloneta, Puerto Rico.

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Abstract Depression is associated with poor adherence to diabetes mellitus (DM) self-care resulting in worse overall clinical outcomes. This study aims to evaluate the impact of a multidisciplinary educational intervention in the outcome of diabetic and depressed patients in a primary care setting. A two-stage design study was implemented among type II diabetes patients: Stage 1, participants were administered the PHQ-9 questionnaire, Glycosylated hemoglobin (HbA1c) levels were measured and biopsychosocial data collected. In Stage 2, an integrated care intervention was done during 6 months by a multidisciplinary team. HbA1c level was used to measure glycemic control and the

PHQ-9 score to assess depression. There were 152 subjects at baseline with a mean age of 62.8 (±12.26), mean HbA1C of 7.97 (±1.7), and 66.9% were female. There was 52.7% with minimum depression, 28.7% had mild depression and 18.42% had moderate to severe depression. When questioned 49.7% of the subjects did not understand what DM was. Only 40.78% completed the study; however the group which dropped out and the one which completed did not differ statistically in baseline measures. Among those who completed the study there

Introducción Varios estudios han examinado la asociación de la diabetes con la depresión y la naturaleza bidireccional de esta relación teniendo en cuenta que la depresión puede ocurrir como consecuencia de padecer diabetes, pero también puede ser un factor de riesgo para la aparición de diabetes tipo 21. De acuerdo con Mezuk et al. 2 padecer de depresión aumenta el riesgo de desarrollar diabetes tipo 2 en un 60% y la diabetes tipo 2 se asocia con un riesgo del 15% de sufrir depresión. El curso de la depresión en pacientes con diabetes y depresión es crónico y severo. Hasta el 80% de los pacientes con diabetes y depresión experimentan una recaída de los síntomas depresivos durante un período de 5 años3. La depresión está asociada con una pobre adherencia al autocuidado de la diabetes, lo que incluye seguir las restricciones en la dieta, el cumplimiento de la medicación y la monitorización de la glucosa en sangre, dando lugar a peores resultados clínicos generales3, 4 . Los síntomas clásicos de la depresión son la falta de energía, anhedonia, trastornos del sueño, trastornos del apetito y el aislamiento social. La depresión es uno de los problemas de salud más graves en el país, asociado con el sufrimiento sustancial, la pérdida de productividad y la pérdida de la vida5. La depresión se produce con frecuencia asociada a la diabetes variando entre 5,4% a 41,3%, dependiendo de la herramienta que se utiliza para evaluar la depresión. Sin embargo no es reconocida y tratada en aproximadamente dos

tercios de los pacientes con ambas condiciones6. La prevalencia de diabetes en el mundo continua en constante aumento en todos los grupos de edad. De acuerdo con la Organización Mundial de la Salud (OMS), la prevalencia de la diabetes estimada en todo el mundo fue del 2,8% en 2000 y se estima que aumente a 4,4% en 20307. Por otra parte, según la OMS la depresión es altamente prevalente siendo la principal causa de discapacidad en el mundo entre los trastornos psiquiátricos y se prevé que sea la segunda condición médica más frecuente en 20208. La población de Puerto Rico comprende sólo el 1,5% de la población total de Estados Unidos, sin embargo, de acuerdo con el Sistema de Vigilancia de Factores de Riesgo del Comportamiento (BRFSS, de sus siglas en inglés) entre 1996 - 2010 Puerto Rico ocupó el primer lugar en la prevalencia de la diabetes entre todos los estados y territorios de Estados Unidos9. La tasa ajustada por edad en Puerto Rico (12.8 / 1 000) fue la más alta de todos los estados y territorios reportados. De acuerdo con el mismo estudio, la prevalencia de DM en el municipio de Barceloneta es del 15,3%. Este valor es el segundo más alto de la isla, sólo superado por el municipio de Arecibo con un 15,4%. Adicionalmente, de acuerdo con el CDC, durante el 2006 y el 2008, Puerto Rico ocupó el primer puesto en el porcentaje de adultos que satisfacen los criterios de depresión mayor y cualquier tipo de depresión (reuniendo solo 2,3 ó 4 de

Revista Puertorriqueña de Medicina y Salúd Pública

the PHQ-9 score (p<0.001). There is a

positive correlation between Final PHQ-9 and Final HbA1C, r=0.32, (95% CI: 0.08 to 0.53), p=0.01. An integrated approach to depression and type 2 diabetes treatment may improve outcomes in primary care. Our results call for greater emphasis on the development of clinical programs to help the patient to better understand theirs diseases, to enhance medication adherence and to prevent further diabetes complications.

Keywords type 2 Diabetes Mellitus, depression, comorbidity, primary health care, Puerto Rico.

los 8 criterios para la depresión) con el 4,5% y el 14,7%, respectivamente10. Este estudio tiene como objetivo evaluar el impacto de una intervención educativa multidisciplinaria en el resultado clínico de los pacientes diabéticos tipo 2 con depresión en un entorno de atención primaria. El objetivo secundario es describir las características los pacientes diabéticos que tienen depresión en nuestra comunidad. Métodos y materiales Participantes: Los sujetos fueron reclutados entre la población diabética tipo 2 que acude a Atlantic Medical Center (AMC), Barceloneta, Puerto Rico. AMC es un centro de atención primaria que opera mediante fondos federales y fondos de Mi Salud que ofrece servicios primarios y preventivos de salud y sirve como clínica ambulatoria del programa de Residencia de Medicina de Familia de Manatí Medical Center. Se incluyeron pacientes de ambos sexos y de edades comprendidas entre los 21 y 85 años. Fueron excluidos pacientes con enfermedad mental grave conocida (psicosis, demencia y problemas de aprendizaje) y pacientes con complicaciones de la diabetes en etapa avanzada y/o enfermedad terminal. Este protocolo fue aprobado por el Consejo de Revisión Institucional de Ponce Health and Sciences University (Protocolo número 141124 - YR el 17/12/2014) y un los pacientes al inicio del estudio.

MSP ARTÍCULO ORIGINAL

moderada o grave (puntuación PHQ-9 ≥ 10) fue analizada por síntomas depresivos o estado fueron remitidos para evaluación psicológica de la diabetes mediante prueba t de Student y terapia conductual al Departamento de para variables continuas y X2 para variables pacientes evaluados al inicio. Medicina Conductual de AMC. El curso del categóricas. Un valor de p ≤ 0,05 se consideró Total 152 tratamiento fue decidido por el psicólogo a Hombre 52 (34.2%) cargo en función de las necesidades individuales Resultados Mujeres 100 (65.8%) de cada paciente. Después de este período se De todos los pacientes diabéticos tipo 2 del midieron una vez más los niveles de HbA1c y AMC (n = 531), inicialmemte solo se pudieron Edad (media≥ DE) 62.8 (±12.26) la puntuación PHQ-9 y se evaluó el impacto contactar a 331, de los cuales 223 cumplían con Rango de edad 37-82 potencial del manejo de la depresión en los los criterios de inclusión y solo 152 estuvieron Empleados 18 (12%) niveles de HbA1c de los pacientes. Como de acuerdo en participar y comenzar la primera Desempleados 81 (54%) variable primaria fue evaluado los niveles de fase del estudio. Las principales características Retirados 51 (34%) HbA1c y como variables secundarias se utilizó la puntuación del cuestionario de depresión evaluados se muestran en la Tabla 1. Al inicio Solteros 23 (15.3%) PHQ-9 y de la encuesta psico-socioeconómico del estudio, la edad media fue de 62,8 (± 12,26), Casados/Viviendo juntos 77 (51.3%) con una media de los niveles de HbA1C de de los pacientes. Divorciados/Separados 50 (33.3%) Instrumentos: Con el fin de evaluar 8,09 (± 1,7), con una media de IMC de 30,2 Años con DM (media≥ DE) 12 la presencia y la gravedad de los síntomas (± 7,0), y el 66,9% eran mujeres. Entre los Años en rango de DM 1-42 de depresión en nuestros pacientes se participantes 12,9% no presentaban síntomas utilizó el cuestionario sobre la depresión de depresión, el 32,3% presentaban depresión Seguro Privado 25 (16.6%) PHQ-9, debidamente traducido al español mínima, el 35,4% depresión leve, 11,4% Seguro gubernamental 116 (77.3%) y estandarizado para la aplicación por tenían depresión moderada, 6,4% tenían Privado + Gobierno 9 (6%) los médicos11. El inventario de depresión depresión moderadamente grave y el 1,6% Complicaciones de la DM PHQ-9 fue elegido por su capacidad para tenía depresión severa. De nuestra población, No reportado (%) 105 (70%) evaluar parámetros como: el estado de ánimo, el 52% era casado, con un alto porcentaje de problemas de sueño, ideas suicidas, falta de desempleo (55%) y aproximadamente la mitad Neuropatía (%) 24 (16%) concentración, problemas de alimentación, de ellos contaban con educación primaria Nefropatía (%) 7 (4.67%) retraso psicomotor, etc. La puntuación de (42%) o sin educación formal (3%). El 76% Oftalmopatía (%) 19 (12.67%) tenían un seguro médico proporcionado por Tratamientos para DM pacientes según el índice de gravedad PHQ-9. las ayudas gubernamentales como Medicare o Medicaid y sólo el 16.6% contaba con un Oral 99 (68%) 12 seguro médico privado. DSM IV TR . En el caso que un paciente Insulina 4 (3%) fue Las respuestas a las preguntas realizadas a Ambos 38 (26%) establecido un protocólo para su remisión al los participantes concernientes al conocimiento Solo dieta 4 (3%) departamento de urgencias para su evaluación acerca la DM, asequibilidad a los medicamentos psiquiátrica, evaluación de riesgos y tratamiento. y apoyo social se resumen en la Tabla 1. Cuando Diseño del estudio: Fue un estudio Se utilizó la hemoglobina glucosilada (HbA1c) se les preguntó acerca de la comprensión de su realizado en dos etapas. En la Etapa 1, se para evaluar la adherencia al tratamiento por utilizó un estudio transversal para evaluar las parte del paciente. Las muestras de sangre asociadas a los pacientes diabéticos tipo 2 en para la medida de HbA1C se obtuvieron en el al cuestionario psicosocial nuestra comunidad. Para esto, se midieron los mismo día, antes o inmediatamente después de Pregunta Sí (%) niveles de hemoglobina glucosilada (HbA1c) completar los cuestionarios. Las mismas fueron y se enviaron a ¿Comprende lo que es 49.7% y fueron utilizados el inventario de depresión la diabetes mellitus? un laboratorio local certificado con un número PHQ-9 y una encuesta de 10 preguntas de identificación codificada. ¿Sabe usted cómo tomar 91.0% (ver Tabla 1), para evaluar el estado y el sus medicamentos? A todos los participantes se les pidió responder sistema psico-socioeconómico de apoyo del ¿Sería capaz de pagar 24.8% paciente. Los datos recogidos se utilizaron a una serie de 10 preguntas para evaluar su sus medicamentos si su situación psico-socioeconómica su sistema de para establecer el estado inicial del paciente seguro no los cubriese? para la siguiente fase. En la etapa 2, una apoyo y posibles factores que conducen a la ¿Espera usted hasta que se 33.1% intervención integrada que proporcionó falta de adhesión o depresión. La adherencia a acaben los medicamentos para reponerlos? educación y recomendaciones de tratamiento, la terapia, dieta y medicamentos, fue evaluada ¿Tiene el apoyo emocional 77.2% seguimiento al estado clínico y adherencia al durante la entrevista médica y combinada a de la familia o amigos? tratamiento fue realizado durante 6 meses los resultados de hemoglobina glucosilada. El análisis de datos fue realizado con el ¿Tiene algún método 80.0% por un equipo multidisciplinario. Este equipo software SPSS 20.0 (IBM SPSS, Chicago, IL, para transportarse a estuvo integrado por médicos del último año sus citas médicas? de Residencia de Medicina de Familia del EE.UU.). El análisis de estadística descriptiva fue ¿Asiste a sus citas 86.9% Manatí Medical Center, médicos de atención realizado para todas las variables y expresado médicas programadas? primaria, psicólogo clínico, trabajador social, como media ± desviación estándar para las ¿Toma sus medicamentos 84.8% nutricionista y educadora de salud. Además, variables continuas con distribución normal. según lo prescrito por su médico? los pacientes identificados con depresión La distribución de las características iniciales Figura 1. Características

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MSP ARTÍCULO ORIGINAL

lo que era la DM y a pesar de que el 91% de

de adaptar el contenido de las intervenciones y los modos de la entrega a las necesidades Figura 1. Cont. medicamentos, el 73,8% declaró no tener los de nuestra comunidad. Teniendo en cuenta Nivel de Escolaridad medios para pagar sus recetas en caso de que que aproximadamente la mitad de nuestros el seguro no los cubriese. pacientes refirieron no entender lo que es 70 Sólo el 40,78% (n = 62) de los participantes la diabetes mellitus, podemos inferir que las 50 completaron la fase II del estudio; sin embargo, complicaciones debido a la no adherencia al 53 el grupo que abandonó y el que terminó no tratamiento y la necesidad de una dieta especial y actividad física puede no ser entendida de 35 25 iniciales (p> 0,05). Las principales razones dadas igual forma. La motivación e implicación de por los pacientes para el abandono fueron el los pacientes entre otros obstáculos, continúan 18 transporte (36,6%), la falta de interés (23,3%) siendo un reto importante. 6 Diferentes vías de acercamiento a la población 0 Iletrados Escuela Escuela Universidad (23,3%) (Figura 2). Al inicio del estudio este han sido evaluadas en varios estudios con Elemental Superior diferentes grados de éxito13. Una evaluación de con el índice de gravedad del inventario PHQ- la depresión y vigilancia del control glucémico Comorbilidades 9 como sigue: 12,9% (n = 8) con puntuación a través del correo no fue exitosa en los Países 14 90 0; 32,2% (n = 20) depresión mínima, el Bajos . Sin embargo, en un estudio similar 35,4% (n = 22) depresión leve; 11,3% (n = 7) en que un programa individualizado que 68 depresión moderada; 6,5% (n = 4) depresión reconocía el contexto social y cultural de moderadamente grave y 1,6% (n = 1) depresión los pacientes se llevó a cabo, mostró tasas 45 severa. Este grupo recibió semanalmente más altas de adherencia a los medicamentos, actividades educativas y motivacionales acerca así como un mayor control de la glucosa de la nutrición, la higiene, la actividad física, y menos síntomas depresivos al final del 23 control de las emociones, y el manejo de la estudio15. Una intervención basada en el depresión durante 6 meses. Los pacientes modelo de habilidades motivacionales y de 0 con depresión moderada o más (PHQ-9 ≥10) comportamiento (IMB por sus siglas en inglés) Hipertensión Dislipidemia Enfermedad vascular recibieron adicionalmente terapia psicológica hecho en Puerto Rico, mostró una mejoría EPOC Hipertiroidismo individual. Ninguno de los pacientes durante cardíaca el estudio expresó ideas suicidas por lo que no grupo de intervención desde el inicio hasta el fue necesario intervenciones que requirieran BMI atención hospitalaria inmediata. conductas de autocuidado, cuando se establece 17 70 Entre los que completaron el estudio se una intervención culturalmente adaptada . 61 En nuestro caso, el grupo que recibió observó una disminución ligera pero no 53 psicoterapia individual (PHQ-9 ≥10) tuvo 53 una mayor reducción de la HbA1c (0,25% -0,42 a 0,18; p = 0,424). Sin embargo, hubo una promedio) que la reducción de la HbA1c 35 28

(0,12%). De acuerdo con un meta-análisis (diferencia de medias -0,89; IC del 95%, -1.58- realizado por Huang et al., las intervenciones -0.19, p = 0,01). Adicionalmente, fue observada integradas con los pacientes diabéticos que sufren depresión mostraron una mejora general en el cumplimiento de la medicación, a la 0,53 p = 0,01). El grupo de pacientes que el tratamiento y remisión de la depresión, recibieron psicoterapia individual (PHQ-9 pero de manera similar a nuestro estudio, no ≥10) tuvo un cambio mayor y estadísticamente observaron una disminución estadísticamente que no recibieron la psicoterapia individual (diferencia de medias 3,14; IC del 95, 1,56 a 4,71; p = 0,0002) (Tabla 2). Discusión La principal limitación de nuestro estudio fue la alta tasa de abandono durante la primera fase del estudio. Sin embargo, la respuesta de los pacientes que permanecieron en el estudio fue altamente positiva con 80% de ellos con una o ninguna sesión perdida. Aunque no hubo variables iniciales entre estos dos grupos el alto

Revista Puertorriqueña de Medicina y Salúd Pública

de media -0.13%, (IC del 95% = -0,46 a 0,19, p> 0,05)18. Este estudio también mostró que la reducción de la HbA1c, en pacientes que inician los medicamentos antidiabéticos orales (OAD) por primera vez, alcanza un pico (media de 1,5%) en 4-6 meses, pero después la reducción parece ser modesta18. Las varias clases de medicamentos ofrecen diferentes reducciones en los valores de HbA1c, por ejemplo agonistas de receptores GLP-1 tienden a disminuir la HbA1c en promedio 0,5% a 1,0% mientras que los inhibidores de la DPP-4 ofrece un

18 0

1 Bajo Peso

Normal Sobre Peso

Obeso

Figura 2. Razones fundamentales por las que los pacientes abandonaron el estudio 30 22

23 15

14 8

8 0

No Trabajo Transporte Salud interesados

Sin tiempo

MSP ARTÍCULO ORIGINAL

a 0,8%18. Aunque en nuestro estudio, los cambios en los niveles de HbA1c no fueron acciones educativas y del comportamiento deben ser consideradas, junto con el uso de medicación antidiabética, como parte de un enfoque holístico en el tratamiento de los pacientes diabéticos. La correlación positiva y estadísticamente

Tabla 2. Prueba estadística (Pares-T). Antes y después de las mediciones.

Variables

Media

95% IC de diferencia Pares T (df)

Δ HbA1C Δ PHQ9

-0.12

1.17

-0.42

0.18

-0.804 (61)

0.424

-0.89

2.73

-1.58

-0.19

-2.554 (61)

0.013**

Referencias 1. Leone T, Coast E, Narayanan S, Aikins AG, Diabetes and depression comorbidity and la utilidad de este tipo de intervención del socioeconomic status in low and middle income manejo del cuidado integral en la mejoría de countries (LMICs): a mapping of the evidence, los síntomas de la depresión en los pacientes. 2012, Globalization and Health, 8 (39): 1-10. La depresión continua sin ser reconocida y 2. Mezuk, B., Eaton, W.W., Albercht, S., & tratada adecuadamente en aproximadamente Golden, S.H. (2008). Depression and type dos tercios de los pacientes con diabetes, 2 diabetes over the lifespan: a meta analysis. a pesar de las importantes implicaciones Diabetes Care, 31(12), 23832390. clínicas asociadas con la comorbilidad 3. Katon WJ, Lin E.H.B, Von Korf M., de las condiciones19. De acuerdo con la Ciechanowski, P., Ludman E.J, Young B. etal, Asociación Americana de Diabetes, los Collaborative Care for Patients with Depression pacientes diabéticos, particularmente and Chronic Illneses, The New England Journal aquellos con un autocuidado deficiente, of Medicine, 2010 November, 363 (27): 2611deben recibir evaluaciones de depresión 2620. de forma rutinaria20, sin embargo, muchos 4. Aarts, S; Van den Akker, M; Van Boxtel, pacientes con diabetes tipo 2 no se manejan M.P.J; Jolles, J; Winkens, B; Metsemakers, adecuadamente. Mejorías en el manejo de J.F.M.Diabetes mellitus type II as a risk factor ambas condiciones puede tener un impacto for depression: a lower than expected risk in a importante sobre el estado funcional del general practice setting. European Journal of paciente y la mortalidad.2, 20 Epidemiology (2009) 24:641–648. 5. Cuijpers P, Smit F, Excess mortality in Conclusión depression: a meta-analysis of community studies. En conclusión, este estudio sugiere que el manejo integrado de la diabetes y 6. Markowitz S, Gonzalez JS, Wilkinson JL, depresión concomitante puede aumentar Safren SA, Treating Depression in Diabetes: significativamente la calidad de vida de Emerging Findings, 2011, Psychomatics, 52 los pacientes. Por otra parte, nuestros (1): 1-18. resultados deben estimular estrategias de 7. Sweileh SW, Abu-Hadeed HM, Al-Jabi SW, investigación y correctivas adecuadas para Zyoud SH, Prevalence of depression among mejorar consistentemente los resultados people with type 2 diabetes mellitus: a cross de estos pacientes en la asistencia primaria. sectional study in Palestine, 2014, BMC Public Una muestra más grande de población y Health, 14:163. enfoques alternativos deben ser abordados 8. Tierney EF, Burrows N, Barker L, et al. en estudios futuros. Small area variation in diabetes prevalence in Puerto Rico, Revista Panam Salud Publica, Agradecimientos 2013; 33(6): 398-406. Los autores agradecen a Iván Iriarte, MD, 9. Murray, CJL. Lopez, AD., editors. The DABFM del Departamento de Medicina de global burden of disease: a comprehensive Familia y Pediatría de Ponce Health Science assessment of mortality and disability for diseases, University por la asistencia en el análisis injuries, and risk factors in 1990 and projected to estadístico así como a Norman Ramírez- 2020. Harvard University School of Public Health Lluch, MD FAAP/FAAOS y Félix Betancourt on behalf of the World Health Organization Bojos, MD, DABFM para la revisión crítica and The World Bank; Cambridge, MA: 1996. 10. Kerr LK, Screening tools for depression del manuscrito. También agradecemos, a Loida Ruiz, MD: Lissette Díaz, MS4; Tania for the primary care, 2001, West Journal of M. Okundaye, MS4 y Nelvin Acevedo MS4 Medicine, 175: 349-352. 11. Gonzalez O, McKnight-Eily LM, Edwards por su ayuda con las actividades educativas VJ, Croft JB, Current depression among adultsy la recopilación de datos. United States 2006-2008, 2010, Morbidity and de depresión y los niveles de HbA1c en

Mortality Weekly Review, 59 (38): 1229-1235. 12. Spitzer RL, Kroenke K, Williams JB (1999). Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. JAMA. Nov 10;282(18):1737–44. 13. American Psychiatry Association, Diagnostic and Statistical Manual of Mental Dissorders, Test Revision, 4th Edition. EH, Eijk Van JT, Assendelft WJ. nterventions to improve the management of diabetes in primary care, outpatient, and community settings: a systematic review. Diabetes Care. 2001 Oct;24(10):1821-33. 15. Pouwer, F; Tack, C.J; Geelhoed-Duijvestijn, P.H; Bazelmans, E; Beekman, A.T; Heine, depression with written feedback in outpatients with diabetes mellitus: a randomised controlled trial. Diabetologia (2011) 54:741–748. 16. Bogner, B; Morales, K; De Vries, H; Cappola, A.Integrated Management of Type 2 Diabetes Mellitus and Depression Treat- ment to Improve Medication Adherence: A Randomized Controlled Trial. Annals of Family Medicine 2012;10:15-22. 17. Osborn, C.Y; Rivet, K; Cruz, N; O’Connel, A; Perez, R.; Kaichman, S; Wolf, S; Fisher, J. A Brief Culturally Tailored Intervention for Puerto Ricans with Type 2 Diabetes:Health Education Behavior. 2010 December; 37(6): 849–862. 18. Huang, Y; Wei, X; Wu, T; Chen, R; Guo, A.Collaborative care for patients with depression and diabetes mellitus: a systematic review and meta-analysis. BMC Psychiatry 2013 13:260. 19. Sherifali, D; Nerenberg, K; Pullenayegum, on A1C Levels: A systematic review and metaanalysis. Diabetes Care August 2010 vol. 33 no. 8 1859-1864. 20. Katon, W.J.The Comorbidity of Diabetes Mellitus and Depression.Americnan Journal of Medicine. 2008; 121(11 Suppl 2): S8–15. 21. American Diabetes Association. Clinical practice recommendations. Diabetes Care. 2010;33(Suppl 1):S1–S100. 22. 20. Centers for Disease Control and Prevention. Current Depression Among Adults United States 2006 and 2008, Morbidity and Mortality Weekly Report. Vol.59, No.38, October 1,2010, 1229-1235. Revista Puertorriqueña de Medicina y Salúd Pública

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Humberto M. Guiot, MD, FACP+; Vivian Colón-López, PhD, MPH*++; Ana P. Ortiz, PhD, MPH*++; Vivian Tamayo-Agrait, MD+; Leticia Román, MS*; Cristina Muñoz-MassÛ, MS, MT* +Escuela de Medicina, Recinto de Ciencias Médicas, Universidad de Puerto Rico ++Escuela Graduada de Salud Pública, Recinto de Ciencias Médicas, Universidad de Puerto Rico *Centro Comprensivo de Cáncer de Puerto Rico

El cáncer de ano en las personas con VIH/SIDA: Un riesgo en aumento

Palabras clave: cáncer de ano, VPH, VIH, SIDA, anoscopía, citología anal, coagulador infrarrojo, Puerto Rico

Resumen

El cáncer se ha convertido en una preocupación de salud para las (VIH). Notablemente, el cáncer de ano es el tipo de cáncer que mayor tendencia de aumento ha mostrado entre los pacientes con VIH en las últimas décadas. El cernimiento de cáncer de premalignas o malignas. Postulamos que detectar el cáncer de ano en etapas tempranas puede ayudar a salvar vidas y que varias modalidades de tratamiento ya disponibles en Puerto Rico podrían detener el progreso de lesiones premalignas a cáncer de ano.

Summary

Cancer has become a health issue among people living trend during the past few decades among patients with HIV. Screening for anal cancer in patients with HIV can help to identify premalignant lesions or cancer. We theorize that early detection of anal cancer can save lives and that several treatment options already available in Puerto Rico might avoid the progression of premalignant lesions into anal cancer.

Introducción

Según estadísticas del Sistema de Vigilancia de VIH de Puerto Rico (PR HIV Surveillance System), hasta septiembre de 2013 Humana (VIH) en Puerto Rico. Según la expectativa de vida ha ido aumentando en este grupo de pacientes, el riesgo de que desarrollen condiciones como el cáncer se ha convertido en una preocupación de salud. El “envejecimiento” de la epidemia global del VIH/SIDA se demuestra por un aumento de más del doble de casos de VIH/SIDA en personas mayores de 50 años desde 1995. 1 Este cambio epidemiológico y clínico en la población viviendo con VIH se debe en gran parte a los avances en la terapia antirretroviral altamente efectiva (HAART, por sus siglas en inglés), la cual ha contribuido a disminuir el riesgo de ciertos tipos de cáncer en pacientes con VIH/SIDA (como sarcoma de Kaposi y el linfoma de tipo non-Hodgkin), pero a su

Keywords: anal cancer, HPV, HIV, AIDS, anoscopy, HRA, anal cytology, IRC, Puerto Rico

vez, no ha logrado disminuir el riesgo de otros tipos de cáncer que, por el contrario, han aumentado en las últimas décadas, como el linfoma de tipo Hodgkin y el cáncer de ano.2,3,4,5 Esta presentación de malignidades ha llevado al desarrollo de investigaciones en el área de cáncer de ano en personas viviendo con VIH en las últimas décadas. Este artículo pretende describir la epidemiología del cáncer anal en la población general de Puerto Rico y, en particular, en la población viviendo con VIH, mientras se muestran aspectos clínicos relacionados con el cernimiento y el diagnóstico de esta malignidad. Se presentan además los esfuerzos de colaboración si estrategias de detección temprana y tratamiento para cáncer inciden en una reducción de cáncer de ano en personas viviendo con VIH. Finalmente, brindamos información de contacto de la Clínica de Neoplasia Anal de la Universidad de Puerto Rico (UPR) en el Recinto de Ciencias Médicas y de recursos de diseminación de información para el paciente sobre cáncer de ano y ensayos clínicos.

Cáncer de ano

El cáncer de ano comprende un 1% a 2% de todos los cánceres gastrointestinales, en su gran mayoría (80%) es de tipo escamoso y al menos 85% de las veces se vincula al Virus del Papiloma Humano (VPH).6,7 Las relaciones sexuales anales no son imprescindibles para llevar al VPH al ano, puesto que por la cercanía con el área genital y por otros tipos de prácticas sexuales el VPH puede depositarse en el área perianal y anal. La zona de transición entre el epitelio columnar (presente en el ano colon y ano proximal) y el epitelio escamoso (presente en el ano distal y el periano) es una zona de metaplasia constante. Una vez el VPH llega a esa zona, se integra a las células escamosas y se replica en grandes cantidades, predisponiendo al surgimiento de células atípicas y cáncer en un proceso bastante similar al que ocurre durante la oncogénesis de cáncer cervical secundario a VPH. Según datos del registro de cáncer de los Estados Unidos (EE.UU.), el cáncer de ano representa el 0.4% de todos los casos nuevos de cáncer.8 El cáncer de ano es más común en mujeres que en hombres.

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Durante el período del 2007-2011, para la población en general, la incidencia de cáncer de ano fue de 1.8 por cada 10,000 personas. Además de la carga de la enfermedad, hay dos aspectos a nivel epidemiológicos que son de importancia en este tipo de cáncer, para el cual no existen pruebas de cernimiento aprobadas hasta el momento: la edad al momento del diagnóstico y la sobrevida. La mediana de edad para el diagnóstico de cáncer de ano es de 60 años. En términos se sobrevida, según datos del registro de cáncer del período del 2004-2010, se estima que un 65.5% de los pacientes diagnosticados con cáncer anal sobrevivirán

en pacientes viviendo con VIH que tienen contajes bajos de células CD4+.20 Si los resultados de una citología anal muestran una celularidad normal, la prueba debe repetirse anualmente en pacientes viviendo con VIH. Si los resultados de la citología son anormales (células atípicas, neoplasia de bajo grado o neoplasia de alto grado), el paciente debe referirse para una anoscopía de alta resolución. Es importante recalcar que el cernimiento en las personas que viven con el VIH debe ser universal, independientemente de las prácticas sexuales.

Cáncer de Ano en Puerto Rico 2000-2008

mortalidad de 35% a los 5 años de diagnóstico.8 En Puerto Rico se reporta una realidad similar. Entre los años 2000 a 2008 se diagnosticaron en la Isla 441 nuevos casos de cáncer de ano y se reportaron 26 muertes por esta condición.10 Según datos del Registro Central de Cáncer de PR, la incidencia de cáncer de ano es mayor en mujeres (1.7 por cada 100,000) que en hombres (0.9 por cada 100,00). Sin embargo, en términos generales se reportó que la tendencia de cáncer anal va en aumento, particularmente en los hombres a razón de un, 26.9%.11 En En Puerto Rico la mediana de edad para el diagnóstico de cáncer anal es similar a los EE.UU. Sin embargo, en términos de sobrevivencia, se estima que un 53% de los hombres y mujeres diagnosticados con cáncer de ano sobrevivirá luego de 3 años después del diagnóstico.12 Particularmente, estos datos sobre la sobrevivencia de cáncer de ano en Puerto Rico se unen a las series de investigaciones en EU y a nivel internacional que promueven el desarrollo de estudios clínicos que evalúen la eficacia de estrategias de cernimiento en la incidencia y mortalidad de cáncer de ano.12 Aunque el cáncer de ano es relativamente raro, en la población viviendo con VIH es la malignidad con la mayor tendencia al aumento en las últimas décadas entre las personas que viven con VIH/SIDA.2,13 En los pacientes que tienen VIH, el aumento en incidencia es todavía mayor que en la población general, sobre todo en el grupo de hombres que tienen sexo con hombres (HSH).14 Estudios indican que los pacientes con VIH que son HSH tienen 40 veces más riesgo de cáncer de ano.15 Similar a otras malignidades en personas con VIH, existe una relación inversamente proporcional entre el desarrollo de cáncer de ano y los niveles más bajos (“nadir”) de células CD4+.16

Cernimiento y diagnóstico de neoplasia anal y cáncer de ano

No existen aún guías nacionales establecidas para el cernimiento de cáncer de ano, pero el cernimiento propuesto por investigadores en el tema incluye tres componentes principales: inspección visual del área, examen digital rectal y citología anal.17 Durante la citología anal, un hisopo (“Q-tip”) de Dacron se inserta en el canal anal para recopilar células y analizarlas bajo el microscopio.18,19 citología anal para detectar enfermedad son altas, especialmente

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Hombres

67%

70%

58%

60% 42%

50% 40%

33%

30%

441 casos nuevos (33% hombres/ 67% mujeres) 26 muertes (42% hombres/ 58% mujeres)

20% 10% 0%

Mujeres

Casos Nuevos

Muertes

En la anoscopía de alta resolución, se examina el área del ano a través de un colposcopio: un tipo de microscopio que hisopos de algodón para teñir los tejidos de manera que puedan visualizarse adecuadamente. Si algún área parece pre-maligna o maligna se tomarán biopsias con unas pinzas especiales para obtener muestras de tejido sumamente pequeñas que se enviarán al patólogo para evaluación y diagnóstico. En la mayoría de los casos, estas biopsias no son dolorosas o, de serlo, la molestia es mínima y momentánea. Una vez se establezca un diagnóstico por patología, los pacientes con cáncer deben referirse para tratamiento inmediato. A los pacientes con neoplasias de alto grado (grado 2 o grado 3) se les podría ofrecer seguimiento más cercano o tratamiento preventivo. Los pacientes con condiloma o neoplasia de bajo grado (grado 1) deben seguirse cada 6 meses.

Tratamiento

La estrategia principal para el evitar el desarrollo de cáncer de ano y otras condiciones anales vinculadas al VPH es la vacunación. Existe una vacuna recombinante cuatrivalente (Gardasil) en contra de los serotipos 6, 11, 16 y 18 del VPH que está aprobada por la Admin istración de Drogas y Alimentos de los EE.UU. (FDA, por sus siglas en inglés) para la prevención de verrugas, cambios pre-cancerosos y cáncer de ano en mujeres y hombres. Aunque tiene indicación y está endosada por las academias más importantes, los porcientos de vacunación en Puerto Rico todavía son bajos y es un área donde todavía hay espacio para mejorar.21

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Condiciones anales durante anoscopía de alta resolución

Figura 1. Condiloma perianal Guiot HM. UPR Anal Neoplasia Clinic.

Figura 2. Condiloma anal Guiot HM. UPR Anal Neoplasia Clinic.

Figura 3. Neoplasia intraepitelial 1 con patrón vascular de estriado Guiot HM. UPR Anal Neoplasia Clinic.

Al momento, se encuentran en estudios clínicos otras vacunas que protección contra el VPH. Aunque las verrugas perianales o anales y las neoplasias de bajo grado tienen poco potencial de convertirse en cáncer de ano, las lesiones anales de alto grado (neoplasias 2 y 3) sí pueden progresar a cáncer y deben observarse de cerca (cada 4-6 meses) o pueden tratarse. El racional del tratamiento es destruir estas lesiones de alto grado para evitar el desarrollo de cáncer de ano. Estudios han demostrado que tratar las neoplasias de alto grado con coagulación infrarroja, para los pacientes evitando el desarrollo de cáncer de ano.22 El coagulador infrarrojo funciona enviando calor para destruir el tejido con neoplasia de alto grado en lapsos de 1.5 segundos luego de haber aplicado anestesia tópica y local. El tejido necrótico luego se remueve hasta llegar al nivel de la submucosa. Las complicaciones son mínimas y los pacientes tienden a tolerarlo muy bien. Investigadores han encontrado que esta técnica evita el surgimiento de cáncer de ano y parece ser más efectivo que terapias tópicas, 23,24

tópica, dentro del ano, para tratar neoplasias de alto grado. Tiene las desventajas de que requiere la participación activa del paciente para aplicarlo y puede ocasionar efectos adversos (irritación, picor,

Figura 4. Lesión intraepitelial de alto grado (2-3) con patrón vascular de puntuación . Guiot HM. UPR Anal Naoplasia Clinic.

Figura 5. Lesión intraepitelial grado 3 con patrón vascular de mosaico Guiot HM. UPR Anal Naoplasia Clinic.

EL ELECTROCAUTERIO ES UNA TÉCNICA QUIRÚRGICA QUE LLEVA FRECUENCIAS ALTAS DE ELECTRICIDAD EN ÁREAS AFECTADAS En estadíos I, II y III se puede ofrecer radioterapia y quimioterapia antes o después de la cirugía. En casos donde el cáncer se ha diseminado a órganos distantes (estadío IV) la enfermedad se considera ya incurable.27

Cernimiento, diagnóstico y tratamiento de neoplasias ana les en Puerto Rico

Los doctores Vivian Tamayo-Agrait y Humberto M. Guiot realizan desde el año 2012 pruebas de citología anal, anoscopía de alta resolución y tratamientos tópicos para neoplasias anales en el Recinto de Ciencias Médicas de la UPR. Recientemente la Clínica de Neoplasia Anal de la Escuela de Medicina de la UPR, donde además de citologías, anoscopías de alta resolución y tratamientos tópicos, también se realizan tratamientos con coagulación infrarroja y próximamente se espera integrar la modalidad de electrocauterio. Con el propósito de servir a la mayor cantidad de pacientes posible, también se acoplarán en los próximos meses otros doctores adiestrados en estas modalidades.

utilizarse para neoplasias extensas o circunferenciales.25 Imiquimod, un modulador inmunogénico en crema, también tiene esta utilidad en neoplasias extensas y circunferenciales.26 Las áreas residuales

Si usted es un proveedor que necesita referir a un paciente o si es un paciente que necesita una evaluación, no dude en comunicarse con nosotros al (787) 679-4330.

pueden después destruirse utilizando coagulación infrarroja, electrocauterio o cirugía como medida de consolidación.

Conclusión

En resumen, el cáncer de ano, causado por el VPH, está en El tratamiento de cáncer de ano puede requerir cirugía. Resecar el aumento en EE.UU. y en Puerto Rico. El conocimiento sobre la área afectada puede ser curativo en el cáncer de ano de estadío 0. condición y la detección temprana pueden salvar vidas.

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En pacientes con cambios premalignos, es posible que algunos tratamientos logren evitar el desarrollo de cáncer de ano. En Puerto Rico ya contamos con alternativas de cernimiento, diagnósitico y tratamiento para beneficio de nuestra población.

Referencias

1. Mahy M et al. Increasing trends in HIV prevalence among people aged 50 years and older: evidence from estimates and survey data. AIDS 28, online edition. 2. Pragna Patel, Debra L. Hanson, MS; Patrick S. Sullivan, et al. Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of Types of Cancer among HIV-Infected Persons Compared with the General Population in the United States, 1992–2003. Ann Intern Med 2008; 148(10):728-736. http://annals.org/article. aspx?articleid=740975). Accedido el Noviembre 25, 2014. 3. Barnes E, Saxon C, Ahmad S. Cancer prevalence in a metropolitan HIV clinic. J Int AIDS Soc 2014 Nov 2; 17(4 Suppl 3):19651. 4. Gobert A, Mounier N, Lavole A, Poizot-Martin I, Spano JP. HIV-related malignancies: state of art. Bull Cancer 2014 Nov 1; 101(11):1020-1029. 5. Anal Cancer. American Society of Colon and Rectal Surgeons. http://www.fascrs.org/patients/conditions/anal_ cancer/. Accedido Junio 15, 2012. 6. What is anal cancer? http://www.webmd.com/cancer/ what-is-anal-cancer. Accedido Junio 27, 2012. 7. Human Papilomavirus, understanding the disease. National network for immunization information (NNii). http://www. immunizationinfo.org/vaccines/human-papillomavirus-hpv. Accedido Junio 23, 2012. 8. SEER Stat Fact Sheets: Anal Cancer. http://seer.cancer. gov/statfacts/html/anus.html. 9. Registro Central de Cáncer de Puerto Rico - Cáncer De Ano. http://www.estadisticas.gobierno.pr/iepr/LinkClick.asp 10. Colón-López V, Ortiz AP, Palefsky J. Burden of Human Papillomavirus Infection and Related Comorbidities in Men: Implications for Research, Disease Prevention and Health Promotion among Hispanic Men. PR Health Sci J 2010; 29(3):232-40. 11. Colón-López V, Ortiz AP, Soto-Salgado M, et al. Anal cancer incidence and mortality in Puerto Rico. PR Health Sci J 2013 June; 32(2):76-81. 12. Colon-Lopez V, Ortiz AP, Soto-Salgado M, et al. Survival from anal cancer among Hispanics-Puerto Rico, 2000-2007. J Gastrointest Cancer 2014 Jun; 45(2):234-8 13. Simard EP, Watson M, Saraiya M, et al. Trends in the occurrence of high-grade anal intraepithelial neoplasia in San Francisco: 2000-2009. Cancer 2013 Oct 1; 119(19):3539-45. 14. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med

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2008 May 20; 148(10):728–36. 15. Margolies, L., Goeren, B. Anal Cancer, HIV, and gay/ bisexual men. Gay Men’s Health Crisis. http://www.gmhc.org/ 16. Y Marrero McFaline, G Ortiz-Lasanta,et al. Factor Associated to Abnormal Anal Cytolgy Among Latino MSM from Puerto Rico 2008. Unpublished data. Abstracto en CROI en México. 17. TM Darragh, JM Berry, N Jay, JM Palefsky. “The Anal Canal and Perianus: HPV-Related Disease. Modern Colposcopy, 3rd Ed. Lippincott Williams and Wilkins. 2012. ASCCP. 18. Anal Cancer Prevention and Screening. The University of Texas MD Anderson Cancer Center. http://www.mdanderson. org/patient-and-cancer-information/cancer-information/ cancer-types/anal cancer/prevention/index.html. 19. Anal Cancer. American Society of Colon and Rectal Surgeons. http://www.fascrs.org/patients/conditions/anal_ cancer/. 20. Nathan M1, Singh N, Garrett N, et al. Performance of anal cytology in a clinical settingwhen measured against histology 24(3):373-9 21. PR Immunization Registry until Monday February 4, 2013. 22. Goldstone SE, Johnstone AA, Moshier EL. Long-term near 100% prevention of progression to anal cancer. Sex Health 2013 Nov; 10(6):576. 23. Marks DK, Goldstone SE. Electrocautery ablation of highgrade anal squamous intraepithelial lesions in HIV-negative and HIV-positive men who have sex with men. J Acquir 24. Richel O, de Vries HJ, van Noesel CJ, et al. Comparison treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial. Lancet Oncol 2013 Apr; 14(4):346-53. intraepithelial lesions (aHSIL). Sex Health 2013 Nov; 10(6):578-9. 26. Fox PA, Nathan M, Francis N, et al. A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod. AIDS 2010 Sep 24; 24(15):2331-5. 27. American Cancer Society.

BECAUSE

RESISTANCE CAN ARISE AT ANY TIME...

Indication PREZCOBIX® (darunavir 800 mg/cobicistat 150 mg) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). Important Safety Information Contraindications • Do not coadminister PREZCOBIX® and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, cisapride, colchicine, dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, lovastatin, lurasidone, methylergonovine, oral midazolam, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s Wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam. Warnings and Precautions • Hepatotoxicity: 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. Drug-induced hepatitis and cases of liver injury, including some fatalities, have been reported. Appropriate laboratory testing should be conducted prior to initiating and during therapy with PREZCOBIX®. Evidence of new or worsening liver dysfunction in patients on PREZCOBIX® should prompt consideration of interruption or discontinuation of treatment. • Severe Skin Reactions: Severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported in patients receiving darunavir coadministered with ritonavir. Mild-to-moderate rash was also reported and often occurred and resolved with continued dosing. Discontinue PREZCOBIX® immediately if signs or symptoms of severe skin reaction develop. • Sulfa Allergy: Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX®. • Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. Prior to starting PREZCOBIX®, assess estimated CrCl. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. • Renal Impairment When Used With Tenofovir Disoproxil Fumarate: Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported with the use of tenofovir DF and cobicistat. Coadministration with tenofovir DF is not recommended in patients who have an estimated CrCl <70 mL/min. In all patients, monitor estimated CrCl, urine glucose, and urine protein prior to initiating and during therapy. Measure serum phosphorus in patients at risk of renal impairment. Coadministration of PREZCOBIX® and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.

• Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: PREZCOBIX® is a CYP3A inhibitor. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PREZCOBIX® or the concomitant medications. This may lead to clinically significant adverse reactions (potentially leading to severe, life threatening, or fatal events) from higher exposures of the concomitant medications or adverse reactions from higher exposures of PREZCOBIX®. Decreased concentrations of PREZCOBIX® may result in loss of therapeutic effect and possible development of resistance. • Antiretrovirals Not Recommended: Do not use PREZCOBIX® in combination with other antiretroviral drugs that require pharmacokinetic boosting or which contain the individual components of PREZCOBIX® (darunavir and cobicistat) or with ritonavir. • Diabetes Mellitus/Hyperglycemia and Hemophilia: New onset or exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. Increased bleeding in hemophiliacs has been reported in patients receiving protease inhibitors. • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. • Immune Reconstitution Syndrome including the occurrence of autoimmune disorders with variable time to onset has been reported. Adverse Reactions • The most common clinical adverse reactions (incidence ≥5%) of at least moderate intensity (≥Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting during the darunavir clinical development program, where darunavir was coadministered with ritonavir. This is not a complete list of all adverse drug reactions reported with the use of PREZCOBIX®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions. Drug Interactions • Consult the full Prescribing Information for PREZCOBIX® for information on potentially significant drug interactions, including clinical comments. Use in Specific Populations • Consult the full Prescribing Information for PREZCOBIX® for information on the Uses in Specific Populations. Please see Brief Summary of Prescribing Information on adjacent pages for more details. 061036-161020 Reference: 1. Data on file. Janssen Therapeutics, Division of Janssen Products, LP.

When selecting ARV therapy,

BUILD A BARRIER FROM THE START

PREZCOBIX® has a high genetic barrier to resistance to help preserve ARV susceptibility1

Indication PREZCOBIX® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). ARV=antiretroviral.

Please see Important Safety Information on the previous page and Brief Summary of Prescribing Information on adjacent pages for more details.

Janssen Therapeutics, Division of Janssen Products, LP Distributed by: Janssen Therapeutics, Division of Janssen Products, LP, Titusville, NJ 08560 © Janssen Therapeutics, Division of Janssen Products, LP 2017 08/17 046468-170809

PREZCOBIXHCP.COM

PREZCOBIX®

PREZCOBIX (darunavir and cobicistat) tablets

Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert.

Table 1: Drugs That Are Contraindicated With PREZCOBIX (continued) Drugs Within Class That Are Contraindicated Drug Class With PREZCOBIX Clinical Comment Ergot derivatives dihydroergotamine, Potential for serious and/ ergotamine, or life-threatening reactions methylergonovine such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent cisapride Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Herbal product St. John’s wort Potential for reduced plasma (Hypericum perforatum) concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. Hepatitis C direct- elbasvir/grazoprevir Potential for the increased risk acting antiviral of alanine transaminase (ALT) elevations. HMG-CoA lovastatin, simvastatin Potential for serious reactions reductase such as myopathy including inhibitors rhabdomyolysis (see Table 2 for dosing recommendations for certain other HMG-CoA reductase inhibitors). PDE-5 inhibitor sildenafil for treatment Potential for sildenafilof pulmonary arterial associated adverse reactions hypertension (which include visual disturbances, hypotension, prolonged erection, and syncope). Sedatives/ orally administered Potential for serious and/or hypnotics midazolam, triazolam life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZCOBIX may cause large increases in the concentrations of these benzodiazepines.

(darunavir and cobicistat) tablets, for oral use

INDICATIONS AND USAGE PREZCOBIX ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). DOSAGE AND ADMINISTRATION Recommended Dosage: PREZCOBIX is a fixed-dose combination product containing 800 mg of darunavir and 150 mg of cobicistat. In treatment-naïve and treatment-experienced adults with no darunavir resistance-associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily orally with food. Administer PREZCOBIX in conjunction with other antiretroviral agents. Testing Prior to Initiation of PREZCOBIX: HIV Genotypic Testing: HIV genotypic testing is recommended for antiretroviral treatment-experienced patients. However, when HIV genotypic testing is not feasible, PREZCOBIX can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients. Creatinine Clearance: Prior to starting PREZCOBIX, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions]. When co-administering PREZCOBIX with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions]. Renal Impairment: PREZCOBIX co-administered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL per minute [see Warnings and Precautions and Adverse Reactions]. Hepatic Impairment: PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations and Clinical Pharmacology (12.3) in Full Prescribing Information]. CONTRAINDICATIONS PREZCOBIX is contraindicated with the following drugs (see Table 1) due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions, Table 2]. Table 1: Drugs That Are Contraindicated With PREZCOBIX Drugs Within Class That Are Contraindicated Drug Class With PREZCOBIX Clinical Comment Alpha 1alfuzosin Potential for serious and/or adrenoreceptor life-threatening reactions such antagonist as hypotension. Antianginal ranolazine Potential for serious and/or life threatening reactions. Antiarrhythmic dronedarone Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Anticonvulsants carbamazepine, Potential for reduced plasma phenobarbital, concentrations of darunavir, phenytoin which may result in loss of therapeutic effect and development of resistance. Anti-gout colchicine Contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/ or life-threatening reactions. Antimycobacterial rifampin Potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. Antipsychotics lurasidone Potential for serious and/or life-threatening reactions. pimozide Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

WARNINGS AND PRECAUTIONS Hepatotoxicity: During the darunavir clinical development program (N=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) was reported in 0.5% of subjects. 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 also been reported with darunavir co-administered with ritonavir. 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 co-administered with ritonavir has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with PREZCOBIX and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZCOBIX 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) in patients on PREZCOBIX should prompt consideration of interruption or discontinuation of treatment.

PREZCOBIX (darunavir and cobicistat) tablets

Severe Skin Reactions: During the darunavir clinical development program (n=3063), where darunavir was co-administered with ritonavir 100 mg once or twice daily, severe skin reactions, accompanied by fever and/ or elevations of transaminases in some cases, was reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue PREZCOBIX 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. Mild-to-moderate rash was also reported and often occurred within the first four weeks of treatment and resolved with continued dosing. Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating PREZCOBIX, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with PREZCOBIX, assess estimated creatinine clearance [see Dosage and Administration]. Dosage recommendations are not available for drugs that require dosage adjustments in PREZCOBIXtreated patients with renal impairment [see Drug Interactions and Clinical Pharmacology (12.2) in Full Prescribing Information]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. New Onset or Worsening Renal Impairment When Used With Tenofovir Disoproxil Fumarate: Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat, a component of PREZCOBIX, was used in an antiretroviral regimen that contained tenofovir DF. Co-administration of PREZCOBIX and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min [see Dosage and Administration]. • Document urine glucose and urine protein at baseline [see Dosage and Administration] and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when PREZCOBIX is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF. • Co-administration of PREZCOBIX and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. See cobicistat full prescribing information for additional information regarding cobicistat. Risk of Serious Adverse Reactions or Loss of Virologic response Due to Drug Interactions: Initiation of PREZCOBIX, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX. Increased concentrations may lead to: • clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications. • clinically significant adverse reactions from higher exposures of PREZCOBIX. Decreased antiretroviral concentrations may lead to: • loss of therapeutic effect of PREZCOBIX and possible development of resistance. See Table 2 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 PREZCOBIX therapy; review concomitant medications during PREZCOBIX therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications and Drug Interactions]. When used with concomitant medications, PREZCOBIX 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 coadministered with ritonavir to certain PREZCOBIX interactions [see Drug Interactions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Antiretrovirals Not Recommended: PREZCOBIX is not recommended in combination with other antiretroviral drugs that require pharmacokinetic boosting (i.e., another protease inhibitor or elvitegravir) because dosing recommendations for such combinations have not been established and co-administration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance. PREZCOBIX is not recommended in combination with products containing the individual components of PREZCOBIX (darunavir and cobicistat) or with ritonavir. For additional recommendations on use of PREZCOBIX with other antiretroviral agents, [see Drug Interactions]. Sulfa Allergy: Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX. 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. 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. Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including PREZCOBIX. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may 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. 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 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: • Hepatotoxicity [see Warnings and Precautions] • Severe skin reactions [see Warnings and Precautions] • Effects on serum creatinine [see Warnings and Precautions] • New onset or worsening renal impairment when used with tenofovir disoproxil fumarate [see Warnings and Precautions] Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During the darunavir clinical development program, where darunavir was co-administered with ritonavir 100 mg once or twice daily, the most common clinical adverse reactions (incidence greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting. See the darunavir

PREZCOBIX (darunavir and cobicistat) tablets

full prescribing information for additional information on adverse reactions reported with darunavir co-administered with ritonavir. See cobicistat full prescribing information for clinical trial information on adverse reactions reported with cobicistat. One single arm clinical trial was conducted with darunavir and cobicistat administered as single entities in 313 HIV-infected subjects. Adverse reactions evaluated through Week 24 did not differ substantially from those reported in clinical trials with darunavir co-administered with ritonavir. Postmarketing Experience: See the darunavir full prescribing information for postmarketing information. DRUG INTERACTIONS Potential for PREZCOBIX 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 PREZCOBIX 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 2). Potential for Other Drugs to Affect PREZCOBIX: Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Co-administration of PREZCOBIX and drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance. Co-administration of PREZCOBIX and other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 2). Potentially Significant Drug Interactions: Table 2 provides dosing recommendations for expected clinically relevant interactions with PREZCOBIX. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. No drug interaction trials have been performed with PREZCOBIX or with darunavir co-administered with cobicistat as single entities. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or with cobicistat alone.

↓ cobicistat darunavir: effect unknown

Co-administration with etravirine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

nevirapine

↓ cobicistat darunavir: effect unknown

Co-administration with nevirapine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.

e.g. amiodarone, ↑ antiarrhythmics disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine

Clinical monitoring is recommended upon co-administration with antiarrhythmics.

digoxin

↑ digoxin

Antibacterials: clarithromycin, erythromycin, telithromycin Anticancer agents: dasatinib, nilotinib

↑ darunavir ↑ cobicistat ↑ antibacterial

When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. Consider alternative antibiotics with concomitant use of PREZCOBIX.

vinblastine, vincristine

↑ anticancer agent

A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with PREZCOBIX. Consult the dasatinib and nilotinib prescribing information for dosing instructions. For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when PREZCOBIX 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.

PREZCOBIX (darunavir and cobicistat) tablets

dabigatran etexilate

rivaroxaban

Concomitant use with dabigatran etexilate is not recommended in specific renal impairment groups (depending on the indication). Please see the dabigatran US prescribing information for specific recommendations. warfarin: effect unknown

warfarin

Co-administration with rivaroxaban is not recommended. Monitor the international normalized ratio (INR) when co-administering with warfarin. For contraindicated anticonvulsants, [see Contraindications].

Anticonvulsants:

Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g. eslicarbazepine, oxcarbazepine

↓ cobicistat darunavir: effect unknown

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 Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g. paroxetine, sertraline

↑ clonazepam

Clinical monitoring of anticonvulsants is recommended.

SSRIs: effects unknown

Tricyclic Antidepressants (TCAs): e.g. amitriptyline, desipramine, imipramine, nortriptyline

↑ TCAs

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.

Other antidepressants: ↑ trazodone trazodone

Anti-gout: colchicine

Antimalarial: artemether/ lumefantrine

↑ colchicine

artemether: effect unknown lumefantrine: effect unknown

Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole. Co-administration with colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications]. For patients without renal or hepatic impairment: • Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) x 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). Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.

PREZCOBIX (darunavir and cobicistat) tablets

Table 2: Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction (see Contraindications for a complete list of contraindicated drugs) (continued) Effect on Concomitant Concentration of Drug Class: Darunavir, Cobicistat, Drug Name or Concomitant Drug Clinical Comment Systemic/Inhaled/ Co-administration with ↓ darunavir Nasal/Ophthalmic systemic dexamethasone ↓ cobicistat Corticosteroids: or other systemic ↑ corticosteroids e.g. corticosteroids that induce betamethasone CYP3A may result in loss of therapeutic effect and budesonide development of resistance ciclesonide to PREZCOBIX. Consider dexamethasone alternative corticosteroids. fluticasone methylprednisolone Co-administration with mometasone corticosteroids of which prednisone exposures are significantly triamcinolone increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone 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 Initiation of bosentan in ↓ darunavir antagonists: patients taking PREZCOBIX: ↓ cobicistat bosentan In patients who have been ↑ bosentan receiving PREZCOBIX for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

rifabutin

↑ rifabutin cobicistat: effects unknown darunavir: effects unknown

When used in combination with PREZCOBIX, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis.

rifapentine

↓ darunavir

Co-administration with rifapentine is not recommended. For contraindicated antipsychotics, [see Contraindications].

e.g. perphenazine, risperidone, thioridazine

↑ antipsychotic

A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZCOBIX.

quetiapine

↑ quetiapine

Antipsychotics:

b-Blockers: e.g. carvedilol, metoprolol, timolol

↑ beta-blockers

Calcium channel blockers: e.g. amlodipine, diltiazem, felodipine, nifedipine, verapamil

↑ calcium channel blockers

Initiation of PREZCOBIX 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 PREZCOBIX: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6. Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A.

Initiation of PREZCOBIX in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZCOBIX. After at least 10 days following the initiation of PREZCOBIX, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Hepatitis C virus (HCV): Direct-Acting Antivirals: simeprevir

darunavir: effects unknown ↑ simeprevir

HMG-CoA reductase inhibitors: e.g. atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin

↑ atorvastatin ↑ fluvastatin ↑ pravastatin ↑ rosuvastatin pitavastatin: effect unknown

Switching from darunavir co-administered with ritonavir to PREZCOBIX in patients on bosentan: Maintain bosentan dose. For contraindicated HCV Direct-Acting Antivirals, [see Contraindications]. No drug interaction data are available. Co-administration with simeprevir is not recommended. For contraindicated HMG-CoA reductase inhibitors, [see Contraindications]. For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety.

PREZCOBIX (darunavir and cobicistat) tablets

Co-administration of everolimus and PREZCOBIX is not recommended. 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. Careful monitoring of therapeutic effects and adverse reactions associated with CYP3Ametabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil is contraindicated [see Contraindications]. The following dose adjustments are recommended for use of tadalafil with PREZCOBIX: • Initiation of tadalafil in patients taking PREZCOBIX: In patients receiving PREZCOBIX for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. • Initiation of PREZCOBIX in patients taking tadalafil: Avoid use of tadalafil during the initiation of PREZCOBIX. Stop tadalafil at least 24 hours prior to starting PREZCOBIX. After at least one week following the initiation of PREZCOBIX, 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 PREZCOBIX: Maintain tadalafil dose.

Immunosuppressant/ neoplastic: everolimus Inhaled beta agonist: salmeterol

↑ salmeterol

Narcotic analgesics metabolized by CYP3A: e.g. fentanyl, oxycodone

↑ fentanyl ↑ oxycodone

tramadol

↑ tramadol

Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/ naloxone, methadone

buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown

A dose decrease may be needed for tramadol with concomitant use. Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking PREZCOBIX: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of PREZCOBIX 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.

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 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 inhibitor-associated adverse reactions.

PREZCOBIX (darunavir and cobicistat) tablets

(95% CI: 0.5% to 4.4%) 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. 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 (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir co-administered with ritonavir. 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 1.6 times higher than human exposures at the recommended daily dose of cobicistat. 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 3.8 times higher than human exposures at the recommended daily dose of cobicistat. 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 1.2 times the human exposures at the recommended daily dose of cobicistat. Lactation: Risk Summary: The Centers for Disease Control and Prevention recommend that HIV infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir or cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are secreted into the milk of lactating rats [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 PREZCOBIX. Data: Animal Data: Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the 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 50% 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. Pediatric Use: Safety, effectiveness, and pharmacokinetics of PREZCOBIX in pediatric patients less than 18 years of age have not been established. Darunavir, a component of PREZCOBIX 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 post-natal 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 PREZCOBIX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of PREZCOBIX 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]. Hepatic Impairment: No clinical trials were conducted with darunavir co-administered with cobicistat in hepatically impaired subjects and the effect of hepatic impairment on darunavir exposure when co-administered with cobicistat has not been evaluated. Based on the recommendations for darunavir co-administered with ritonavir, a dose adjustment for patients with mild or moderate hepatic impairment is not necessary. No pharmacokinetic or safety data are available regarding the use of darunavir in subjects with severe hepatic impairment. Therefore, PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

metabolized by CYP3A: ↑ sedatives/hypnotics 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.

Drugs without Clinically Significant Interactions with PREZCOBIX: Clinically relevant drug-drug interactions are not anticipated with concomitant use of darunavir and cobicistat with rilpivirine, dolutegravir, raltegravir, nucleoside reverse transcriptase inhibitors (NRTIs) other than didanosine, or acid modifying medications (antacids, H 2-receptor antagonists, proton pump inhibitors). USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZCOBIX during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary: There are insufficient data with PREZCOBIX in pregnant women from the APR to inform a drug-associated risk of pregnancy outcomes. Available data from the APR show no difference in rate of overall birth defects for darunavir 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 APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. 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. In animal reproduction studies, no adverse developmental effects were observed when the components of PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX [see Data]. No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose. Clinical Considerations: Dose Adjustment During Pregnancy and the Postpartum Period: Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of PREZCOBIX cannot be predicted from studies of other darunavir-containing regimens in pregnant women. Data: Human Data: Darunavir: Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 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 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir-containing regimens and 1.7%

PREZCOBIX (darunavir and cobicistat) tablets Renal Impairment: A renal impairment trial was not conducted for darunavir co-administered with cobicistat [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Cobicistat has been shown to decrease estimated 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 PREZCOBIX [see Warnings and Precautions and Clinical Pharmacology (12.2) in Full Prescribing Information]. OVERDOSAGE Human experience of acute overdose with PREZCOBIX is limited. No specific antidote is available for overdose with PREZCOBIX. Treatment of overdose with PREZCOBIX consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since both darunavir and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Instructions for Use: Advise patients to take PREZCOBIX with food every day on a regular dosing schedule, as missed doses can result in development of resistance. Inform patients not to alter the dose of PREZCOBIX or discontinue therapy with PREZCOBIX without consulting their physician [see Dosage and Administration]. Hepatotoxicity: Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with PREZCOBIX. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop [see Warnings and Precautions]. Severe Skin Reactions: Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, could potentially occur with PREZCOBIX. Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop, including but not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis [see Warnings and Precautions]. Renal Impairment: Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat is used in combination with a tenofovir DF-containing regimen [see Warnings and Precautions]. Drug Interactions: PREZCOBIX may interact with many drugs; therefore, inform patients of the potential serious drug interactions with PREZCOBIX, and that some drugs are contraindicated with PREZCOBIX and other drugs may require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johnâ&#x20AC;&#x2122;s wort. Instruct patients receiving hormonal contraceptives to use additional or alternative contraceptive (non-hormonal) measures during therapy with PREZCOBIX because no data are available to make recommendations regarding use of hormonal contraceptives and PREZCOBIX [see Contraindications and Drug Interactions]. Immune Reconstitution Syndrome: Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions]. Fat Redistribution: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZCOBIX and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions]. Pregnancy Registry: Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to PREZCOBIX [see Use in Specific Populations]. Lactation: Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations].

Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 ÂŠ 2015 Janssen Pharmaceutical Companies 050735-170620

www.medicinaysaludpublica.com Servicio de Noticias Científicas de Medicina y Salud Pública de Puerto Rico

Periodistas: Belinda Burgos, Mayra Acevedo, Marcela Moreno y Alejandra González

Equipo dominicano de salubristas enseña la importancia de educar a comunidades vulnerables Equipo dominicano de profesionales salubristas visitó comunidades aisladas y pobres en República Dominicana, con el principal objetivo de llevar médicos, medicamentos y alimentos a los más vulnerables. Niños desnutridos, adultos con graves enfermedades dermatológicas, mujeres con neumonía y ancianos abandonados, son parte de la comunidad de La Piedra que resultó beneficiada por el equipo de salud pública. Durante la jornada de salud, el equipo liderado por la doctora Raiza Hidalgo, trabajo en la importancia de La doctora Raiza Hidalgo, con su equipo de salubristas, realiza educar a las comunidades vulnerables, sobre el papel de visitas médicas domiciliarias en la comunidad de la Guerra y la contaminación ambiental y en la propagación de las enfermedades para frenar su expansión. La Caleta. Más información: http://www.medicinaysaludpublica.com/equipo-dominicano-de-salubristas-ensena-la-importancia-de-educar-acomunidades-vulnerables/

República Dominicana: pionera en la especialidad de diabetología en el Caribe

Doctora Violeta González Pantaleón, directora académica de la Escuela de Medicina de la Universidad Iberoamericana (UNIBE) de la República Dominicana. Más información: http://www.medicinaysaludpublica.com/ republica-dominicana-pionera-en-la-especialidad-dediabetologia-en-el-caribe/ 94

Revista Puertorriqueña de Medicina y Salúd Pública

La Doctora Violeta González, directora académica de la Escuela de Medicina de la Universidad Iberoamericana (UNIBE) de República Dominicana, explicó en qué consiste la diabetes, condición que afecta a aproximadamente un 30% de la población dominicana y resaltó que desde 1988, el Instituto Nacional de Diabetología y Nutrición (INDEN), adscrito a la institución académica, gradúa los únicos diabetólogos de toda la región caribe mostrando su incansable compromiso por evitar complicaciones y desarrollar la adherencia al tratamiento permanente para tener una vida estable. Destacó, que los profesionales también son entrenados para tratar la diabetes a nivel pediátrico y resaltó la importancia de que ellos cuenten con conocimientos en otras áreas como endocrinología y nutrición La institución y la especialidad funcionan como camino clínico protector de pacientes con diabetes, razón por la cual, la carrera se encuentra avalada por el Ministerio de Salud.

Revista

Se realiza Primer Congreso de Autoinmunidad en Bogotá, Colombia

Doctor Juan Manuel Anaya, Director del Centro de Estudios de Enfermedades Autoinmunes y Yehuda Shoenfeld Fundador y jefe del Centro Zabludowicz de Enfermedades Autoinmunes.

Durante el congreso el doctor Yehuda Shoenfeld, dijo “Cuando salimos del canal vaginal recibimos bacterias que desarrollan alergias o enfermedades autoinmunes”. Y señaló que, para él, nacer a través de cesárea no es recomendable, pues la persona tiene mayor incidencia a desarrollar riesgo de alergias o enfermedades autoinmunes que quienes nacen por parto natural. Más información: http://www.medicinaysaludpublica.com/ autoinmunidad-todo-es-el-microbioma/

Resaltan avances en el campo de las enfermedades hepáticas durante Congreso de Autoinmunidad en Colombia

Doctor Eric Gershwin, Editor del Journal of Autoimmunology y jefe de servicio de reumatología.

En el marco del primer congreso en Colombia de autoinmunidad, el Dr. Eric Gershwin, editor del Journal of Autoimmunology y jefe de servicio de reumatología de la Universidad de California, habló sobre enfermedades hepáticas autoinmunes, condición que afecta con mayor frecuencia a mujeres y que tiene más de 100 causas que pueden afectar de 5 a 8% de la población. Más información: http://www.medicinaysaludpublica. com/avances-cientificos-en-las-enfermedades-hepaticasautoinmunes/

Trombosis de vena ovárica detrás de un dolor pélvico Uno de los énfasis de los especialistas en el campo de la ginecología es el de intentar que el dolor pélvico en las mujeres no sea subestimado, pues el mismo puede ser consecuencia de complicaciones tan serias como la endometriosis o como el reciente caso originado en Puerto Rico, donde se halló una trombosis de vena ovárica del lado izquierdo. Se trata de una complicación extremadamente rara, que ocurre en solo 0.05% aproximadamente de los casos en mujeres con factor de riesgo de coagulación. La patólogía puede deberse a malignidades, complicaciones de embarazos y desórdenes inflamatorios en el área de la pelvis. Para este caso, una mujer de 51 años se presentó en el Hospital Auxilio Mutuo con síntomas como dolor intenso en el área baja de la pelvis del lado izquierdo, sin

Amalia López Cardona, médico general.

historial de trombofilia en familia y sin haber atravesado alguna cirugía asociada a síndromes de dolor pélvico. Al realizarle un examen vía CT Scan, se reveló que la causalidad del intenso dolor era una trombosis de vena ovárica. La importancia del caso es que la rara patología se presentó de manera no específica, y puede desarrollar malignidad asociada a cáncer de no tratarse a tiempo. Otros autores del caso fueron los doctores Miriam Castro, Deborah Zamora y Francisco Díaz Lozada.

Más información: http: //www.medicinaysaludpublica.com/el-dolor-pelvico-no-debe-ser-subestimado/ Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Los psiquiatras del país se entrenan en afecciones endocrinológicas

Uso de antibiótico “dispara” cuadro de dermatomiositis en paciente puertorriqueña

Doctor Erick Medina, presidente de la Asociación de Psiquiatras del Oeste

El presidente de la Asociación de Psiquiatra del Oeste, el doctor Erik Medina enfatizó en los avances de enfermedades metabólicas y su impacto en las enfermedades mentales y explicó cómo de manera clínica inf luyen las condiciones endocrinológicas de enfermedades como el lupus y la diabetes en las afecciones mentales. Resaltó la importancia de que los psiquiatras realicen estudios de laboratorios que permitan identificar el origen de los síntomas de cada persona. Dijo además, que se deben hacer referidos dirigidos a la condición del paciente, como lo es el endocrinólogo.

Antibiótico para síntomas urinarios provocó enfermedad autoinmune. La paciente ingería ciprof loxacina, que posee agentes con actividad microbiana y toxicidad selectiva que a diferencia de los antibióticos, no son producidos por microorganismos, por esto, se han retirado debido a su toxicidad.

Más información: http://www.medicinaysaludpublica. com/los-psiquiatras-del-pais-se-entrenan-en-afeccionesendocrinologicas/

Más información: http://www.medicinaysaludpublica.com/ uso-de-antibiotico-dispara-un-cuadro-de-dermatomiositisen-paciente-puertorriquena/

Leudal León, médico general.

Jugo de carambola provoca daño renal agudo en paciente en Puerto Rico

Carlos Cedeño, médico general.

Un paciente de 48 años de edad acudió a la sala de emergencias del Hospital Auxilio Mutuo, con síntomas como náuseas, vómitos y con insuficiencia renal aguda según se halló en laboratorios realizados. Los médicos, identificaron que el paciente había ingerido jugo de carambola. “En la literatura científica se conoce que esta fruta puede ser nefro-tóxica y que la intoxicación por la fruta se ha descrito más en pacientes con enfermedad renal aguda. Interesantemente, este paciente tenía diabetes, sin ningún daño renal, según estudios previos que se le habían realizado”, explicó el doctor Carlos Cedeño, uno de los autores del caso. La carambola es un fruto en forma de estrella oriunda de países tropicales como Colombia, República Dominicana, Venezuela, México, Cuba, Perú, entre otros.

Más información: http://www.medicinaysaludpublica.com/jugo-de-carambola-provoca-dano-renal-agudo-en-pacienteen-puerto-rico/ 96

Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Por encima del estándar nacional

Residentes egresados de la Universidad de Puerto Rico

Por cuarto año consecutivo, el 100% de los residentes egresados de Medicina de Familia del Recinto de Ciencias Médicas (RCM) de la Universidad de Puerto Rico aprobaron el American Board of Family Medicine.

los residentes de Medicina de Familia del Recinto de Ciencias Médicas

“El resultado exitoso y consistente demuestra la vocación y excelencia de nuestros egresados, así como la enseñanza de calidad y alto nivel que reciben”, sostuvo el presidente interino de la UPR, Dr. Darrel Hillman Barrera.

Más información: http://www.medicinaysaludpublica.com/por-encima-del-estandar-nacional-los-residentes-de-medicina-defamilia-del-recinto-de-ciencias-medicas/

Científicos del país podrían cambiar el curso clínico para tratar el cáncer de ovario

Se estrena nueva cirujana pediátrica en el Mayagüez Medical Center

Doctor Guillermo Armaiz, investigador de la Ponce Health Science University.

Astrid Soares Medina, cirujana pediátrica.

El cáncer de ovario se ubica entre las primeras diez causas de muerte en las mujeres. Actualmente, investigadores del país buscan determinar cómo el estrés crónico y los desórdenes de comportamiento afectan la progresión del cáncer de ovario y además, el poder identificar cómo estos padecimientos provocan cambios en el sistema inmune para que sea propicio para el crecimiento del tumor.

La doctora Astrid Medina es cirujana pediátrica con una subespecialidad en obesidad infantil y cirugía bariátrica de adolescentes. Además, está certificada en realizar dichas cirugías en los 26 países de la unión europea. La especialista indicó que ofrecerá servicios en cirugía pediátrica general para neonatos, infantes, lactantes, edad pediátrica y edad adolescentes hasta los 21 años.

Más información: http://www.medicinaysaludpublica.com/ cientificos-del-pais-podrian-cambiar-el-curso-clinico-paratratar-el-cancer-de-ovario/

Más información: http://www.medicinaysaludpublica.com/ se-estrena-nueva-cirujana-pediatrica-en-el-mayaguezmedical-center/ Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Centro Comprensivo de Cáncer inaugura Centro de imágenes para dar diagnóstico temprano a cáncer de mama

Inauguración Centro de la Mujer

En el marco del Día Internacional de la Mujer, el Centro Comprensivo de Cáncer (CCC) inauguró el Centro de la Mujer, un espacio único con la tecnología más avanzada para el diagnóstico del cáncer de mama. Este servicio está disponible para el público general desde el 15 de marzo de 2018 y será el primero dentro del nuevo Hospital del CCC, que continuará abriendo servicios en los próximos meses. El Centro de la Mujer cuenta con dos máquinas de mamografías digital con herramientas de oncología diagnóstica que permiten realizar imágenes con contraste y en 3D por tomosíntesis. También, se podrán realizar biopsias y sonomamografías, entre otros servicios.

Más información: http://www.medicinaysaludpublica.com/centro-comprensivo-de-cancer-inaugura-centro-de-imagenes-para-dardiagnostico-temprano-a-cancer-de-mama/

Labor científica por la diabetes en Puerto Rico

50 mil mujeres puertorriqueñas sufren de Endometriosis

Dr David Rivera, investigador de la UCC adscrito al Departamento de Bioquímica.

Idhaliz Flores, investigadora de la Escuela de Medicina de Ponce.

Científicos centran su interés en saber cómo altos niveles de glucosa en el cerebro alteran la función normal del astrocito y se esfuerzan por buscar una relación directa por la cual ellas puedan estar contribuyendo a elevar los riesgos de desarrollar accidentes cerebrovasculares en altas concentraciones de glucosa.

Al contrario de lo que pasa con otras enfermedades, el retraso en el diagnóstico de la endometriosis no es por desconocimiento o falta de casos. Se calcula que en Puerto Rico hay cerca de cincuenta mil mujeres incluyendo adolescentes que sufren la enfermedad. Según la doctora Idhaliz Flores, una mujer puede tardar hasta ocho años en descubrir que tiene este trastorno.

Más información: http://www.medicinaysaludpublica.com/ labor-cientifica-por-la-diabetes-en-puerto-rico/

Más información: http://www.medicinaysaludpublica.com/50mil-mujeres-puertorriquenas-sufren-de-endometriosis-2/

Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Arriba Puerto Rico, único equipo de alta tecnología para combatir el cáncer

Mujeres embarazadas reflejan una baja tasa de vacunación contra influenza y pertussis

Se celebra un nuevo avance en la salud pública puertorriqueña, esta vez en la prevención de cánceres de colon y de seno.

Josefina Romagueras, ginecóloga.

Llega a Puerto Rico el único equipo en el que se podrán realizar endoscopias digestivas de alta resolución, mamografía con contraste y laringoscopia. Este logro se dio gracias a un donativo recibido de $766,886 por parte de la Organización Direct Relief para la expansión de servicios médicos ambulatorios en Puerto Rico. Más información: http://www.medicinaysaludpublica.com/ autoinmunidad-todo-es-el-microbioma/

Investigadores del Departamento de Ginecología y Obstetricia del Recinto de Ciencias Médicas, realizaron un estudio con pacientes puertorriqueñas en estado de gestación, el cual reflejó que el 12.3% recibió la vacuna contra la influenza durante su embarazo. “El estudio demuestra la necesidad de crear estrategias educativas que mejoren en el aumento de las tasas de vacunación entre las mujeres embarazadas”, agregó la ginecóloga. Más información: http://www.medicinaysaludpublica.com/ mujeres-embarazadas-reflejan-una-baja-tasa-de-vacunacioncontra-influenza-y-pertussis/

Especialistas logran mejorar la salud cardiovascular en la región norte del País

Doctor Valentín del Río, cardiólogo intervencional

La falta de transportación y largas distancias ya no son detractores de la salud coronaria de los pacientes de la región norte del país, pues desde el 2015, la administración de Manatí Medical Center identificó la necesidad, los especialistas y la tecnología necesaria para crear un instituto de cardiología intervencional

que pudiera ofrecer los servicios clínicos que tanto necesita la población. Antes, quienes necesitaban recibir los servicios especializados en cardiología experimentaban deterioros en su salud debido a la falta de transportación y largas distancias, ahora es más accesible y cómodo por la ubicación del Instituto, un paciente de Ciales o Florida tarda aproximadamente 20 minutos en llegar y antes podía tardar 60 minutos o más. Entre los servicios clínicos especializados que el MMC Cardiovascular Interventional Institute se encuentran las angioplastías con implantación de “stents”, cateterismos, estudios vasculares y revascularización periférica. Más información: http://www.medicinaysaludpublica.com/ especialistas-logran-mejorar-la-salud-cardiovascular-en-laregion-norte-del-pais/ Revista Puertorriqueña de Medicina y Salúd Pública

Revista

Científicos puertorriqueños logran demostrar resistencia a medicamento cardiovascular

Grupo de investigadores de la Escuela de Farmacia del Recinto de Ciencias Médicas. Más información: http://www.medicinaysaludpublica.com/ cientificos-puertorriquenos-logran-demostrar-resistencia-amedicamento-cardiovascular/

El estudio logró demostrar la resistencia hacia el clopidogrel, medicamento altamente utilizado en pacientes cardíacos. “Estamos siguiendo unas guías americanas hechas para blancos americanos o afroamericanos en nuestra población. No se ha realizado en Puerto Rico un estudio que demuestre que esto funciona en nuestros pacientes. Quisimos estudiar las características genéticas de estas personas que no responden al medicamento y que se puedan buscar otras alternativas médicas para tratarlos”, explicó uno de los investigadores. El estudio tomó una muestra de 100 pacientes con distintas enfermedades cardíacas, como enfermedad coronaria aguda (57%) y la enfermedad arterial periférica (32%) y entre los datos más destacados se halló el que uno de cada tres pacientes presentó resistencia al fármaco, para un total de 35% de la muestra. De igual modo, pacientes con diabetes presentaban un riesgo mayor de mortalidad y resistencia al medicamento.

Estudiantes de la Escuela de Medicina de la Universidad de Puerto Rico reciben prestigiosa beca

Estudiantes becados de la UPR

Más información: http://www.medicinaysaludpublica.com/ estudiantes-de-la-escuela-de-medicina-de-la-upr-recibenprestigiosa-beca/ 100

Revista Puertorriqueña de Medicina y Salúd Pública

Con la finalidad de promover el desarrollo académico de los estudiantes boricuas en el ámbito de la innovación médica, el doctor Antonio Grillo-López y su esposa, María del Socorro Marxuach Grillo, otorgaron la Beca Familia Grillo-Marxuach a los estudiantes de la Escuela de Medicina del Recinto de Ciencias Médicas (RCM) Luis Vilanova y Lauren Rivera. Cynthia Hernández, Directora Asociada de la Oficina de Desarrollo de la Escuela de Medicina, explicó que “la Escuela de Medicina tiene como prioridad mantener la calidad de la enseñanza para nuestros estudiantes ante los retos económicos que estamos enfrentando. Esta generosa donación y la creación de esta beca Grillo Marxuach no solo ayuda a los estudiantes a bajar la deuda una vez acabada su carrera de medicina, sino también es nuestra esperanza de que una vez terminen, continúen con la misma determinación y humildad sirviendo a nuestra comunidad y a nuestra Escuela”.

Revista

Melanoma rectal causa revés clínico en Puerto Rico

Descubren translocación robertsoniana durante la etapa de gestación

Andrea Camarena residente de ginecología y obstetricia. Una patología tumoral positiva a melanoma se presentó en el área del recto de una paciente e invadió el hígado y los pulmones.

Un agresivo cáncer se halló en una paciente de 83 años, quien presentó sangrado rectal, dolor en dicha área, estreñimiento, entre otros. Además, arrojó positivo a marcadores de melanina en pruebas inmunohistoquímicas. El melanoma de esta forma provocó un revés clínico, pues se trata de una de sus variantes más raras en la literatura, que solo ocurre en un 0.05% en el área del ano y recto. Más información: http://www.medicinaysaludpublica.com/ melanoma-rectal-causa-reves-clinico-en-puerto-rico/

En una de las pacientes del Centro de Medicina, se encontró que su bebé presentaba una translocación robertsoniana. La paciente tenía 32 años y era su tercer embarazo. Para hallar este tipo de anomalías genéticas se debe recurrir a la amniocentesis con el fin de extraer líquido amniótico, y realizarle un estudio llamado cariotipo, el cual permite ver los cromosomas para así identificar si existe una translocación. Más información: http://www.medicinaysaludpublica.com/ descubren-translocacion-robertsoniana-durante-la-etapa-degestacion/

Universidad Central del Caribe tiene nueva presidenta

Waleska Crepos nueva presidenta UCC

Se trata de la doctora Waleska Crespo Rivera, quien se desempeñaba como directora ejecutiva en el “Healthsouth Rehabilitation Hospital” en

Manatí y quien también se desempeñó en el Centro Cardiovascular de Puerto Rico y el Caribe bajo la misma posición. Crespo Rivera es Graduada del Recinto de Ciencias Médicas (RCM) en un doctorado en Salud Pública con concentración en Gerencia y Administración de Servicios de Salud. “Mi enfoque será continuar expandiendo la oferta académica de la institución y el que nuestros estudiantes puedan continuar teniendo oportunidades en el campo. Estamos trabajando porque en agosto estrenamos la primera escuela de formación quiropráctica en el país ante la necesidad de que muchos interesados en este campo tienen que irse a los Estados Unidos”, dijo la doctora. Más información: http://www.medicinaysaludpublica.com/ucctiene-nueva-presidenta/

Revista Puertorriqueña de Medicina y Salúd Pública

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Doctor Melvin Bonilla

Doctor Melvin Bonilla: Una trayectoria que honra la nefrología La pasión del doctor Melvin Bonilla, va más allá de mejorar la práctica clínica de la nefrología pediátrica en Puerto Rico. Este especialista, se ha enfocado en perfeccionar el peritaje científico y clínico de los pediatras que se forman en el Departamento de Pediatría del Recinto de Ciencias Médicas (RCM). El reto más grande lo aceptó cuando decidió ser parte de un esfuerzo clínico que ha buscado evitar que los niños puertorriqueños con fallo renal crónico tengan que salir del País, en la mayoría de los casos, sin los recursos económicos disponibles para ser trasplantados. Este sueño ya está en su etapa final, gracias a este especialista y las manos de otros médicos, en el 2018 Puerto Rico volverá a presenciar un trasplante de riñón en un paciente con enfermedad crónica renal. Un espacio editorial no es suficiente para cobijar los logros de este destacado puertorriqueño, al que además, se le dedicó este año la convención de la Asociación de Médicos Pediatras de la Región Este (AMPRE). Sin embargo, en esta sección especial, nos honramos de destacar la carrera de uno de los pocos neurólogos pediátricos del País que ha sido el rostro clínico de pacientes ofreciéndoles una oportunidad de vida.

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LA INNOVACIÓN GUÍA NUESTRA CIENCIA. LA HUMANIDAD GUÍA NUESTRO PROPÓSITO.

Como compañía biofarmacéutica global, combinamos la ciencia, la pasión y la experiencia para mejorar la salud y el cuidado de la salud de nuevas maneras. Tener un impacto extraordinario es más que nuestra promesa. Es nuestro propósito. abbvie.com Más de 170 países Más de 28,000 empleados 21 Centros de Investigación y Desarrollo y de Manufactura UNA Prioridad: Nuestros pacientes